Cancer vaccine compositions and methods for using same to prevent and/or treat cancer

Abstract

The present invention is based, in part, on cancer vaccine compositions that comprise PTEN- and p53-deficient cancer cells with activated TGF-Smad/p63 signaling pathway, and methods for using same to prevent and/or treat cancer.

Claims

1. A cancer vaccine comprising cancer cells, wherein the cancer cells: a) lack functional PTEN; b) lack functional p53; and c) comprise an activated TGF-Smad/p63 signaling pathway by contact with a TGF protein.

2. The cancer vaccine of claim 1, wherein a) the TGF protein is selected from the group consisting of TGF1, TGF2, and TGF3; b) the cancer cells are contacted with the TGF protein in vitro, in vivo, and/or ex vivo; c) the cancer cells have increased nuclear localization of Smad2, and/or association of p63 and Smad2 in the nucleus of the cancer cells, relative to cancer cells that have not been contacted with the TGF protein; d) the cancer cells are derived from a solid or hematological cancer; e) the cancer cells are derived from a cancer cell line; f) the cancer cells are derived from primary cancer cells; g) the cancer cells are breast cancer cells; h) the cancer cells are derived from a triple-negative breast cancer (TNBC); i) contact with the TGF protein induces epithelial-to-mesenchymal (EMT) transition in the cancer cells; j) contact with the TGF protein upregulates the expression levels of ICOSL, PYCARD, SFN, PERP, RIPK3, CASP9, and/or SESN1 in the cancer cells; k) contact with the TGF protein downregulates the expression levels of KSR1, KSR1, EIF4EBP1, ITGA5, EMILIN1, CD200, and/or CSF1 in the cancer cells; l) The cancer cells are capable of activating co-cultured dendritic cells (DCs) in vitro; m) the cancer cells are capable of upregulating CD40, CD80, CD86, CD103, CD8, HLA-DR, MHC-II, and/or IL1- in the co-cultured dendritic cells in vitro; n) the cancer cells are capable of activating co-cultured T cells in the presence of DCs in vitro; o) the cancer cells are capable of increasing secretion of TNF and/or IFN by the co-cultured T cells in the presence of DCs in vitro; p) the cancer cells do not form a tumor in an immune-competent subject; q) the cancer vaccine triggers cytotoxic T cell-mediated antitumor immunity; r) the cancer vaccine increases CD4+ T cells and CD8+ T cells in blood and/or tumor microenvironment; s) the cancer vaccine increases TNF- and INF-secreting CD4+ and CD8+ T cells in blood and/or tumor microenvironment; t) the cancer vaccine upregulates expression of Icos, Klrc1, Il2rb, Pik3cd, H2-D1, Cc18, Ifng, Icosl, Il2ra, Cxcr3, Ccr7, Cxcl10, Cd74, H2-Ab1, Hspa1b, Cd45, Lifr, and/or Tnf in tumor tissues; u) the cancer vaccine increases the amount of tumor-infiltrating dendritic cells; v) the cancer vaccine upregulates CD80, CD103, and/or MHC-II in tumor-associated DCs; w) the cancer vaccine reduces the number of proliferating cells in a cancer and/or reduces the volume or size of a tumor comprising cancer cells; x) the cancer vaccine induces a tumor-specific memory T cell response; y) the cancer vaccine increases the percentages of CD4+ central memory (T.sub.CM) T cells and/or CD4+ effector memory (T.sub.EM) T cells in a spleen and/or lymph nodes; z) the cancer vaccine increases the percentage of splenic CD8+ T.sub.CM cells; aa) the cancer vaccine increases the percentage of CD8+ T.sub.EM cells in a spleen and/or lymph nodes; bb) the cancer vaccine increases the amount of tumor infiltrating CD4+ T cells and/or CD8+ T cells; cc) the cancer vaccine increases the amount of tumor infiltrating CD4+ T.sub.CM cells and/or CD4+ T.sub.EM cells; dd) the cancer vaccine increases the amount of tumor infiltrating CD8+ T.sub.CM cells and/or CD8+ T.sub.EM cells; ee) the cancer cells are non-replicative; ff) the cancer vaccine is administered to a subject in combination with an immunotherapy and/or cancer therapy, optionally wherein the immunotherapy and/or cancer therapy is administered before, after, or concurrently with the cancer vaccine; gg) the cancer vaccine prevents recurrent and metastatic tumor lesions; hh) the cancer vaccine is administered to the subject intratumorally or subcutaneously; ii) the subject is an animal model of the cancer, optionally wherein the animal model is a mouse model; or jj) the subject is a mammal, optionally wherein the mammal is in remission for a cancer.

3. The cancer vaccine of claim 2, wherein a) the cancer cells are contacted with the TGF protein in vitro or ex vivo; b) the cancer cells are administered to a subject, wherein the TGF protein is administered to the subject to thereby contact the cancer cells in vivo, optionally wherein the TGF protein is administered before, after, or concurrently with administration of the cancer cells; c) the cancer vaccine reduces the number of proliferating cells in a cancer and/or reduces the volume or size of a tumor comprising cancer cells at the primary site of immunization; d) the cancer vaccine reduces the number of proliferating cells in a cancer and/or reduces the volume or size of a tumor comprising cancer cells in a tissue that is distal to the site of immunization; e) the cancer cells are non-replicative due to irradiation, optionally wherein the irradiation is at a sub-lethal dose; f) the immunotherapy is cell-based; g) the immunotherapy comprises a cancer vaccine and/or virus; h) the immunotherapy inhibits an immune checkpoint, optionally wherein i) the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilins, and A2aR; i) the cancer therapy is selected from the group consisting of radiation, a radiosensitizer, and a chemotherapy; j) the mammal is a mouse or a human; and/or k) the mammal is a human.

4. A method of preventing reoccurrence of a cancer, and/or treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of a cancer vaccine comprising cancer cells, wherein the cancer cells: a) lack functional PTEN; b) lack functional p53; and c) comprise an activated TGF-Smad/p63 signaling pathway by contact with a TGF protein, optionally wherein the subject is afflicted with a cancer.

5. The method of claim 4, wherein a) the TGF protein is selected from the group consisting of TGF1, TGF2, and TGF3; b) the cancer cells are contacted with the TGF protein in vitro, in vivo, and/or ex vivo; c) the cancer cells have increased nuclear localization of Smad2, and/or association of p63 and Smad2 in the nucleus of the cancer cells, relative to cancer cells that have not been contacted with the TGF protein; d) the cancer cells are derived from a solid or hematological cancer; e) the cancer cells are derived from a cancer cell line; f) the cancer cells are derived from primary cancer cells; g) the cancer cells are breast cancer cells; h) the cancer cells are derived from a triple-negative breast cancer (TNBC); i) the cancer cells are derived from a cancer that is the same type as the cancer treated with the cancer vaccine; j) the cancer cells are derived from a cancer that is a different type from the cancer treated with the cancer vaccine; k) the cancer treated with the cancer vaccine is characterized by loss of PTEN, p53, and/or p110, optionally wherein the cancer further expresses Myc; l) The cancer treated with the cancer vaccine has functional PTEN and/or p53, optionally wherein the cancer has a Kras activating mutation G12D; m) the cancer vaccine is syngeneic or xenogeneic to the subject; n) the cancer vaccine is autologous, matched allogeneic, mismatched allogeneic, or congenic to the subject; o) the cancer treated with the cancer vaccine is selected from the group consisting of breast tumor, ovarian tumor, or brain tumor; p) contact with the TGF protein induces epithelial-to-mesenchymal (EMT) transition in the cancer cells; q) contact with the TGF protein upregulates the expression levels of ICOSL, PYCARD, SFN, PERP, RIPK3, CASP9, and/or SESN1 in the cancer cells; r) contact with the TGF protein downregulates the expression levels of KSR1, KSR1, EIF4EBP1, ITGA5, EMILIN1, CD200, and/or CSF1 in the cancer cells; s) the cancer cells are capable of activating co-cultured dendritic cells (DCs) in vitro; t) the cancer cells are capable of upregulating CD40, CD80, CD86, CD103, CD8, HLA-DR, MHC-II, and/or IL1- in co-cultured dendritic cells in vitro; u) the cancer cells are capable of activating co-cultured T cells in the presence of DCs in vitro; v) the cancer cells are capable of increasing secretion of TNF and/or IFN by co-cultured T cells in the presence of DCs in vitro; w) the cancer cells do not form a tumor in an immune-competent subject; x) the cancer vaccine triggers cytotoxic T cell-mediated antitumor immunity; y) the cancer vaccine increases CD4+ T cells and CD8+ T cells in blood and/or tumor microenvironment; z) the cancer vaccine increases TNF- and INF-secreting CD4+ and CD8+ T cells in blood and/or tumor microenvironment; aa) the cancer vaccine upregulates expression of Icos, Klrc1, 112rb, Pik3cd, H2-D1, Ccl8, Ifng, Icosl, Il2ra, Cxcr3, Ccr7, Cxcl10, Cd74, H2-Ab1, Hspa1b, Cd45, Lifr, and/or Tnf in tumor tissues; bb) the cancer vaccine increases the amount of tumor-infiltrating dendritic cells; cc) the cancer vaccine upregulates CD80, CD103, and/or MHC-II in tumor-associated DCs; dd) the cancer vaccine reduces the number of proliferating cells in a cancer and/or reduces the volume or size of a tumor comprising cancer cells; ee) the cancer vaccine induces a tumor-specific memory T cell response; ff) the cancer vaccine increases the percentages of CD4+ central memory (T.sub.CM) T cells and/or CD4+ effector memory (T.sub.EM) T cells in a spleen and/or lymph nodes; gg) the cancer vaccine increases the percentage of splenic CD8+ T.sub.CM cells; hh) the cancer vaccine increases the percentage of CD8+ T.sub.EM cells in a spleen and/or lymph nodes; ii) the cancer vaccine increases the amount of tumor infiltrating CD4+ T cells and/or CD8+ T cells; jj) the cancer vaccine increases the amount of tumor infiltrating CD4+ T.sub.CM cells and/or CD4+ T.sub.EM cells; kk) the cancer vaccine increases the amount of tumor infiltrating CD8+ T.sub.CM cells and/or CD8+ T.sub.EM cells; ll) the cancer cells are non-replicative; mm) the method further comprising administering to the subject an immunotherapy and/or cancer therapy, optionally wherein the immunotherapy and/or cancer therapy is administered before, after, or concurrently with the cancer vaccine; nn) the cancer vaccine is administered in a pharmaceutically acceptable formulation; oo) the cancer vaccine prevents recurrent and metastatic tumor lesions; pp) the cancer vaccine is administered to the subject intratumorally or subcutaneously; qq) the subject is an animal model of the cancer, optionally wherein the animal model is a mouse model; or rr) the subject is a mammal, optionally wherein the mammal is in remission for a cancer.

6. The method of claim 5, wherein a) the cancer cells are contacted with the TGF protein in vitro or ex vivo; b) the cancer cells are administered to a subject, wherein the TGF protein is administered to the subject to thereby contact the cancer cells in vivo, optionally wherein the TGF protein is administered before, after, or concurrently with administration of the cancer cells; c) the cancer vaccine reduces the number of proliferating cells in a cancer and/or reduces the volume or size of a tumor comprising cancer cells at the primary site of immunization; d) the cancer vaccine reduces the number of proliferating cells in a cancer and/or reduces the volume or size of a tumor comprising cancer cells in a tissue that is distal to the site of immunization; e) the cancer cells are non-replicative due to irradiation, optionally wherein the irradiation is at a sub-lethal dose; f) the immunotherapy is cell-based; g) the immunotherapy comprises a cancer vaccine and/or virus; h) the immunotherapy inhibits an immune checkpoint, optionally wherein i) the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilins, and A2aR; i) the cancer therapy is selected from the group consisting of radiation, a radiosensitizer, and a chemotherapy; j) the mammal is a mouse or a human; and/or k) the mammal is a human.

7. A method of assessing the efficacy of the cancer vaccine of claim 1 for treating a subject afflicted with a cancer, comprising: a) detecting in a subject sample at a first point in time the number of proliferating cells in the cancer and/or the volume or size of a tumor; b) repeating step a) during at least one subsequent point in time after administration of the cancer vaccine; and c) comparing the number of proliferating cells in the cancer and/or the volume or size of a tumor detected in steps a) and b), wherein the absence of, or a significant decrease in number of proliferating cells in the cancer and/or the volume or size of a tumor in the subsequent sample as compared to the number and/or the volume or size in the sample at the first point in time, indicates that the cancer vaccine treats cancer in the subject.

8. The method of claim 7, wherein a) between the first point in time and the subsequent point in time, the subject has undergone treatment, completed treatment, and/or is in remission for the cancer; b) the first and/or at least one subsequent sample is selected from the group consisting of ex vivo and in vivo samples; c) the first and/or at least one subsequent sample is a portion of a single sample or pooled samples obtained from the subject; d) the first and/or at least one subsequent sample comprises cells, serum, peripheral lymphoid organs, and/or intratumoral tissue obtained from the subject; e) the method further comprisies determining responsiveness to the agent by measuring at least one criteria selected from the group consisting of clinical benefit rate, survival until mortality, pathological complete response, semi-quantitative measures of pathologic response, clinical complete remission, clinical partial remission, clinical stable disease, recurrence-free survival, metastasis free survival, disease free survival, circulating tumor cell decrease, circulating marker response, and RECIST criteria; f) the cancer vaccine is administered in a pharmaceutically acceptable formulation; g) the cancer vaccine prevents recurrent and metastatic tumor lesions; h) the cancer vaccine is administered to the subject intratumorally or subcutaneously; i) the subject is an animal model of the cancer, optionally wherein the animal model is a mouse model; and/or j) the subject is a mammal, optionally wherein the mammal is in remission for a cancer.

9. The method of claim 8, wherein the mammal is a mouse or a human.

10. The cancer vaccine of claim 1, wherein the TGF protein is TGF1.

11. The method of claim 4, wherein the TGF protein is TGF1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1A-FIG. 1C show that TGF-treated PP (PP.sub.T) tumor cells do not form tumors in immune competent mice. FIG. 1A shows the workflows for investigating the roles of TGF in a mouse model of TNBC derived from concurrent ablation of p53 (encoded by Trp53 in mice) and Pten (termed PP). FIG. 1B shows expression levels of EMT markers detected in PP and TGF-treated PP (PP.sub.T) cells by real-time PCR. Data are shown as means.e.m. *indicates P<0.05, ***indicates P<0.001, ****indicates P<0.0001; n=4 for each group. FIG. 1C shows in vivo growth of PP and PP.sub.T cells (n=10 per group). PP and TGF-treated PP (PP.sub.T) tumor cells were injected into syngeneic FVB wild type mice.

(2) FIG. 2A-FIG. 2B show that PP.sub.T tumor cells formed tumors in immune-compromised mice with a longer latency. The growth rates of PP and PP.sub.T tumors in nude (FIG. 2A) and SCID (FIG. 2B) mice; n=10 per group.

(3) FIG. 3A-FIG. 3I show that PP.sub.T tumor cells-induced antitumor immunity was T cell-dependent. FIG. 3A shows growth of PP and PP.sub.T cells in FVB wild type mice (n=10 per group). FIG. 3B shows growth of PP.sub.T tumor cells in FVB wild type mice treated with anti-CD3 or anti-IgG (n=10 per group). FIG. 3C shows a schematic diagram of the work flow for analyzing local and systemic antitumor immune response in syngeneic mice. Splenic, peripheral blood, and tumor infiltrating CD45+CD3+CD4+ T cells (FIGS. 3D-3F) and CD45+CD3+CD8+ T cells (FIGS. 3G-3I) were detected by flow cytometry. The proportions of TNF- and IFN--secreting CD4+(FIGS. 3E and 3F) and CD8+(FIGS. 3H and 3I) T cells in the spleen, blood, and tumor microenvironment are shown. Data are shown as means.e.m. *indicates P<0.05, **indicates P<0.01, ***indicates P<0.001, ****indicates P<0.0001; n=5 for each group.

(4) FIG. 4A-FIG. 4I show that antitumor immunity induced by activated TGF in tumor cells was provoked via enhanced activation of DC and T cells. A customized mouse transcriptome profiling was performed to compare gene expression profiles between PP and PP.sub.T 6-day-old tumor tissues (FIGS. 4A-4C). Gene ontology (GO) enrichment and KEGG pathway analyses were performed on up-regulated genes (rpm.sub.PPT vs rpm.sub.pp>2-fold). FIG. 4A shows relevant GO terms/KEGG pathways. FIG. 4B shows expression of some important targets from transcriptome data as verified by real-time PCR. Data are shown as mean s.e.m. *indicates P<0.05, **indicates P<0.01, ***indicates P<0.001, ****indicates P<0.0001; n=5 for each group. FIG. 4C shows related gene interaction networks that positively regulate antitumor immunity. FIGS. 4D and 4E show the proportions of tumor-infiltrating CD45+CD11C+ DCs in PP and PP.sub.T 6-day tumor tissues as analyzed by flow cytometry (FIG. 4D). The expression of MHC-II, CD80, and CD103 were gated in DCs (FIG. 4E); n=5 for each group. FIG. 4F shows a schematic diagram of work flow for analyzing the effect of PP and PP.sub.T on DC and T cell activation. FIG. 4G shows detection of DC activation markers by flow cytometry; n=6 for each group, ****indicates P<0.0001. Matched allogenic immature DCs harvested from the bone marrow of syngeneic healthy FVB mice were incubated with PP or PP.sub.T cells. FIGS. 4H and 4I show determination of activation of CD4+(FIG. 4H) and CD8+(FIG. 4I) T cells by flow cytometry; n=6 per group. ****indicates P<0.0001. T cells and DCs were co-cultured with or without tumor cells overnight.

(5) FIG. 5A-FIG. 5D show that dendritic cells were required for activation of T cells by PP.sub.T tumor cells. FIGS. 5A and 5B show expression of MHC-II in CD45+ and CD45-cells in 6-day-old PP and PP.sub.T tumor tissues as analyzed by flow cytometry; n=5 for each group. ****indicates P<0.0001. FIGS. 5C and 5D show expression of TNF and IFN- in CD4+(FIG. 5C) and CD8+(FIG. 5D) T cells as detected by flow cytometry; n=3 per group. T cells isolated from nave mice were incubated with PP or PP.sub.T cells overnight.

(6) FIG. 6A-FIG. 6C show Smad2/p63 complex-mediated antitumor immunity induced by TGF. FIG. 6A shows the Smad-related transcription factors network in PP.sub.T cell as calculated based on a customized mouse transcriptome profiling. The size and color of nodes indicate the value of reads per million (rpm) for indicated genes. Smads stands for Smad2, Smad3, and Smad4 complex. FIG. 6B shows growth of PP.sub.T-scramble or PP.sub.T-shTrp63 tumors in syngeneic mice; n=10 per group. FIG. 6C shows expression of MHC-II, CD80 and CD103 in DCs as detected by flow cytometry; n=4 per group. Matched allogenic immature DCs harvested from the bone marrow of syngeneic healthy FVB mice were co-cultured with PP.sub.T-scramble or PP.sub.T-shTrp63 cells.

(7) FIG. 7A-FIG. 7D show that TGF induced Smad2/p63 complex formation in PP.sub.T cells. FIG. 7A shows expression of p63 protein in PP and PP.sub.T cells. FIGS. 7B and 7C show cellular localization of Smad2 and p63 as analyzed by confocal microscopy (FIG. 7B) and western blotting (FIG. 7C). FIG. 7D shows protein-protein interaction for Smad2 and p63 as analyzed by co-immunoprecipitation assays.

(8) FIG. 8A-FIG. 8D show that TGF reprogramed PP cells through the p63/Smad2 signaling pathway. Genes that were co-upregulated (FIG. 8A) and co-downregulated (FIG. 8B) by knocking down of Smad or p63 were determined by comparing transcriptomes in control, p63- and Smad2-knockdown PP.sub.T cells. Relevant GO terms and KEGG pathways (lower panels) are also shown. Relevant targets co-upregulated (FIG. 8C) and co-downregulated (FIG. 8D) by p63 or Smad2 knockdown in PP.sub.T cells are shown by heat maps.

(9) FIG. 9A-FIG. 9F show that TGF activated antitumor immunity in a p63-dependent manner in human breast cancer cells. FIG. 9A shows expression levels of p63 protein in human breast cancer cell lines. FIG. 9B shows that immature human DCs were incubated with human breast cancer cells, MCF7 or HCC1954, as indicated. Both MCF7T and HCC1954T were treated with TGF. FIGS. 9C-9E show expression of CD80, CD86 and CD103 in DCs by flow cytometry; n=4 per group; *indicates P<0.05, **indicates P<0.01, ***indicates P<0.001. FIG. 9F shows the relationships between TP63-Smad signature (PYCARD, RIPK3, CASP9, SESN1, and TP63 high; KSR1, EIF4EBP1, ITGA5, and EMILIN1 low) and patient survival according to the Curtis Breast dataset. ****indicates P<0.0001.

(10) FIG. 10A-FIG. 10B show that PP tumor cells failed to grow when co-injected with PP.sub.T into syngeneic mice. PP and PP.sub.T cell mixtures (1:1) were injected into syngeneic mice. Tumor growth (FIG. 10A; n=10 per group) and long-term survival (FIG. 10B; n=5 per group) are shown.

(11) FIG. 11A-FIG. 11D show that immunization with TGF-activated tumor cells induced immune memory response. Spleens and lymph nodes were collected at week one, two, and six after injection of PP.sub.T cells. Proportions of CD45+CD3+CD4+FOXP3-CD44+KLRG1-CD62L+ central memory T cells (CD4+ T.sub.CM cells) (FIG. 11A), CD45+CD3+CD4+FOXP3-CD44+KLRG1+CD62L effector memory T cells (CD4+ T.sub.EM cells) (FIG. 11B), CD45+CD3+CD8+FOXP3-CD44+KLRG1-CD62L+ central memory T cells (CD8+ T.sub.CM cells) (FIG. 11C), and CD45+CD3+CD8+FOXP3-CD44+KLRG1+CD62L effector memory T cells (CD8+ T.sub.EM cells) (FIG. 11D) were analyzed by flow cytometry. *indicates P<0.05, **indicates P<0.01, ***indicates P<0.001, ****indicates P<0.0001; n=5 mice per group.

(12) FIG. 12A-FIG. 12G show that immunization with TGF-activated tumor cells induced an immune memory response against parental tumors. FIG. 12A shows a schematic diagram of the work flow for determining the efficacy of PP.sub.T immunization on PP tumor rejection. FIGS. 12B-12E show PP cells or PP tumor fragments were transplanted into control and PP.sub.T-immunized mice. Tumor growth curves (FIGS. 12B and 12D; n=10 per group) and long-term survival of mice (FIGS. 12C and 12E; n=5 per group) are shown. FIGS. 12F and 12G show that PP tumor cells were injected into PP.sub.T-immunized or control mice via tail vein injection. Lung metastatic nodules were examined after 4 weeks; n=5 mice per group, ****indicates P<0.0001.

(13) FIG. 13A-FIG. 13D show that PP tumor challenge induces memory T cell responses in the tumor microenvironment (TME) in PP.sub.T immunized mice. FIG. 13A shows workflows for determining the memory in the TME. FIG. 13B shows the proportions of the tumor infiltrating CD4+ and CD8+ T cells in the CD45+ leukocytes of PP tumors transplaned into PP.sub.T immunized or control mice. FIG. 13C shows proportions of CD45+CD3+CD4+FOXP3-CD44+KLRG1-CD62L+ central memory T cells (CD4+ T.sub.CM cells), CD45+CD3+CD4+FOXP3-CD44+KLRG1+CD62L effector memory T cells (CD4+ T.sub.EM cells). FIG. 13D shows proportions of CD45+CD3+CD8+FOXP3-CD44+KLRG1-CD62L+ central memory T cells (CD8+ T.sub.CM cells), and CD45+CD3+CD8+FOXP3-CD44+KLRG1+CD62L effector memory T cells (CD8+ T.sub.EM cells). Analyses were done by flow cytometry. *P<0.05, ***P<0.001, ****P<0.0001; n=6 for each group.

(14) FIG. 14A-FIG. 14C show that the vaccine effects of PP.sub.T cells were not dampened by irradiation. Mice were immunized with 100 Gy gamma ray irradiated PBS, PP or PP.sub.T cells. 4 weeks after vaccination, PP tumor fragments were transplanted into the third fat pad of indicated mice. The growth of PP tumors (FIG. 14B, n=10 for each group) and survival of mice (FIG. 14C, n=5 per group) are shown.

(15) FIG. 15A-FIG. 1511 show that PP.sub.T cells can be used as allogeneic vaccines against different types of cancers. Indicated tumor cell lines were injected into PBS or PP.sub.T cells vaccinated mice. The growth of PPA (FIG. 15A; a mouse breast cancer model characterized by triple loss of p53, PTEN, and P110), C260 (FIG. 15C; a p53/PTEN double loss and Myc high mouse ovarian cancer model), D658 (FIG. 15E; a Kras mutated recurrent breast cancer cell line generated from a PIK3CA.sup.H1047A mouse model of breast cancer), and d333 (FIG. 15G; a brain tumor derived from p53 and PTEN double loss mouse) tumors were shown. n=10 for each group. The survival of mice transplanted with indicated tumors were also shown in FIGS. 15B, 15D, 15F, and 15H. n=5 per group.

(16) FIG. 16 shows a schematic diagram of TGF-Smad signaling pathway and molecular events adapted from Zhang et al. (2013) J. Cell Sci. 126:4809-4813.

(17) FIG. 17 shows that TGF activation in tumor cells induced anti-tumor immune response by engagement of dendritic cells and subsequent T cell activation. In p63-positive tumor cells, TGF induces Smad nuclear localization and promote the formation of a p63 and Smad transcriptional complex that upregulates multiple immune regulatory pathways and downregulates several major oncogenic signaling pathways, thereby triggering antitumor immunity through activation of dendritic cells (DCs) and T cells.

(18) FIG. 18 shows a schematic diagram of a representative embodiment of a vaccine platform encompassed by the present invention.

(19) FIG. 19 shows gating strategy for T cell populations. Flow cytometry gating for CD4+, CD8+, and CD4+ regulatory T cell in spleen, lymph node, blood, and tumors was shown. Representative plots from splenocytes were shown.

(20) FIG. 20 shows gating strategy for Memory T cell populations. Flow cytometry gating for CD4+ central memory T cell (CD4+ T.sub.CM), CD4+ effector memory T cell (CD4+ T.sub.EM), CD8+ central memory T cell (CD8+ T.sub.CM), and CD8+ effector memory T cell (CD8+ T.sub.EM) in spleen, lymph node, blood, and tumors was shown. Representative plots from splenocytes were shown.

(21) FIG. 21 shows gating strategy for tumor infiltrating dendritic cell. Flow cytometry gating for tumor infiltrating dendritic cell (DC) in order to examine the expressions of MHCII, CD80, and CD103 was shown.

(22) For any figure showing a bar histogram, curve, or other data associated with a legend, the bars, curve, or other data presented from left to right for each indication correspond directly and in order to the boxes from top to bottom of the legend.

DETAILED DESCRIPTION OF THE INVENTION

(23) It has been determined herein that PTEN- and p53-deficient tumor cells bearing activated TGF-Smad/p63 signaling (e.g., treated with at least one TGF superfamily protein) failed to form tumors in immunocompetent hosts in a T cell-dependent manner. For example, treatment of tumor cells derived from a syngeneic mouse breast tumor model driven by concurrent loss of p53 and Pten with TGF in vitro completely abrogated their ability to form tumors in immunocompetent mice in a T cell-dependent manner. It was also demonstrated that these cells triggered robust anti-tumor immunity via engagement and activation of dendritic cells (DCs), which in turn activated T cells to target tumor cells. In addition, it was found that p63 is a key co-factor for TGF/Smad-mediated transcription in response to TGF stimulation. For example, activation of the TGF-Smad/p63 axis upregulated transcriptional outputs that induce activation of multiple immune pathways, and these effects were abolished when either p63 or Smad2 was depleted. Moreover, administration of tumor cells bearing activated TGF-Smad/p63 signaling protect hosts from recurrent and metastatic tumor lesions through induction of long-term memory T cell responses. It was also found that the survivals of breast cancer patients were highly correlated with the TGF-Smad/p63 signatures. These results uncover a new molecular switch underlying the opposing effects of TGF in tumor development and provide a strategy for developing effective tumor vaccines through TGF-based reprogramming. Accordingly, compositions and methods for preventing and/or treating cancer using a cancer vaccine that comprises cancer cells that are (1) Pten-deficient, (2) p53-deficient, and (3) modified to active TGF-Smad/p63 signaling pathway, are provided. In addition, methods of assessing the efficacy of the cancer vaccine for preventing and/or treating cancer is also provided.

I. Definitions

(24) The articles a and an are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, an element means one element or more than one element.

(25) The term administering is intended to include routes of administration which allow an agent to perform its intended function. Examples of routes of administration for treatment of a body which can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal, etc.), oral, inhalation, and transdermal routes. The injection can be bolus injections or can be continuous infusion. Depending on the route of administration, the agent can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally affect its ability to perform its intended function. The agent may be administered alone, or in conjunction with a pharmaceutically acceptable carrier. The agent also may be administered as a prodrug, which is converted to its active form in vivo.

(26) The term altered amount or altered level refers to increased or decreased copy number (e.g., germline and/or somatic) of a biomarker nucleic acid, e.g., increased or decreased expression level in a cancer sample, as compared to the expression level or copy number of the biomarker nucleic acid in a control sample. The term altered amount of a biomarker also includes an increased or decreased protein level of a biomarker protein in a sample, e.g., a cancer sample, as compared to the corresponding protein level in a normal, control sample. Furthermore, an altered amount of a biomarker protein may be determined by detecting posttranslational modification such as methylation status of the marker, which may affect the expression or activity of the biomarker protein.

(27) The amount of a biomarker in a subject is significantly higher or lower than the normal amount of the biomarker, if the amount of the biomarker is greater or less, respectively, than the normal level by an amount greater than the standard error of the assay employed to assess amount, and preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 350%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or than that amount. Alternately, the amount of the biomarker in the subject can be considered significantly higher or lower than the normal amount if the amount is at least about two, and preferably at least about three, four, or five times, higher or lower, respectively, than the normal amount of the biomarker. Such significance can also be applied to any other measured parameter described herein, such as for expression, inhibition, cytotoxicity, cell growth, and the like.

(28) The term altered level of expression of a biomarker refers to an expression level or copy number of the biomarker in a test sample, e.g., a sample derived from a patient suffering from cancer, that is greater or less than the standard error of the assay employed to assess expression or copy number, and is preferably at least twice, and more preferably three, four, five or ten or more times the expression level or copy number of the biomarker in a control sample (e.g., sample from a healthy subjects not having the associated disease) and preferably, the average expression level or copy number of the biomarker in several control samples. The altered level of expression is greater or less than the standard error of the assay employed to assess expression or copy number, and is preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 350%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more times the expression level or copy number of the biomarker in a control sample (e.g., sample from a healthy subjects not having the associated disease) and preferably, the average expression level or copy number of the biomarker in several control samples. In some embodiments, the level of the biomarker refers to the level of the biomarker itself, the level of a modified biomarker (e.g., phosphorylated biomarker), or to the level of a biomarker relative to another measured variable, such as a control (e.g., phosphorylated biomarker relative to an unphosphorylated biomarker).

(29) The term altered activity of a biomarker refers to an activity of the biomarker which is increased or decreased in a disease state, e.g., in a cancer sample, as compared to the activity of the biomarker in a normal, control sample. Altered activity of the biomarker may be the result of, for example, altered expression of the biomarker, altered protein level of the biomarker, altered structure of the biomarker, or, e.g., an altered interaction with other proteins involved in the same or different pathway as the biomarker or altered interaction with transcriptional activators or inhibitors.

(30) The term altered structure of a biomarker refers to the presence of mutations or allelic variants within a biomarker nucleic acid or protein, e.g., mutations which affect expression or activity of the biomarker nucleic acid or protein, as compared to the normal or wild-type gene or protein. For example, mutations include, but are not limited to substitutions, deletions, or addition mutations. Mutations may be present in the coding or non-coding region of the biomarker nucleic acid.

(31) Unless otherwise specified here within, the terms antibody and antibodies broadly encompass naturally-occurring forms of antibodies (e.g. IgG, IgA, IgM, IgE) and recombinant antibodies, such as single-chain antibodies, chimeric and humanized antibodies and multi-specific antibodies, as well as fragments and derivatives of all of the foregoing, which fragments and derivatives have at least an antigenic binding site. Antibody derivatives may comprise a protein or chemical moiety conjugated to an antibody.

(32) In addition, intrabodies are well-known antigen-binding molecules having the characteristic of antibodies, but that are capable of being expressed within cells in order to bind and/or inhibit intracellular targets of interest (Chen et al. (1994) Human Gene Ther. 5:595-601). Methods are well-known in the art for adapting antibodies to target (e.g., inhibit) intracellular moieties, such as the use of single-chain antibodies (scFvs), modification of immunoglobulin VL domains for hyperstability, modification of antibodies to resist the reducing intracellular environment, generating fusion proteins that increase intracellular stability and/or modulate intracellular localization, and the like. Intracellular antibodies can also be introduced and expressed in one or more cells, tissues or organs of a multicellular organism, for example for prophylactic and/or therapeutic purposes (e.g., as a gene therapy) (see, at least PCT Publs. WO 08/020079, WO 94/02610, WO 95/22618, and WO 03/014960; U.S. Pat. No. 7,004,940; Cattaneo and Biocca (1997) Intracellular Antibodies: Development and Applications (Landes and Springer-Verlag publs.); Kontermann (2004) Methods 34:163-170; Cohen et al. (1998) Oncogene 17:2445-2456; Auf der Maur et al. (2001) FEBS Lett. 508:407-412; Shaki-Loewenstein et al. (2005) J. Immunol. Meth. 303:19-39).

(33) The term antibody as used herein also includes an antigen-binding portion of an antibody (or simply antibody portion). The term antigen-binding portion, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a biomarker polypeptide or fragment thereof). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term antigen-binding portion of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab).sub.2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent polypeptides (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; and Osbourn et al. 1998, Nature Biotechnology 16: 778). Such single chain antibodies are also intended to be encompassed within the term antigen-binding portion of an antibody. Any VH and VL sequences of specific scFv can be linked to human immunoglobulin constant region cDNA or genomic sequences, in order to generate expression vectors encoding complete IgG polypeptides or other isotypes. VH and VL can also be used in the generation of Fab, Fv or other fragments of immunoglobulins using either protein chemistry or recombinant DNA technology. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123).

(34) Still further, an antibody or antigen-binding portion thereof may be part of larger immunoadhesion polypeptides, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion polypeptides include use of the streptavidin core region to make a tetrameric scFv polypeptide (Kipriyanov et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, biomarker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv polypeptides (Kipriyanov et al. (1994) Mol. Immunol. 31:1047-1058). Antibody portions, such as Fab and F(ab).sub.2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion polypeptides can be obtained using standard recombinant DNA techniques, as described herein.

(35) Antibodies may be polyclonal or monoclonal; xenogeneic, allogeneic, or syngeneic; or modified forms thereof (e.g. humanized, chimeric, etc.). Antibodies may also be fully human. Preferably, antibodies of the invention bind specifically or substantially specifically to a biomarker polypeptide or fragment thereof. The terms monoclonal antibodies and monoclonal antibody composition, as used herein, refer to a population of antibody polypeptides that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope of an antigen, whereas the term polyclonal antibodies and polyclonal antibody composition refer to a population of antibody polypeptides that contain multiple species of antigen binding sites capable of interacting with a particular antigen. A monoclonal antibody composition typically displays a single binding affinity for a particular antigen with which it immunoreacts.

(36) Antibodies may also be humanized, which is intended to include antibodies made by a non-human cell having variable and constant regions which have been altered to more closely resemble antibodies that would be made by a human cell. For example, by altering the non-human antibody amino acid sequence to incorporate amino acids found in human germline immunoglobulin sequences. The humanized antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs. The term humanized antibody, as used herein, also includes antibodies in which CDR sequences derived from the germline of another mammalian species, have been grafted onto human framework sequences.

(37) The term biomarker refers to a measurable entity of the present invention that has been determined to be predictive of cancer therapy effects. Biomarkers can include, without limitation, nucleic acids (e.g., genomic nucleic acids and/or transcribed nucleic acids) and proteins. Many biomarkers are also useful as therapeutic targets.

(38) A blocking antibody or an antibody antagonist is one which inhibits or reduces at least one biological activity of the antigen(s) it binds. In certain embodiments, the blocking antibodies or antagonist antibodies or fragments thereof described herein substantially or completely inhibit a given biological activity of the antigen(s).

(39) The term body fluid refers to fluids that are excreted or secreted from the body as well as fluids that are normally not (e.g. amniotic fluid, aqueous humor, bile, blood and blood plasma, cerebrospinal fluid, cerumen and earwax, cowper's fluid or pre-ejaculatory fluid, chyle, chyme, stool, female ejaculate, interstitial fluid, intracellular fluid, lymph, menses, breast milk, mucus, pleural fluid, pus, saliva, sebum, semen, serum, sweat, synovial fluid, tears, urine, vaginal lubrication, vitreous humor, vomit).

(40) The terms cancer or tumor or hyperproliferative refer to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features.

(41) Cancer cells are often in the form of a tumor, but such cells may exist alone within an animal, or may be a non-tumorigenic cancer cell, such as a leukemia cell. As used herein, the term cancer includes premalignant as well as malignant cancers. Cancers include, but are not limited to, B cell cancer, e.g., multiple myeloma, Waldenstrm's macroglobulinemia, the heavy chain diseases, such as, for example, alpha chain disease, gamma chain disease, and mu chain disease, benign monoclonal gammopathy, and immunocytic amyloidosis, melanomas, breast cancer, lung cancer, bronchus cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, cancer of hematologic tissues, and the like. Other non-limiting examples of types of cancers applicable to the methods encompassed by the present invention include human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, liver cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, bone cancer, brain tumor, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. In some embodiments, cancers are epithlelial in nature and include but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, gynecologic cancers, renal cancer, laryngeal cancer, lung cancer, oral cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer. In other embodiments, the cancer is breast cancer, prostate cancer, lung cancer, or colon cancer. In still other embodiments, the epithelial cancer is non-small-cell lung cancer, nonpapillary renal cell carcinoma, cervical carcinoma, ovarian carcinoma (e.g., serous ovarian carcinoma), or breast carcinoma. The epithelial cancers may be characterized in various other ways including, but not limited to, serous, endometrioid, mucinous, clear cell, Brenner, or undifferentiated.

(42) The term coding region refers to regions of a nucleotide sequence comprising codons which are translated into amino acid residues, whereas the term noncoding region refers to regions of a nucleotide sequence that are not translated into amino acids (e.g., 5 and 3 untranslated regions).

(43) The term complementary refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that an adenine residue of a first nucleic acid region is capable of forming specific hydrogen bonds (base pairing) with a residue of a second nucleic acid region which is antiparallel to the first region if the residue is thymine or uracil. Similarly, it is known that a cytosine residue of a first nucleic acid strand is capable of base pairing with a residue of a second nucleic acid strand which is antiparallel to the first strand if the residue is guanine. A first region of a nucleic acid is complementary to a second region of the same or a different nucleic acid if, when the two regions are arranged in an antiparallel fashion, at least one nucleotide residue of the first region is capable of base pairing with a residue of the second region. Preferably, the first region comprises a first portion and the second region comprises a second portion, whereby, when the first and second portions are arranged in an antiparallel fashion, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion. More preferably, all nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion.

(44) The terms conjoint therapy and combination therapy, as used herein, refer to the administration of two or more therapeutic substances. The different agents comprising the combination therapy may be administered concomitant with, prior to, or following the administration of one or more therapeutic agents.

(45) The term control refers to any reference standard suitable to provide a comparison to the expression products in the test sample. In one embodiment, the control comprises obtaining a control sample from which expression product levels are detected and compared to the expression product levels from the test sample. Such a control sample may comprise any suitable sample, including but not limited to a sample from a control cancer patient (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal patient or the cancer patient, cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient, adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository. In another preferred embodiment, the control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment (for example, standard of care cancer therapy). It will be understood by those of skill in the art that such control samples and reference standard expression product levels can be used in combination as controls in the methods of the present invention. In one embodiment, the control may comprise normal or non-cancerous cell/tissue sample. In another preferred embodiment, the control may comprise an expression level for a set of patients, such as a set of cancer patients, or for a set of cancer patients receiving a certain treatment, or for a set of patients with one outcome versus another outcome. In the former case, the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level. In another preferred embodiment, the control may comprise normal cells, cells from patients treated with combination chemotherapy, and cells from patients having benign cancer. In another embodiment, the control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population. Such a population may comprise normal subjects, cancer patients who have not undergone any treatment (i.e., treatment naive), cancer patients undergoing standard of care therapy, or patients having benign cancer. In another preferred embodiment, the control comprises a ratio transformation of expression product levels, including but not limited to determining a ratio of expression product levels of two genes in the test sample and comparing it to any suitable ratio of the same two genes in a reference standard; determining expression product levels of the two or more genes in the test sample and determining a difference in expression product levels in any suitable control; and determining expression product levels of the two or more genes in the test sample, normalizing their expression to expression of housekeeping genes in the test sample, and comparing to any suitable control. In particularly preferred embodiments, the control comprises a control sample which is of the same lineage and/or type as the test sample. In another embodiment, the control may comprise expression product levels grouped as percentiles within or based on a set of patient samples, such as all patients with cancer. In one embodiment a control expression product level is established wherein higher or lower levels of expression product relative to, for instance, a particular percentile, are used as the basis for predicting outcome. In another preferred embodiment, a control expression product level is established using expression product levels from cancer control patients with a known outcome, and the expression product levels from the test sample are compared to the control expression product level as the basis for predicting outcome. As demonstrated by the data below, the methods of the invention are not limited to use of a specific cut-point in comparing the level of expression product in the test sample to the control.

(46) The copy number of a biomarker nucleic acid refers to the number of DNA sequences in a cell (e.g., germline and/or somatic) encoding a particular gene product. Generally, for a given gene, a mammal has two copies of each gene. The copy number can be increased, however, by gene amplification or duplication, or reduced by deletion. For example, germline copy number changes include changes at one or more genomic loci, wherein said one or more genomic loci are not accounted for by the number of copies in the normal complement of germline copies in a control (e.g., the normal copy number in germline DNA for the same species as that from which the specific germline DNA and corresponding copy number were determined). Somatic copy number changes include changes at one or more genomic loci, wherein said one or more genomic loci are not accounted for by the number of copies in germline DNA of a control (e.g., copy number in germline DNA for the same subject as that from which the somatic DNA and corresponding copy number were determined).

(47) The term immune cell refers to cells that play a role in the immune response. Immune cells are of hematopoietic origin, and include lymphocytes, such as B cells and T cells; natural killer cells; myeloid cells, such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes.

(48) Macrophages (and their precursors, monocytes) are the big eaters of the immune system. These cells reside in every tissue of the body, albeit in different guises, such as microglia, Kupffer cells and osteoclasts, where they engulf apoptotic cells and pathogens and produce immune effector molecules. Upon tissue damage or infection, monocytes are rapidly recruited to the tissue, where they differentiate into tissue macrophages. Macrophages are remarkably plastic and can change their functional phenotype depending on the environmental cues they receive. Through their ability to clear pathogens and instruct other immune cells, these cells have a central role in protecting the host but also contribute to the pathogenesis of inflammatory and degenerative diseases. Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages. M1 macrophages are activated by LPS and IFN-gamma, and secrete high levels of IL-12 and low levels of IL-10. M2 is the phenotype of resident tissue macrophages, and can be further elevated by IL-4. M2 macrophages produce high levels of IL-10, TGF and low levels of IL-12. Tumor-associated macrophages are mainly of the M2 phenotype, and seem to actively promote tumor growth.

(49) Myeloid derived suppressor cells (MDSCs) are an intrinsic part of the myeloid cell lineage and are a heterogeneous population comprised of myeloid cell progenitors and precursors of granulocytes, macrophages and dendritic cells. MDSCs are defined by their myeloid origin, immature state and ability to potently suppress T cell responses. They regulate immune responses and tissue repair in healthy individuals and the population rapidly expands during inflammation, infection and cancer. MDSC are one of the major components of the tumor microenvironment. The main feature of these cells is their potent immune suppressive activity. MDSC are generated in the bone marrow and, in tumor-bearing hosts, migrate to peripheral lymphoid organs and the tumor to contribute to the formation of the tumor microenvironment. This process is controlled by a set of defined chemokines, many of which are upregulated in cancer. Hypoxia appears to have a critical role in the regulation of MDSC differentiation and function in tumors. Therapeutic strategies are now being developed to target MDSCs to promote antitumour immune responses or to inhibit immune responses in the setting of autoimmune disease or transplant rejection.

(50) Dendritic cells (DCs) are professional antigen-presenting cells located in the skin, mucosa and lymphoid tissues. Their main function is to process antigens and present them to T cells to promote immunity to foreign antigens and tolerance to self antigens. They also secrete cytokines to regulate immune responses.

(51) Conventional T cells, also known as Tconv or Teffs, have effector functions (e.g., cytokine secretion, cytotoxic activity, anti-self-recognization, and the like) to increase immune responses by virtue of their expression of one or more T cell receptors. Tcons or Teffs are generally defined as any T cell population that is not a Treg and include, for example, nave T cells, activated T cells, memory T cells, resting Tcons, or Tcons that have differentiated toward, for example, the Th1 or Th2 lineages. In some embodiments, Teffs are a subset of non-Treg T cells. In some embodiments, Teffs are CD4+ Teffs or CD8+ Teffs, such as CD4+ helper T lymphocytes (e.g., Th0, Th1, Tfh, or Th17) and CD8+ cytotoxic T lymphocytes. As described further herein, cytotoxic T cells are CD8+ T lymphocytes. Nave Tcons are CD4.sup.+ T cells that have differentiated in bone marrow, and successfully underwent a positive and negative processes of central selection in a thymus, but have not yet been activated by exposure to an antigen. Nave Tcons are commonly characterized by surface expression of L-selectin (CD62L), absence of activation markers such as CD25, CD44 or CD69, and absence of memory markers such as CD45RO. Nave Tcons are therefore believed to be quiescent and non-dividing, requiring interleukin-7 (IL-7) and interleukin-15 (IL-15) for homeostatic survival (see, at least WO 2010/101870). The presence and activity of such cells are undesired in the context of suppressing immune responses. Unlike Tregs, Tcons are not anergic and can proliferate in response to antigen-based T cell receptor activation (Lechler et al. (2001) Philos. Trans. R. Soc. Lond. Biol. Sci. 356:625-637). In tumors, exhausted cells can present hallmarks of anergy.

(52) The term immunotherapy or immunotherapies refer to any treatment that uses certain parts of a subject's immune system to fight diseases such as cancer. The subject's own immune system is stimulated (or suppressed), with or without administration of one or more agent for that purpose. Immunotherapies that are designed to elicit or amplify an immune response are referred to as activation immunotherapies. Immunotherapies that are designed to reduce or suppress an immune response are referred to as suppression immunotherapies. Any agent believed to have an immune system effect on the genetically modified transplanted cancer cells can be assayed to determine whether the agent is an immunotherapy and the effect that a given genetic modification has on the modulation of immune response. In some embodiments, the immunotherapy is cancer cell-specific. In some embodiments, immunotherapy can be untargeted, which refers to administration of agents that do not selectively interact with immune system cells, yet modulates immune system function. Representative examples of untargeted therapies include, without limitation, chemotherapy, gene therapy, and radiation therapy.

(53) Immunotherapy is one form of targeted therapy that may comprise, for example, the use of cancer vaccines and/or sensitized antigen presenting cells. For example, an oncolytic virus is a virus that is able to infect and lyse cancer cells, while leaving normal cells unharmed, making them potentially useful in cancer therapy. Replication of oncolytic viruses both facilitates tumor cell destruction and also produces dose amplification at the tumor site. They may also act as vectors for anticancer genes, allowing them to be specifically delivered to the tumor site. The immunotherapy can involve passive immunity for short-term protection of a host, achieved by the administration of pre-formed antibody directed against a cancer antigen or disease antigen (e.g., administration of a monoclonal antibody, optionally linked to a chemotherapeutic agent or toxin, to a tumor antigen). For example, anti-VEGF and mTOR inhibitors are known to be effective in treating renal cell carcinoma. Immunotherapy can also focus on using the cytotoxic lymphocyte-recognized epitopes of cancer cell lines. Alternatively, antisense polynucleotides, ribozymes, RNA interference molecules, triple helix polynucleotides and the like, can be used to selectively modulate biomolecules that are linked to the initiation, progression, and/or pathology of a tumor or cancer.

(54) Immunotherapy can involve passive immunity for short-term protection of a host, achieved by the administration of pre-formed antibody directed against a cancer antigen or disease antigen (e.g., administration of a monoclonal antibody, optionally linked to a chemotherapeutic agent or toxin, to a tumor antigen). Immunotherapy can also focus on using the cytotoxic lymphocyte-recognized epitopes of cancer cell lines. Alternatively, antisense polynucleotides, ribozymes, RNA interference molecules, triple helix polynucleotides and the like, can be used to selectively modulate biomolecules that are linked to the initiation, progression, and/or pathology of a tumor or cancer.

(55) In some embodiments, immunotherapy comprises inhibitors of one or more immune checkpoints. The term immune checkpoint refers to a group of molecules on the cell surface of CD4+ and/or CD8+ T cells that fine-tune immune responses by down-modulating or inhibiting an anti-tumor immune response. Immune checkpoint proteins are well-known in the art and include, without limitation, CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilins, and A2aR (see, for example, WO 2012/177624). The term further encompasses biologically active protein fragment, as well as nucleic acids encoding full-length immune checkpoint proteins and biologically active protein fragments thereof. In some embodiment, the term further encompasses any fragment according to homology descriptions provided herein. In one embodiment, the immune checkpoint is PD-1.

(56) Anti-immune checkpoint therapy refers to the use of agents that inhibit immune checkpoint nucleic acids and/or proteins. Inhibition of one or more immune checkpoints can block or otherwise neutralize inhibitory signaling to thereby upregulate an immune response in order to more efficaciously treat cancer. Exemplary agents useful for inhibiting immune checkpoints include antibodies, small molecules, peptides, peptidomimetics, natural ligands, and derivatives of natural ligands, that can either bind and/or inactivate or inhibit immune checkpoint proteins, or fragments thereof; as well as RNA interference, antisense, nucleic acid aptamers, etc. that can downregulate the expression and/or activity of immune checkpoint nucleic acids, or fragments thereof. Exemplary agents for upregulating an immune response include antibodies against one or more immune checkpoint proteins block the interaction between the proteins and its natural receptor(s); a non-activating form of one or more immune checkpoint proteins (e.g., a dominant negative polypeptide); small molecules or peptides that block the interaction between one or more immune checkpoint proteins and its natural receptor(s); fusion proteins (e.g. the extracellular portion of an immune checkpoint inhibition protein fused to the Fc portion of an antibody or immunoglobulin) that bind to its natural receptor(s); nucleic acid molecules that block immune checkpoint nucleic acid transcription or translation; and the like. Such agents can directly block the interaction between the one or more immune checkpoints and its natural receptor(s) (e.g., antibodies) to prevent inhibitory signaling and upregulate an immune response. Alternatively, agents can indirectly block the interaction between one or more immune checkpoint proteins and its natural receptor(s) to prevent inhibitory signaling and upregulate an immune response. For example, a soluble version of an immune checkpoint protein ligand such as a stabilized extracellular domain can binding to its receptor to indirectly reduce the effective concentration of the receptor to bind to an appropriate ligand. In one embodiment, anti-PD-1 antibodies, anti-PD-L1 antibodies, and/or anti-PD-L2 antibodies, either alone or in combination, are used to inhibit immune checkpoints. These embodiments are also applicable to specific therapy against particular immune checkpoints, such as the PD-1 pathway (e.g., anti-PD-1 pathway therapy, otherwise known as PD-1 pathway inhibitor therapy).

(57) The term immune response includes T cell mediated and/or B cell mediated immune responses. Exemplary immune responses include T cell responses, e.g., cytokine production and cellular cytotoxicity. In addition, the term immune response includes immune responses that are indirectly effected by T cell activation, e.g., antibody production (humoral responses) and activation of cytokine responsive cells, e.g., macrophages.

(58) The term immunotherapeutic agent can include any molecule, peptide, antibody or other agent which can stimulate a host immune system to generate an immune response to a tumor or cancer in the subject. Various immunotherapeutic agents are useful in the compositions and methods described herein.

(59) The term inhibit includes decreasing, reducing, limiting, and/or blocking, of, for example a particular action, function, and/or interaction. In some embodiments, the interaction between two molecules is inhibited if the interaction is reduced, blocked, disrupted or destabilized.

(60) In some embodiments, cancer is inhibited if at least one symptom of the cancer is alleviated, terminated, slowed, or prevented. As used herein, cancer is also inhibited if recurrence or metastasis of the cancer is reduced, slowed, delayed, or prevented.

(61) The term interaction, when referring to an interaction between two molecules, refers to the physical contact (e.g., binding) of the molecules with one another. Generally, such an interaction results in an activity (which produces a biological effect) of one or both of said molecules.

(62) An isolated protein refers to a protein that is substantially free of other proteins, cellular material, separation medium, and culture medium when isolated from cells or produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. An isolated or purified protein or biologically active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the antibody, polypeptide, peptide or fusion protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language substantially free of cellular material includes preparations of a biomarker polypeptide or fragment thereof, in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly produced. In one embodiment, the language substantially free of cellular material includes preparations of a biomarker protein or fragment thereof, having less than about 30% (by dry weight) of non-biomarker protein (also referred to herein as a contaminating protein), more preferably less than about 20% of non-biomarker protein, still more preferably less than about 10% of non-biomarker protein, and most preferably less than about 5% non-biomarker protein. When antibody, polypeptide, peptide or fusion protein or fragment thereof, e.g., a biologically active fragment thereof, is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the protein preparation.

(63) As used herein, the term isotype refers to the antibody class (e.g., IgM, IgG1, IgG2C, and the like) that is encoded by heavy chain constant region genes.

(64) The normal level of expression of a biomarker is the level of expression of the biomarker in cells of a subject, e.g., a human patient, not afflicted with a cancer. An over-expression or significantly higher level of expression of a biomarker refers to an expression level in a test sample that is greater than the standard error of the assay employed to assess expression, and is preferably at least 10%, and more preferably 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or more higher than the expression activity or level of the biomarker in a control sample (e.g., sample from a healthy subject not having the biomarker associated disease) and preferably, the average expression level of the biomarker in several control samples. A significantly lower level of expression of a biomarker refers to an expression level in a test sample that is at least 10%, and more preferably 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or more lower than the expression level of the biomarker in a control sample (e.g., sample from a healthy subject not having the biomarker associated disease) and preferably, the average expression level of the biomarker in several control samples.

(65) An over-expression or significantly higher level of expression of a biomarker refers to an expression level in a test sample that is greater than the standard error of the assay employed to assess expression, and is preferably at least 10%, and more preferably 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or more higher than the expression activity or level of the biomarker in a control sample (e.g., sample from a healthy subject not having the biomarker associated disease) and preferably, the average expression level of the biomarker in several control samples. A significantly lower level of expression of a biomarker refers to an expression level in a test sample that is at least 10%, and more preferably 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or more lower than the expression level of the biomarker in a control sample (e.g., sample from a healthy subject not having the biomarker associated disease) and preferably, the average expression level of the biomarker in several control samples.

(66) The term predictive includes the use of a biomarker nucleic acid and/or protein status, e.g., over- or under-activity, emergence, expression, growth, remission, recurrence or resistance of tumors before, during or after therapy, for determining the likelihood of response of a cancer to a cancer vaccine alone or in combination with an immunotherapy and/or cancer therapy. Such predictive use of the biomarker may be confirmed by, e.g., (1) increased or decreased copy number (e.g., by FISH, FISH plus SKY, single-molecule sequencing, e.g., as described in the art at least at J. Biotechnol., 86:289-301, or qPCR), overexpression or underexpression of a biomarker nucleic acid (e.g., by ISH, Northern Blot, or qPCR), increased or decreased biomarker protein (e.g., by IHC), or increased or decreased activity, e.g., in more than about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100%, or more of assayed human cancers types or cancer samples; (2) its absolute or relatively modulated presence or absence in a biological sample, e.g., a sample containing tissue, whole blood, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, or bone marrow, from a subject, e.g. a human, afflicted with cancer; (3) its absolute or relatively modulated presence or absence in clinical subset of patients with cancer (e.g., those responding to the cancer vaccine alone or in combination with an immunotherapy and/or cancer therapy, or those developing resistance thereto).

(67) The terms prevent, preventing, prevention, prophylactic treatment, and the like refer to reducing the probability of developing a disease, disorder, or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition.

(68) The term cancer response, response to immunotherapy, or response to modulators of T-cell mediated cytotoxicity/immunotherapy combination therapy relates to any response of the hyperproliferative disorder (e.g., cancer) to a cancer agent, such as a modulator of T-cell mediated cytotoxicity, and an immunotherapy, preferably to a change in tumor mass and/or volume after initiation of neoadjuvant or adjuvant therapy. Hyperproliferative disorder response may be assessed, for example for efficacy or in a neoadjuvant or adjuvant situation, where the size of a tumor after systemic intervention can be compared to the initial size and dimensions as measured by CT, PET, mammogram, ultrasound or palpation. Responses may also be assessed by caliper measurement or pathological examination of the tumor after biopsy or surgical resection. Response may be recorded in a quantitative fashion like percentage change in tumor volume or in a qualitative fashion like pathological complete response (pCR), clinical complete remission (cCR), clinical partial remission (cPR), clinical stable disease (cSD), clinical progressive disease (cPD) or other qualitative criteria. Assessment of hyperproliferative disorder response may be done early after the onset of neoadjuvant or adjuvant therapy, e.g., after a few hours, days, weeks or preferably after a few months. A typical endpoint for response assessment is upon termination of neoadjuvant chemotherapy or upon surgical removal of residual tumor cells and/or the tumor bed. This is typically three months after initiation of neoadjuvant therapy. In some embodiments, clinical efficacy of the therapeutic treatments described herein may be determined by measuring the clinical benefit rate (CBR). The clinical benefit rate is measured by determining the sum of the percentage of patients who are in complete remission (CR), the number of patients who are in partial remission (PR) and the number of patients having stable disease (SD) at a time point at least 6 months out from the end of therapy. The shorthand for this formula is CBR=CR+PR+SD over 6 months. In some embodiments, the CBR for a particular cancer therapeutic regimen is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or more. Additional criteria for evaluating the response to cancer therapies are related to survival, which includes all of the following: survival until mortality, also known as overall survival (wherein said mortality may be either irrespective of cause or tumor related); recurrence-free survival (wherein the term recurrence shall include both localized and distant recurrence); metastasis free survival; disease free survival (wherein the term disease shall include cancer and diseases associated therewith). The length of said survival may be calculated by reference to a defined start point (e.g., time of diagnosis or start of treatment) and end point (e.g., death, recurrence or metastasis). In addition, criteria for efficacy of treatment can be expanded to include response to chemotherapy, probability of survival, probability of metastasis within a given time period, and probability of tumor recurrence. For example, in order to determine appropriate threshold values, a particular cancer therapeutic regimen can be administered to a population of subjects and the outcome can be correlated to biomarker measurements that were determined prior to administration of any cancer therapy. The outcome measurement may be pathologic response to therapy given in the neoadjuvant setting. Alternatively, outcome measures, such as overall survival and disease-free survival can be monitored over a period of time for subjects following cancer therapy for which biomarker measurement values are known. In certain embodiments, the doses administered are standard doses known in the art for cancer therapeutic agents. The period of time for which subjects are monitored can vary. For example, subjects may be monitored for at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, or 60 months. Biomarker measurement threshold values that correlate to outcome of a cancer therapy can be determined using well-known methods in the art, such as those described in the Examples section.

(69) The term resistance refers to an acquired or natural resistance of a cancer sample or a mammal to a cancer therapy (i.e., being nonresponsive to or having reduced or limited response to the therapeutic treatment), such as having a reduced response to a therapeutic treatment by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more, such 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold or more, or any range in between, inclusive. The reduction in response can be measured by comparing with the same cancer sample or mammal before the resistance is acquired, or by comparing with a different cancer sample or a mammal that is known to have no resistance to the therapeutic treatment. A typical acquired resistance to chemotherapy is called multidrug resistance. The multidrug resistance can be mediated by P-glycoprotein or can be mediated by other mechanisms, or it can occur when a mammal is infected with a multi-drug-resistant microorganism or a combination of microorganisms. The determination of resistance to a therapeutic treatment is routine in the art and within the skill of an ordinarily skilled clinician, for example, can be measured by cell proliferative assays and cell death assays as described herein as sensitizing. In some embodiments, the term reverses resistance means that the use of a second agent in combination with a primary cancer therapy (e.g., chemotherapeutic or radiation therapy) is able to produce a significant decrease in tumor volume at a level of statistical significance (e.g., p<0.05) when compared to tumor volume of untreated tumor in the circumstance where the primary cancer therapy (e.g., chemotherapeutic or radiation therapy) alone is unable to produce a statistically significant decrease in tumor volume compared to tumor volume of untreated tumor. This generally applies to tumor volume measurements made at a time when the untreated tumor is growing log rhythmically.

(70) The terms response or responsiveness refers to a cancer response, e.g. in the sense of reduction of tumor size or inhibiting tumor growth. The terms can also refer to an improved prognosis, for example, as reflected by an increased time to recurrence, which is the period to first recurrence censoring for second primary cancer as a first event or death without evidence of recurrence, or an increased overall survival, which is the period from treatment to death from any cause. To respond or to have a response means there is a beneficial endpoint attained when exposed to a stimulus. Alternatively, a negative or detrimental symptom is minimized, mitigated or attenuated on exposure to a stimulus. It will be appreciated that evaluating the likelihood that a tumor or subject will exhibit a favorable response is equivalent to evaluating the likelihood that the tumor or subject will not exhibit favorable response (i.e., will exhibit a lack of response or be non-responsive).

(71) An RNA interfering agent as used herein, is defined as any agent which interferes with or inhibits expression of a target biomarker gene by RNA interference (RNAi). Such RNA interfering agents include, but are not limited to, nucleic acid molecules including RNA molecules which are homologous to the target biomarker gene of the present invention, or a fragment thereof, short interfering RNA (siRNA), and small molecules which interfere with or inhibit expression of a target biomarker nucleic acid by RNA interference (RNAi).

(72) RNA interference (RNAi) is an evolutionally conserved process whereby the expression or introduction of RNA of a sequence that is identical or highly similar to a target biomarker nucleic acid results in the sequence specific degradation or specific post-transcriptional gene silencing (PTGS) of messenger RNA (mRNA) transcribed from that targeted gene (see Coburn and Cullen (2002) J. Virol. 76:9225), thereby inhibiting expression of the target biomarker nucleic acid. In one embodiment, the RNA is double stranded RNA (dsRNA). This process has been described in plants, invertebrates, and mammalian cells. In nature, RNAi is initiated by the dsRNA-specific endonuclease Dicer, which promotes processive cleavage of long dsRNA into double-stranded fragments termed siRNAs. siRNAs are incorporated into a protein complex that recognizes and cleaves target mRNAs. RNAi can also be initiated by introducing nucleic acid molecules, e.g., synthetic siRNAs or RNA interfering agents, to inhibit or silence the expression of target biomarker nucleic acids. As used herein, inhibition of target biomarker nucleic acid expression or inhibition of marker gene expression includes any decrease in expression or protein activity or level of the target biomarker nucleic acid or protein encoded by the target biomarker nucleic acid. The decrease may be of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% or more as compared to the expression of a target biomarker nucleic acid or the activity or level of the protein encoded by a target biomarker nucleic acid which has not been targeted by an RNA interfering agent.

(73) In addition to RNAi, genome editing can be used to modulate the copy number or genetic sequence of a biomarker of interest, such as constitutive or induced knockout or mutation of a biomarker of interest. For example, the CRISPR-Cas system can be used for precise editing of genomic nucleic acids (e.g., for creating non-functional or null mutations). In such embodiments, the CRISPR guide RNA and/or the Cas enzyme may be expressed. For example, a vector containing only the guide RNA can be administered to an animal or cells transgenic for the Cas9 enzyme. Similar strategies may be used (e.g., designer zinc finger, transcription activator-like effectors (TALEs) or homing meganucleases). Such systems are well-known in the art (see, for example, U.S. Pat. No. 8,697,359; Sander and Joung (2014) Nat. Biotech. 32:347-355; Hale et al. (2009) Cell 139:945-956; Karginov and Hannon (2010) Mol. Cell 37:7; U.S. Pat. Publ. 2014/0087426 and 2012/0178169; Boch et al. (2011) Nat. Biotech. 29:135-136; Boch et al. (2009) Science 326:1509-1512; Moscou and Bogdanove (2009) Science 326:1501; Weber et al. (2011) PLoS One 6:e19722; Li et al. (2011) Nucl. Acids Res. 39:6315-6325; Zhang et al. (2011) Nat. Biotech. 29:149-153; Miller et al. (2011) Nat. Biotech. 29:143-148; Lin et al. (2014) Nucl. Acids Res. 42:e47). Such genetic strategies can use constitutive expression systems or inducible expression systems according to well-known methods in the art.

(74) Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA molecules. piRNAs form RNA-protein complexes through interactions with piwi proteins. These piRNA complexes have been linked to both epigenetic and post-transcriptional gene silencing of retrotransposons and other genetic elements in germ line cells, particularly those in spermatogenesis. They are distinct from microRNA (miRNA) in size (26-31 nt rather than 21-24 nt), lack of sequence conservation, and increased complexity. However, like other small RNAs, piRNAs are thought to be involved in gene silencing, specifically the silencing of transposons. The majority of piRNAs are antisense to transposon sequences, suggesting that transposons are the piRNA target. In mammals it appears that the activity of piRNAs in transposon silencing is most important during the development of the embryo, and in both C. elegans and humans, piRNAs are necessary for spermatogenesis. piRNA has a role in RNA silencing via the formation of an RNA-induced silencing complex (RISC).

(75) Aptamers are oligonucleotide or peptide molecules that bind to a specific target molecule. Nucleic acid aptamers are nucleic acid species that have been engineered through repeated rounds of in vitro selection or equivalently, SELEX (systematic evolution of ligands by exponential enrichment) to bind to various molecular targets such as small molecules, proteins, nucleic acids, and even cells, tissues and organisms. Peptide aptamers are artificial proteins selected or engineered to bind specific target molecules. These proteins consist of one or more peptide loops of variable sequence displayed by a protein scaffold. They are typically isolated from combinatorial libraries and often subsequently improved by directed mutation or rounds of variable region mutagenesis and selection. The Affimer protein, an evolution of peptide aptamers, is a small, highly stable protein engineered to display peptide loops which provides a high affinity binding surface for a specific target protein. It is a protein of low molecular weight, 12-14 kDa, derived from the cysteine protease inhibitor family of cystatins. Aptamers are useful in biotechnological and therapeutic applications as they offer molecular recognition properties that rival that of the commonly used biomolecule, antibodies. In addition to their discriminate recognition, aptamers offer advantages over antibodies as they can be engineered completely in a test tube, are readily produced by chemical synthesis, possess desirable storage properties, and elicit little or no immunogenicity in therapeutic applications.

(76) As used herein, the term intracellular immunoglobulin molecule is a complete immunoglobulin which is the same as a naturally-occurring secreted immunoglobulin, but which remains inside of the cell following synthesis. An intracellular immunoglobulin fragment refers to any fragment, including single-chain fragments of an intracellular immunoglobulin molecule. Thus, an intracellular immunoglobulin molecule or fragment thereof is not secreted or expressed on the outer surface of the cell. Single-chain intracellular immunoglobulin fragments are referred to herein as single-chain immunoglobulins. As used herein, the term intracellular immunoglobulin molecule or fragment thereof is understood to encompass an intracellular immunoglobulin, a single-chain intracellular immunoglobulin (or fragment thereof), an intracellular immunoglobulin fragment, an intracellular antibody (or fragment thereof), and an intrabody (or fragment thereof). As such, the terms intracellular immunoglobulin, intracellular Ig, intracellular antibody, and intrabody may be used interchangeably herein, and are all encompassed by the generic definition of an intracellular immunoglobulin molecule, or fragment thereof. An intracellular immunoglobulin molecule, or fragment thereof of the present invention may, in some embodiments, comprise two or more subunit polypeptides, e.g., a first intracellular immunoglobulin subunit polypeptide and a second intracellular immunoglobulin subunit polypeptide. However, in other embodiments, an intracellular immunoglobulin may be a single-chain intracellular immunoglobulin including only a single polypeptide. As used herein, a single-chain intracellular immunoglobulin is defined as any unitary fragment that has a desired activity, for example, intracellular binding to an antigen. Thus, single-chain intracellular immunoglobulins encompass those which comprise both heavy and light chain variable regions which act together to bind antigen, as well as single-chain intracellular immunoglobulins which only have a single variable region which binds antigen, for example, a camelized heavy chain variable region as described herein. An intracellular immunoglobulin or Ig fragment may be expressed anywhere substantially within the cell, such as in the cytoplasm, on the inner surface of the cell membrane, or in a subcellular compartment (also referred to as cell subcompartment or cell compartment) such as the nucleus, Golgi, endoplasmic reticulum, endosome, mitochondria, etc. Additional cell subcompartments include those that are described herein and well known in the art.

(77) The term sample used for detecting or determining the presence or level of at least one biomarker is typically whole blood, plasma, serum, saliva, urine, stool (e.g., feces), tears, and any other bodily fluid (e.g., as described above under the definition of body fluids), or a tissue sample (e.g., biopsy) such as bone marrow and bone sample, or surgical resection tissue. In certain instances, the method of the present invention further comprises obtaining the sample from the individual prior to detecting or determining the presence or level of at least one marker in the sample.

(78) The term sensitize means to alter cancer cells or tumor cells in a way that allows for more effective treatment of the associated cancer with a cancer therapy (e.g., anti-immune checkpoint, chemotherapeutic, and/or radiation therapy). In some embodiments, normal cells are not affected to an extent that causes the normal cells to be unduly injured by the therapies. An increased sensitivity or a reduced sensitivity to a therapeutic treatment is measured according to a known method in the art for the particular treatment and methods described herein below, including, but not limited to, cell proliferative assays (Tanigawa N, Kern D H, Kikasa Y, Morton D L, Cancer Res 1982; 42: 2159-2164), cell death assays (Weisenthal L M, Shoemaker R H, Marsden J A, Dill P L, Baker J A, Moran E M, Cancer Res 1984; 94: 161-173; Weisenthal L M, Lippman M E, Cancer Treat Rep 1985; 69: 615-632; Weisenthal L M, In: Kaspers G J L, Pieters R, Twentyman P R, Weisenthal L M, Veerman A J P, eds. Drug Resistance in Leukemia and Lymphoma. Langhorne, P A: Harwood Academic Publishers, 1993: 415-432; Weisenthal L M, Contrib Gynecol Obstet 1994; 19: 82-90). The sensitivity or resistance may also be measured in animal by measuring the tumor size reduction over a period of time, for example, 6 month for human. A composition or a method sensitizes response to a therapeutic treatment if the increase in treatment sensitivity or the reduction in resistance is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more, such 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold or more, or any range in between, inclusive, compared to treatment sensitivity or resistance in the absence of such composition or method. The determination of sensitivity or resistance to a therapeutic treatment is routine in the art and within the skill of an ordinarily skilled clinician. It is to be understood that any method described herein for enhancing the efficacy of a cancer therapy can be equally applied to methods for sensitizing hyperproliferative or otherwise cancerous cells (e.g., resistant cells) to the cancer therapy.

(79) Short interfering RNA (siRNA), also referred to herein as small interfering RNA is defined as an agent which functions to inhibit expression of a target biomarker nucleic acid, e.g., by RNAi. An siRNA may be chemically synthesized, may be produced by in vitro transcription, or may be produced within a host cell. In one embodiment, siRNA is a double stranded RNA (dsRNA) molecule of about 15 to about 40 nucleotides in length, preferably about 15 to about 28 nucleotides, more preferably about 19 to about 25 nucleotides in length, and more preferably about 19, 20, 21, or 22 nucleotides in length, and may contain a 3 and/or 5 overhang on each strand having a length of about 0, 1, 2, 3, 4, or 5 nucleotides. The length of the overhang is independent between the two strands, i.e., the length of the overhang on one strand is not dependent on the length of the overhang on the second strand. Preferably the siRNA is capable of promoting RNA interference through degradation or specific post-transcriptional gene silencing (PTGS) of the target messenger RNA (mRNA).

(80) In another embodiment, an siRNA is a small hairpin (also called stem loop) RNA (shRNA). In one embodiment, these shRNAs are composed of a short (e.g., 19-25 nucleotide) antisense strand, followed by a 5-9 nucleotide loop, and the analogous sense strand. Alternatively, the sense strand may precede the nucleotide loop structure and the antisense strand may follow. These shRNAs may be contained in plasmids, retroviruses, and lentiviruses and expressed from, for example, the pol III U6 promoter, or another promoter (see, e.g., Stewart, et al. (2003) RNA April; 9(4):493-501 incorporated by reference herein).

(81) RNA interfering agents, e.g., siRNA molecules, may be administered to a patient having or at risk for having cancer, to inhibit expression of a biomarker gene which is overexpressed in cancer and thereby treat, prevent, or inhibit cancer in the subject.

(82) The term small molecule is a term of the art and includes molecules that are less than about 1000 molecular weight or less than about 500 molecular weight. In one embodiment, small molecules do not exclusively comprise peptide bonds. In another embodiment, small molecules are not oligomeric. Exemplary small molecule compounds which can be screened for activity include, but are not limited to, peptides, peptidomimetics, nucleic acids, carbohydrates, small organic molecules (e.g., polyketides) (Cane et al. (1998) Science 282:63), and natural product extract libraries. In another embodiment, the compounds are small, organic non-peptidic compounds. In a further embodiment, a small molecule is not biosynthetic.

(83) The term specific binding refers to antibody binding to a predetermined antigen. Typically, the antibody binds with an affinity (K.sub.D) of approximately less than 10.sup.7M, such as approximately less than 10.sup.8 M, 10.sup.9M or 10.sup.10 M or even lower when determined by surface plasmon resonance (SPR) technology in a BIACORE assay instrument using an antigen of interest as the analyte and the antibody as the ligand, and binds to the predetermined antigen with an affinity that is at least 1.1-, 1.2-, 1.3-, 1.4-, 1.5-, 1.6-, 1.7-, 1.8-, 1.9-, 2.0-, 2.5-, 3.0-, 3.5-, 4.0-, 4.5-, 5.0-, 6.0-, 7.0-, 8.0-, 9.0-, or 10.0-fold or greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen. The phrases an antibody recognizing an antigen and an antibody specific for an antigen are used interchangeably herein with the term an antibody which binds specifically to an antigen. Selective binding is a relative term referring to the ability of an antibody to discriminate the binding of one antigen over another.

(84) The term subject refers to any healthy animal, mammal or human, or any animal, mammal or human afflicted with a cancer, e.g., brain, lung, ovarian, pancreatic, liver, breast, prostate, and/or colorectal cancers, melanoma, multiple myeloma, and the like. The term subject is interchangeable with patient.

(85) The term survival includes all of the following: survival until mortality, also known as overall survival (wherein said mortality may be either irrespective of cause or tumor related); recurrence-free survival (wherein the term recurrence shall include both localized and distant recurrence); metastasis free survival; disease free survival (wherein the term disease shall include cancer and diseases associated therewith). The length of said survival may be calculated by reference to a defined start point (e.g. time of diagnosis or start of treatment) and end point (e.g. death, recurrence or metastasis). In addition, criteria for efficacy of treatment can be expanded to include response to chemotherapy, probability of survival, probability of metastasis within a given time period, and probability of tumor recurrence.

(86) The term synergistic effect refers to the combined effect of two or more cancer agents (e.g., a cancer vaccine in combination with immunotherapy) can be greater than the sum of the separate effects of the cancer agents/therapies alone.

(87) The term T cell includes CD4.sup.+ T cells and CD8.sup.+ T cells. The term T cell also includes both T helper 1 type T cells and T helper 2 type T cells. The term antigen presenting cell includes professional antigen presenting cells (e.g., B lymphocytes, monocytes, dendritic cells, Langerhans cells), as well as other antigen presenting cells (e.g., keratinocytes, endothelial cells, astrocytes, fibroblasts, and oligodendrocytes).

(88) The term therapeutic effect refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in an animal or human. The phrase therapeutically-effective amount means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. In certain embodiments, a therapeutically effective amount of a compound will depend on its therapeutic index, solubility, and the like. For example, certain compounds discovered by the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.

(89) The terms therapeutically-effective amount and effective amount as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment. Toxicity and therapeutic efficacy of subject compounds may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD.sub.50 and the ED.sub.50. Compositions that exhibit large therapeutic indices are preferred. In some embodiments, the LD.sub.50 (lethal dosage) can be measured and can be, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more reduced for the agent relative to no administration of the agent. Similarly, the ED.sub.50 (i.e., the concentration which achieves a half-maximal inhibition of symptoms) can be measured and can be, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more increased for the agent relative to no administration of the agent. Also, Similarly, the IC.sub.50 (i.e., the concentration which achieves half-maximal cytotoxic or cytostatic effect on cancer cells) can be measured and can be, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more increased for the agent relative to no administration of the agent. In some embodiments, cancer cell growth in an assay can be inhibited by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100%. In another embodiment, at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100% decrease in a solid malignancy can be achieved.

(90) The term substantially free of chemical precursors or other chemicals includes preparations of antibody, polypeptide, peptide or fusion protein in which the protein is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. In one embodiment, the language substantially free of chemical precursors or other chemicals includes preparations of antibody, polypeptide, peptide or fusion protein having less than about 30% (by dry weight) of chemical precursors or non-antibody, polypeptide, peptide or fusion protein chemicals, more preferably less than about 20% chemical precursors or non-antibody, polypeptide, peptide or fusion protein chemicals, still more preferably less than about 10% chemical precursors or non-antibody, polypeptide, peptide or fusion protein chemicals, and most preferably less than about 5% chemical precursors or non-antibody, polypeptide, peptide or fusion protein chemicals.

(91) A transcribed polynucleotide or nucleotide transcript is a polynucleotide (e.g. an mRNA, hnRNA, a cDNA, or an analog of such RNA or cDNA) which is complementary to or homologous with all or a portion of a mature mRNA made by transcription of a biomarker nucleic acid and normal post-transcriptional processing (e.g. splicing), if any, of the RNA transcript, and reverse transcription of the RNA transcript.

(92) The term host cell is intended to refer to a cell into which a nucleic acid encompassed by the present invention, such as a recombinant expression vector encompassed by the present invention, has been introduced. The terms host cell and recombinant host cell are used interchangeably herein. It should be understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

(93) The term vector refers to a nucleic acid capable of transporting another nucleic acid to which it has been linked. One type of vector is a plasmid, which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as recombinant expression vectors or simply expression vectors. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, plasmid and vector may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

(94) As used herein, the term unresponsiveness includes refractivity of cancer cells to therapy or refractivity of therapeutic cells, such as immune cells, to stimulation, e.g., stimulation via an activating receptor or a cytokine. Unresponsiveness can occur, e.g., because of exposure to immunosuppressants or exposure to high doses of antigen. As used herein, the term allergy or tolerance includes refractivity to activating receptor-mediated stimulation. Such refractivity is generally antigen-specific and persists after exposure to the tolerizing antigen has ceased. For example, anergy in T cells (as opposed to unresponsiveness) is characterized by lack of cytokine production, e.g., IL-2. T cell anergy occurs when T cells are exposed to antigen and receive a first signal (a T cell receptor or CD-3 mediated signal) in the absence of a second signal (a costimulatory signal). Under these conditions, reexposure of the cells to the same antigen (even if reexposure occurs in the presence of a costimulatory polypeptide) results in failure to produce cytokines and, thus, failure to proliferate. Anergic T cells can, however, proliferate if cultured with cytokines (e.g., IL-2). For example, T cell anergy can also be observed by the lack of IL-2 production by T lymphocytes as measured by ELISA or by a proliferation assay using an indicator cell line. Alternatively, a reporter gene construct can be used. For example, anergic T cells fail to initiate IL-2 gene transcription induced by a heterologous promoter under the control of the 5 IL-2 gene enhancer or by a multimer of the AP1 sequence that can be found within the enhancer (Kang et al. (1992) Science 257:1134).

(95) The term TGF-Smad/p63 signaling pathway refers to one branch of the TGF signaling pathway. The TGF signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including but are not limited to cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In some embodiments, TGF superfamily ligands (e.g., TGF1, TGF2, and/or TGF3) bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs; e.g., SMAD1, SMAD2, SMAD3, SMAD5, or SMAD9) which can now bind the coSMAD (e.g., SMAD4). R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression. In the branch of the TGF-Smad/p63 signaling pathway, R-SMAD/coSMAD complexes further associate with p63 in the nucleus to regulate target gene expression. In one embodiment, R-SMAD is Smad2. TGF-Smad/p63 signaling pathway activation can be assessed by analyzing, for example, Smad2 phosphorylation, Smad2 nuclear translocation, association of Smad2 with p63, and/or the activation of the TGF-Smad/p63 signature genes. The TGF-Smad/p63 signatures may include, but are not limited to, upregulation of ICOSL, PYCARD, SFN, PERP, RIPK3, and/or SESN1, and/or downregulation of KSR1, EIF4EBP1, ITGA5, EMILIN1, CD200, and/or CSF1.

(96) In some embodiments, upon binding to its receptors, TGF promotes the formation of TGFBRII and TGFBR1 heterodimers on cell plasma membrane. The cytoplasmic signaling molecules R-Smads (such as Smad2 and Smad3) are then phosphorylated by the activated TGFBRI. The activated R-Smads form a complex with Co-Smad (such as Smad4) and translocate into the cell nucleus. As demonstrated herein, by partnering with p63 (or other p53 family members such as p53 or p73), the Smads/p63 trancriptional complex upregulates proinflammatory genes (such as Icosl, Nfkbib, Tnfaip3, Pik3r1, and Perp) and dowregulates oncogenic genes (such as Cd200, Cxcl5, Csf1, Pdgfrb, Fgfr1, Vegfa). Therefore tumor cells with activated TGF-Smads/p63 signatures display strong eat me signals to the immune system and trigger antitumor immune responses by recruiting antigen presenting cells (such dendritic cell). The dendritic cells (DCs) take up tumor specific antigens and promote tumor specific effector and memory T cell responses to provide the host with full protection against tumors. The TGF-Smad/p63 signaling pathway can be activated by modulating signaling molecules involved in this pathway. In specific embodiments, Smad superfamilies (including Smad1, Smad2, Smad3, Smad4, Smad5, Smad6, Smad7, and Smad9) and p53 superfamilies (including p53, p63, and p73) are modulated to activate the TGF-Smad/p63 signaling pathway in the compositions and methods encompassed by the present invention.

(97) The TGF-Smad/p63 signaling pathway can be by activated by providing a TGF superfamily ligand or an agonist of the TGF signaling pathway. It can also be regulated and/or at the level of Smad and p63. Exemplary agents useful for activating TGF-Smad/p63 signaling pathway, or other biomarkers described herein, include small molecules, peptides, and nucleic acids, etc. that can upregulate the expression and/or activity of one or more biomarkers listed in Table 1, or fragments thereof; and/or decrease the copy number, amount, and/or activity of one or more biomarkers listed in Table 2, or fragments thereof. Exemplary agents useful for activating TGF-Smad/p63 signaling pathway, or other biomarkers described herein, also include TGF superfamily ligands.

(98) In one embodiment, suitable agonists include naturally-occurring agonists of the TGF superfamily member, or fragments and variants thereof. For example, agonists of TGF signaling may include a soluble form of endoglin, see, for example, U.S. Pat. Nos. 5,719,120, 5,830,847, and 6,015,693, each of which is incorporated herein by reference in its entirety. In another embodiment, suitable agonists may include inhibitors of naturally-occurring TGF antagonists. Multiple naturally-occurring modulators have been identified that regulate TGF signaling. For example, access of TGF ligands to receptors is inhibited by the soluble proteins LAP, decorin and 2-macroglobulin that bind and sequester the ligands (Balemans and Van Hul (2002) Dev. Biol. 250:231-250). TGF ligand access to receptors is also controlled by membrane-bound receptors. BAMBI acts as a decoy receptor, competing with the type I receptor (Onichtchouk et al. (1999) Nature 401:480-485); betaglycan (TGF type II receptor) enhances TGF binding to the type II receptor (Brown et al. (1999) Science 283:2080-2082, Massagu (1998) Annu. Rev. Biochem. 67:753-791, del Re et al. (2004) J. Biol. Chem. 279:22765-22772); and endoglin enhances TGF binding to ALK1 in endothelial cells (Marchuk (1998) Curr. Opin. Hematol. 5:332-338; Massagu (2000) Nat. Rev. Mol. Cell. Biol. 1: 169-178; Shi and Massagu (2003) Cell 113:685-700). Cripto, an EGF-CFC GPI-anchored membrane protein, acts as a co-receptor, increasing the binding of the TGF ligands, nodal, Vg1, and GDF1 to activin receptors (Cheng et al. (2003) Genes Dev. 17:31-36, Shen and Schier (2000) Trends Genet. 16:303-309) while blocking activin signaling. Suitable agonists also include synthetic or human recombinant compounds. Classes of molecules that can function as agonists include, but are not limited to, small molecules, antibodies (including fragments or variants thereof, such as Fab fragments, Fab2 fragments and scFvs), and peptidomimetics.

(99) As used herein, the term TGF superfamily refers to a large family of multifunctional proteins that regulate a variety of cellular functions including cellular proliferation, migration, differentiation and apoptosis. The TGF superfamily presently comprises more than 30 members, including, among others, activins, inhibins, Transforming Growth Factors-beta (TGFs), Growth and Differentiation Factors (GDFs), Bone Morphogenetic Proteins (BMPs), and Mllerian inhibiting Substance (MIS). All of these molecules are peptide growth factors that are structurally related to TGF. They all share a common motif called a cysteine knot, which is constituted by seven especially conservative cysteine residues organized in a rigid structure (Massagu (1998) Annu. Rev. Biochem. 67:753-791). Unlike classical hormones, members of the TGF superfamily are multifunctional proteins whose effects depend on the type and stage of the target cells as much as the growth factors themselves.

(100) TGF superfamily members suitable for use in the practice of the present invention include any member of the TGF superfamily that can activate the TGF-Smad/p63 signaling pathway. In one embodiment, TGF superfamily members are from the TGF family, which include but are not limited to, LAP, TGF1, TGF2, TGF3, and TGF5. In another embodiment, TGF superfamily members are from the Activin family, which include but are not limited to, Activin A, Activin AB, Activin AC, Activin B, Activin C, C17ORF99, INHBA, INHBB, Inhibin, Inhibin A, and Inhibin B. In still another embodiment, TGF superfamily members are from the BMP (Bone Morphogenetic Protein) family, which include but are not limited to, BMP-1/PCP, BMP-2, BMP-2/BMP-6 Heterodimer, BMP-2/BMP-7 Heterodimer, BMP-2a, BMP-3, BMP-3b/GDF-10, BMP-4, BMP-4/BMP-7 Heterodimer, BMP-5, BMP-6, BMP-7, BMP-8, BMP-8a, BMP-8b, BMP-9, BMP-10, BMP-15/GDF-9B, and Decapentaplegic/DPP. In yet another embodiment, TGF superfamily members are from the GDNF family, which include but are not limited to, Artemin, GDNF, Neurturin, and Persephin. Additional TGF superfamily members include Lefty A, Lefty B, MIS/AMH, Nodal, and SCUBE3.

(101) In certain embodiments, TGF superfamily members are from the TGF family. TGF, the founding member of TGF family, has been shown to play a variety of roles ranging from embryonic pattern formation to cell growth regulation in adult tissues. Mammalian cells can produce three different isoforms of TGF: TGF1, TGF2, and TGF3. These isoforms exhibit the same basic structure (they are homodimers of 112 amino acids that are stabilized by intra- and inter-chain disulfide bonds) and their amino acid sequences present a high degree of homology (>70%). However, each isoform is encoded by a distinct gene, and each is expressed in both a tissue-specific and developmentally regulated fashion (Massagu (1998) Annu. Rev. Biochem. 67:753-791). TGF exerts its biological functions by signal transduction cascades that ultimately activate and/or suppress expression of a set of specific genes. Cross-linking studies have shown that TGF mainly binds to three high-affinity cell-surface proteins, called TGF receptors of type I, type II, and type III (Massagu and Like (1985) J. Biol. Chem. 260:2636-2645, Cheifetz et al. (1986) J. Biol. Chem. 261:9972-9978). In some embodiments, TGF triggers its signal by first binding to its type II receptor, then recruiting and activating its type I receptors. The activated type I receptors then phosphorylate its intracellular signal transducer molecules, the Smad proteins (Heldin et al. (1997) Nature 390:465-471; Derynck et al. (1998) Cell 95:737-740).

(102) The term TGF1 or Transforming Growth Factor Beta 1 refers to a secreted ligand of the TGF superfamily of proteins. Ligands of this family bind various TGF receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide can also form heterodimers with other TGF family members. Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, LAP and TGF1 chains remain non-covalently linked rendering TGF1 inactive during storage in extracellular matrix. At the same time, LAP chain interacts with milieu molecules, LTBP1, LRRC32/GARP and LRRC33/NRROS, that control activation of TGF1 and maintain it in a latent state during storage in extracellular milieus. TGF-beta-1 is released from LAP by integrins. Integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF1. Once activated following release of LAP, TGF1 acts by binding to TGF receptors, which transduce signal. In preferred embodiment, the term TGF1 refers to the activated TGF1.

(103) TGF1 regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. TGF1 plays an important role in bone remodeling. It acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts. It can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner. At high concentrations, TGF1 leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development. At low concentrations in concert with IL-6 and IL-21, TGF1 leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells. TGF1 stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP). TGF1 mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (Hwangbo et al. (2016) Oncogene 35:389-401). It can also induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (Hwangbo et al. (2016) Oncogene 35:389-401). TGF1 is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease.

(104) The term TGF1 is intended to include fragments, variants (e.g., allelic variants), and derivatives thereof. Representative human TGF1 cDNA and human TGF1 protein sequences are well-known in the art and are publicly available from the National Center for Biotechnology Information (NCBI). For example, one human TGF1 isoform is known. The human TGF1 transcript (NM 000660.7) encodes TGF1 proprotein preproprotein (NP_000651.3). Nucleic acid and polypeptide sequences of TGF1 orthologs in organisms other than humans are well known and include, for example, chimpanzee TGF1 (XM_016936045.2 and XP 016791534.1; XM_512687.6 and XP_512687.2; and XM_009435655.3 and XP_009433930.1); dog TGF1 (NM_001003309.1 and NP_001003309.1), cattle TGF1 (NM_001166068.1 and NP_001159540.1), mouse TGF1 (NM_011577.2 and NP_035707.1), and rat TGF1 (NM_021578.2 and NP_067589.1).

(105) The term TGF2 or transforming growth factor-beta 2 refers to a secreted ligand of the TGF superfamily of proteins. As described herein, ligands of this family bind various TGF receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF family members. Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, LAP and TGF2 chains remain non-covalently linked rendering TGF2 inactive during storage in extracellular matrix. At the same time, LAP chain interacts with milieu molecules, such as LTBP1 and LRRC32/GARP, that control activation of TGF2 and maintain it in a latent state during storage in extracellular milieus. Once activated following release of LAP, TGF2 acts by binding to TGF receptors, which transduce signal. In preferred embodiment, the term TGF2 refers to the activated TGF2. Disruption of the TGF/SMAD pathway has been implicated in a variety of human cancers. TGF2 regulates various processes such as angiogenesis and heart development (Boileau et al. (2012) Nat. Genet. 44:916-921, Lindsay et al. (2012) Nat. Genet. 44:922-927). A chromosomal translocation that includes TGF2 gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in TGF2 gene can be associated with Loeys-Dietz syndrome.

(106) The term TGF2 is intended to include fragments, variants (e.g., allelic variants), and derivatives thereof. Representative human TGF2 cDNA and human TGF2 protein sequences are well-known in the art and are publicly available from the National Center for Biotechnology Information (NCBI). For example, two human TGF2 isoforms are known. The TGF2 transcript variant 1 (NM_001135599.3) represents the longest transcript and encodes the longer isoform 1 (NP_001129071.1). The TGF2 transcript variant 2 (NM_003238.5) lacks an in-frame exon in the 5 coding region compared to variant 1. The resulting isoform 2 (NM_003238.5) is shorter than isoform 1. Both isoforms may undergo similar proteolytic processing. Nucleic acid and polypeptide sequences of TGF2 orthologs in organisms other than humans are well known and include, for example, chimpanzee TGF2 (XM_001172158.6 and XP_001172158.1, and XM_514203.7 and XP_514203.2); monkey TGF2 (NM_001266518.1 and NP_001253447.1); dog TGF2 (XM_005640824.2 and XP_005640881.1, XM_545713.6 and XP_545713.2; and XM_853584.5 and XP_858677.1), cattle TGF2 (NM_001113252.1 and NP_001106723.1), mouse TGF2 (NM_001329107.1 and NP_001316036.1; and NM_009367.4 and NP_033393.2), rat TGF2 (NM_031131.1 and NP_112393.1), and chicken TGF2 (NM_001031045.3 and NP_001026216.2).

(107) The term TGF3 or transforming growth factor-beta 3 refers to a secreted ligand of the TGF superfamily of proteins. As described herein, ligands of this family bind various TGF receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF family members. Activation of TGF3 into mature form follows different steps. Following cleavage of the proprotein in the Golgi apparatus, LAP and TGF3 chains remain non-covalently linked rendering TGF3 inactive during storage in extracellular matrix. At the same time, LAP chain interacts with milieu molecules, such as LTBP1 and LRRC32/GARP that control activation of TGF3 and maintain it in a latent state during storage in extracellular milieus. TGF3 is released from LAP by integrins. Integrin-binding results in distortion of the LAP chain and subsequent release of the active TGF-3. Once activated following release of LAP, TGF-3 acts by binding to TGF receptors, which transduce signal. In preferred embodiment, the term TGF3 refers to the activated TGF3.

(108) TGF3 is involved in embryogenesis and cell differentiation, and can play a role in wound healing. TGF3 is required in various processes such as secondary palate development. Mutations in TGF3 gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1.

(109) The term TGF3 is intended to include fragments, variants (e.g., allelic variants), and derivatives thereof. Representative human TGF3 cDNA and human TGF3 protein sequences are well-known in the art and are publicly available from the National Center for Biotechnology Information (NCBI). For example, three human TGF3 isoforms are known. The TGF3 transcript variant 1 (NM_003239.4) represents the longest transcript and encodes the longer isoform 1 (NP_003230.1). The TGF3 transcript variant 2 (NM_001329939.1) differs in the 5 UTR compared to variant 1, and encodes the same isoform (NP_001316868.1) as that of variant 1. The TGF3 transcript variant 3 (NM_001329938.2) lacks several exons and its 3 terminal exon extends past a splice site that is used in variant 1. This results in an early stop codon and a novel 3 UTR compared to variant 1. The encoded isoform 2 (NP_001316867.1) has a shorter C-terminus than isoform 1. Nucleic acid and polypeptide sequences of TGF3 orthologs in organisms other than humans are well known and include, for example, chimpanzee TGF3 (XM_016926465.2 and XP_016781954.1, XM_016926464.2 and XP_016781953.1, XM_001161669.5 and XP_001161669.1, and XM_009428178.2 and XP_009426453.1); monkey TGF3 (NM_001257475.1 and NP_001244404.1); dog TGF3 (XM_849026.5 and XP_854119.2), cattle TGF3 (NM_001101183.1 and NP_001094653.1), mouse TGF3 (NM_009368.3 and NP_033394.2), rat TGF3 (NM_013174.2 and NP_037306.1), and chicken TGF3 (NM_205454.1 and NP_990785.1).

(110) The term Smad refers to a family of receptor-activated, signal transducing transcription factors that transmit signals from TGF family receptors. Members of the Smad family of proteins have been identified based on homology to the Drosophila gene Mothers against dpp (mad), which encodes an essential element in the Drosophila dpp signal transduction pathway (Sekelsky et al. (1995) Genetics 139:1347-1358, Newfeld et al. (1996) Development 122:2099-2108). Smad proteins are generally characterized by highly conserved amino- and carboxy-terminal domains separated by a proline-rich linker. The amino terminal domain (the MH1 domain) mediates DNA binding, and the carboxy terminal domain (the MH2 domain) associates with the receptor.

(111) At least eight Smad proteins have been identified and shown to participate in signal responses induced by TGF family members (Kretzschmar and Massagu (1998) Current Opinion in Genetics and Development 8:103-111). These Smads can be divided into three subgroups. One group (Smads1, 2, 3, 5 and 9) includes Smads that are direct substrates of a TGF family receptor kinase. Another group (Smad 4) includes Smads that are not direct receptor substrates, but participate in signaling by associating with receptor-activated Smads. The third group of Smads (Smad6 and Smad7) consists of proteins that inhibit activation of Smads in the first two groups.

(112) Smads have specific roles in pathways of different TGF family members. Among Smad proteins identified for TGF family members, Smad2 and Smad3 are specific for TGF signaling (Heldin et al. (1997) Nature 390:465-471). The activated Smad2 and Smad3 interact with common mediator Smad4 and translocate into nuclei, where they activate a set of specific genes (Heldin et al. (1997) Nature 390:465-471). The TGF pathway uses the signal inhibitory proteins Smad6 and Smad7 to balance the net output of the signaling, as well as direct activation of Smad2 and/or Smad3.

(113) While Smad2 and Smad3 have intrinsic transactivation activity as transcription factors (Zawel et al. (1998) Mol. Cell. 1:611-617), studies have demonstrated that they activate specific gene expression largely through specifically interacting with other nuclear factors (Derynck et al. (1998) Cell 95:737-740). A specific TGF-mediated effect on a given cell type can be achieved by activating a specific Smad protein, resulting in alterations in expression of specific genes. Smad proteins of particular interest include, for example, Smad2 (Nakao et al (1997) J. Biol. Chem. 272:2896-2900).

(114) The term SMAD2 refers to SMAD family member 2, which belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene mothers against decapentaplegic (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. SMAD2 mediates the signal of TGF, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. SMAD2 is recruited to the TGF receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF signal, SMAD2 is phosphorylated by the TGF receptors. The phosphorylation induces the dissociation of SMAD2 with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of SMAD2 into the nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors (e.g., p63). It binds the TRE element in the promoter region of many genes that are regulated by TGF. SMAD2 can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. SMAD2 can act as a tumor suppressor in colorectal carcinoma. It positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. In one embodiment, the human SMAD2 protein has 467 amino acids and a molecular mass of 52306 Da.

(115) The term SMAD2 is intended to include fragments, variants (e.g., allelic variants), and derivatives thereof. Representative human SMAD2 cDNA and human SMAD2 protein sequences are well-known in the art and are publicly available from the National Center for Biotechnology Information (NCBI). For example, three human SMAD2 isoforms are known. The SMAD2 transcript variant 2 (NM_001003652.4) represents the longest transcript and encodes the longer isoform 1 (NP_001003652.1). The SMAD2 transcript variant 1 (NM_005901.6) uses an alternate exon (1b) in the 5 UTR compared to variant 2, but encodes the same isoform 1 (NP_005892.1). The SMAD2 transcript variant 3 (NM_005901.6) lacks an in-frame exon in the 5 coding region, compared to variant 2, resulting in an isoform 2 (NP_001129409.1) that is shorter than isoform 1. Nucleic acid and polypeptide sequences of SMAD2 orthologs in organisms other than humans are well known and include, for example, chimpanzee SMAD2 (XM_512121.7 and XP_512121.1; XM_001149646.5 and XP_001149646.1; XM_009433959.2 and XP_009432234.1; XM_016933662.1 and XP_016789151.1; XM_016933657.1 and XP_016789146.1, XM_016933659.1 and XP_016789148.1, XM_016933658.1 and XP_016789147.1, XM_009433960.3 and XP_009432235.1, and XM_016933663.1 and XP_016789152.1); monkey SMAD2 (NM_001266803.1 and NP_001253732.1); dog SMAD2 (XM_005622832.3 and XP_005622889.1, XM_022421406.1 and XP_022277114.1; XM_847706.5 and XP_852799.1; XM_005622830.3 and XP_005622887.1; XM_005622831.3 and XP_005622888.1; XM_861095.5 and XP_866188.1; and XM_022421405.1 and XP_022277113.1), cattle SMAD2 (NM_001046218.1 and NP_001039683.1), mouse SMAD2 (NM_001252481.1 and NP_001239410.1; NM_001311070.1 and NP_001297999.1; and NM_010754.5 and NP_034884.2), rat SMAD2 (NM_001277450.1 and NP_001264379.1; and NM_019191.2 and NP_062064.1), and chicken SMAD2 (NM_204561.1 and NP_989892.1). Representative sequences of SMAD2 orthologs are presented below in Table 1.

(116) Anti-SMAD2 antibodies suitable for detecting SMAD2 protein are well-known in the art and include, for example, antibodies AM06653SU-N and AM31101PU-N(OriGene Technologies, Rockville, MD), AF3797, NB100-56462, NBP2-67376, and NBP2-44217 (antibodies from Novus Biologicals, Littleton, CO), ab40855, ab63576, and ab202445, (antibodies from AbCam, Cambridge, MA), etc. In addition, reagents are well-known for detecting SMAD2 expression. Moreover, multiple siRNA, shRNA, CRISPR constructs for reducing SMAD2 Expression can be found in the commercial product lists of the above-referenced companies, such as siRNA products #sc-38374 and #sc-44338 and CRISPR product #sc-400475 from Santa Cruz Biotechnology, RNAi products SR320897, TG309255, TR309255, and TL309255, and CRISPR products KN404604 and KN516271 (Origene), and multiple CRISPR products from GenScript (Piscataway, NJ). It is to be noted that the term can further be used to refer to any combination of features described herein regarding SMAD2 molecules. For example, any combination of sequence composition, percentage identify, sequence length, domain structure, functional activity, etc. can be used to describe an SMAD2 molecule encompassed by the present invention.

(117) The term p63 or TP63 refers to a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of p63 gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in p63 gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. P63 acts as a sequence specific DNA binding transcriptional activator or repressor. The isoforms contain a varying set of transactivation and auto-regulating transactivation inhibiting domains thus showing an isoform specific activity. Isoform 2 activates RIPK4 transcription. P63 can be required in conjunction with TP73/p73 for initiation of p53/TP53 dependent apoptosis in response to genotoxic insults and the presence of activated oncogenes. It is involved in Notch signaling by probably inducing JAG1 and JAG2. P63 plays a role in the regulation of epithelial morphogenesis. The ratio of DeltaN-type and TA*-type isoforms can govern the maintenance of epithelial stem cell compartments and regulate the initiation of epithelial stratification from the undifferentiated embryonal ectoderm. P63 is required for limb formation from the apical ectodermal ridge. P63 activates transcription of the p21 promoter. In one embodiment, the human P63 protein has 680 amino acids and a molecular mass of 76785 Da.

(118) The term p63 or TP63 is intended to include fragments, variants (e.g., allelic variants), and derivatives thereof. Representative human p63 cDNA and human p63 protein sequences are well-known in the art and are publicly available from the National Center for Biotechnology Information (NCBI). For example, 13 human XBP1 isoforms are known. The p63 transcript variant 1 (NM_003722.5) represents the longest transcript and encodes the longest isoform, p63 isoform 1 (NP_003713.3). The p63 transcript variant 2 (NM_001114978.2) lacks an exon in the 3 coding region that results in a frameshift, compared to variant 1. The resulting isoform (2, also known as TAp63beta and TA-beta; NP_001108450.1) is shorter and has a distinct C-terminus, compared to isoform 1. The p63 transcript variant 3 (NM_001114979.2) differs in the 3 UTR and coding region, compared to variant 1. The resulting isoform (3, also known as TAp63gamma, TA-gamma, and p51A; NP_001108451.1) is shorter and has a distinct C-terminus, compared to isoform 1. The p63 transcript variant 4 (NM_001114980.2) differs in the 5 UTR and coding region, compared to variant 1. The resulting isoform (4, also known as deltaNp63alpha, deltaN-alpha, P51delNalpha, CUSP, and p73H; NP_001108452.1) is shorter and has a distinct N-terminus, compared to isoform 1. The p63 transcript variant 5 (NM_001114981.2) differs in the 5 UTR and coding region, and also lacks an exon in the 3 coding region that results in a frameshift, compared to variant 1. The resulting isoform (5, also known as deltaNp63beta, P51delNbeta, and deltaN-beta; NP_001108453.1) is shorter and has distinct N- and C-termini, compared to isoform 1. The p63 transcript variant 6 (NM_001114982.2) differs in the 5 UTR and coding region, and in the 3 UTR and coding region, compared to variant 1. The resulting isoform (6, also known as deltaNp63gamma, P51delNgamma, and deltaN-gamma; NP_001108454.1) is shorter and has distinct N- and C-termini, compared to isoform 1. The p63 transcript variant 7 (NM_001329144.2) lacks two exons in the 3 coding region, which leads to a frameshift compared to variant 1. The encoded isoform (7, also known as TAp63delta, TA-delta, and P51delta; NP_001316073.1) has a shorter and distinct C-terminus, compared to isoform 1. The p63 transcript variant 8 (NM_001329145.2) has multiple differences compared to variant 1. These differences result in the use of an alternate start codon and introduce a frameshift in the 3 coding region. The encoded isoform (8, also known as deltaN-delta; NP_001316074.1) has shorter and distinct N- and C-termini, compared to isoform 1. The p63 transcript variant 9 (NM_001329146.2) lacks several 5 exons, and uses an alternate start codon, compared to variant 1. The encoded isoform (9, also known as deltaNp73L; NP_001316075.1) has a shorter and distinct N-terminus, compared to isoform 1. The p63 transcript variant 10 (NM_001329148.2) uses an alternate in-frame splice site in the central coding region, compared to variant 1. The encoded isoform (10, also known as p63-delta; NP_001316077.1) is shorter than isoform 1. The p63 transcript variant 11 (NM_001329149.2) has multiple differences compared to variant 1. These differences result in the use of an alternate start codon and introduce a frameshift in the 3 coding region. The encoded isoform (11) (NP_001316078.1) is shorter and has distinct N- and C-termini, compared to isoform 1. The p63 transcript variant 12 (NM_001329150.2) has multiple differences compared to variant 1. These differences result in the use of an alternate start codon and introduce a frameshift in the 3 coding region. The encoded isoform (12) (NP_001316079.1) is shorter and has distinct N- and C-termini, compared to isoform 1. The p63 transcript variant 13 (NM_001329964.1) represents use of an alternate promoter and therefore differs in the 5 UTR and 5 coding region, compared to variant 1. The promoter and 5 terminal exon sequence is from an endogenous retroviral LTR (PMID: 21994760). The resulting isoform (13, also known as GTAp63; NP_001316893.1) is shorter and has a distinct N-terminus, compared to isoform 1. The encoded protein is expressed predominantly in testicular germ cells and eliminates germ cells that have suffered DNA damage. Nucleic acid and polypeptide sequences of p63 orthologs in organisms other than humans are well known and include, for example, chimpanzee p63 (XM_009447014.3 and XP_009445289.1; XM_001160376.5 and XP_001160376.1; XM_009447013.3 and XP_009445288.1; XM_003310173.3 and XP_003310221.1; XM_001160425.5 and XP_001160425.1; X1\4016942495.2 and XP_016797984.1; and XM_001160182.3 and XP_001160182.1); monkey p63 (XM_028843565.1 and XP_028699398.1; XM_015132502.2 and XP_014987988.1; XM_015132501.2 and XP_014987987.1; XM_001092093.3 and XP_001092093.1; XM_028843566.1 and XP_028699399.1; XM_028843567.1 and XP_028699400.1; XM_001091977.4 and XP_001091977.3; XM_015132503.2 and XP_014987989.1; and XM_015132504.2 and XP_014987990.2); dog p63 (XM_022414176.1 and XP_022269884.1; XM_005639826.3 and XP_005639883.1; XM_856247.5 and XP_861340.3; XM_005639828.3 and XP_005639885.1; XM_005639827.2 and XP_005639884.1; XM_856275.3 and XP_861368.1; and XM_022414177.1 and XP_022269885.1), cattle p63 (NM_001191337.1 and NP_001178266.1), mouse p63 (NM_001127259.1 and NP_001120731.1; NM_001127260.1 and NP_001120732.1; NM_001127261.1 and NP_001120733.1; NM_001127262.1 and NP_001120734.1; NM_001127263.1 and NP_001120735.1; NM_001127264.1 and NP_001120736.1; NM_001127265.1 and NP_001120737.1; and NM_011641.2 and NP_035771.1), rat p63 (NM_001127339.1 and NP_001120811.1; NM_001127341.1 and NP_001120813.1; NM_001127342.1 and NP_001120814.1; NM_001127343.1 and NP_001120815.1; NM_001127344.1 and NP_001120816.1; and NM_019221.3 and NP_062094.1), and chicken p63 (NM_204351.1 and NP_989682.1). Representative sequences of p63 orthologs are presented below in Table 1.

(119) Anti-p63 antibodies suitable for detecting p63 protein are well-known in the art and include, for example, antibodies TA323790 and CF811064 (OriGene Technologies, Rockville, MD), AF1916 (antibody from Novus Biologicals, Littleton, CO), ab124762, ab53039, and ab735, ab97865 (antibodies from AbCam, Cambridge, MA), etc. In addition, reagents are well-known for detecting p63 expression. Moreover, multiple siRNA, shRNA, CRISPR constructs for reducing p63 Expression can be found in the commercial product lists of the above-referenced companies, such as siRNA products #sc-36620 and #sc-36621 from Santa Cruz Biotechnology, RNAi products TR308688, TG308688, TL308688, and SR322466, and CRISPR products KN208013 and KN208013BN (Origene), and multiple CRISPR products from GenScript (Piscataway, NJ). It is to be noted that the term can further be used to refer to any combination of features described herein regarding p63 molecules. For example, any combination of sequence composition, percentage identify, sequence length, domain structure, functional activity, etc. can be used to describe an p63 molecule encompassed by the present invention.

(120) The term TP53 refers to Tumor Protein P53, a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. TP53 mutations are universal across cancer types. The loss of a tumor suppressor is most often through large deleterious events, such as frameshift mutations, or premature stop codons. In TP53 however, many of the observed mutations in cancer are found to be single nucleotide missense variants. These variants are broadly distributed throughout the gene, but with the majority localizing in the DNA binding domain. There is no single hotspot in the DNA binding domain, but a majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546). While a large proportion of cancer genomics research is focused on somatic variants, TP53 is also of note in the germline. Germline TP53 mutations are the hallmark of Li-Fraumeni syndrome, and many (both germline and somatic) variants have been found to have a prognostic impact on patient outcomes. TP53 acts as a tumor suppressor in many tumor types by inducing growth arrest or apoptosis depending on the physiological circumstances and cell type. TP53 is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF, TP53 is involved in activating oxidative stress-induced necrosis, and the function is largely independent of transcription. TP53 induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. TP53 is implicated in Notch signaling cross-over. TP53 prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 of TP53 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 of TP53 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 of TP53 inhibits isoform 1-mediated apoptosis. TP53 regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (Miki et al., (2013) Nat Commun 4:2444). In some embodiments, human TP53 protein has 393 amino acids and a molecular mass of 43653 Da. The known binding partners of TP53 include, e.g., AXIN1, ING4, YWHAZ, HIPK1, HIPK2, WWOX, GRK5, ANKRD2, RFFL, RNF 34, and TP53INP1.

(121) The term TP53 is intended to include fragments, variants (e.g., allelic variants), and derivatives thereof. Representative human TP53 cDNA and human TP53 protein sequences are well-known in the art and are publicly available from the National Center for Biotechnology Information (NCBI). For example, at least 12 different human TP53 isoforms are known. Human TP53 isoform a (NP_000537.3, NP_001119584.1) is encodable by the transcript variant 1 (NM_000546.5) and the transcript variant 2 (NM_001126112.2). Human TP53 isoform b (NP_001119586.1) is encodable by the transcript variant 3 (NM_001126114.2). Human TP53 isoform c (NP_001119585.1) is encodable by the transcript variant 4 (NM_001126113.2). Human TP53 isoform d (NP_001119587.1) is encodable by the transcript variant 5 (NM_001126115.1). Human TP53 isoform e (NP_001119588.1) is encodable by the transcript variant 6 (NM_001126116.1). Human TP53 isoform f (NP_001119589.1) is encodable by the transcript variant 7 (NM_001126117.1). Human TP53 isoform g (NP_001119590.1, NP_001263689.1, and NP_001263690.1) is encodable by the transcript variant 8 (NM_001126118.1), the transcript variant 1 (NM_001276760.1), and the transcript variant 2 (NM_001276761.1). Human TP53 isoform h (NP_001263624.1) is encodable by the transcript variant 4 (NM_001276695.1). Human TP53 isoform i (NP_001263625.1) is encodable by the transcript variant 3 (NM_001276696.1). Human TP53 isoform j (NP_001263626.1) is encodable by the transcript variant 5 (NM_001276697.1). Human TP53 isoform k (NP_001263627.1) is encodable by the transcript variant 6 (NM_001276698.1). Human TP53 isoform 1 (NP_001263628.1) is encodable by the transcript variant 7 (NM_001276699.1). Nucleic acid and polypeptide sequences of TP53 orthologs in organisms other than humans are well known and include, for example, chimpanzee TP53 (XM_001172077.5 and XP_001172077.2, and XM_016931470.2 and XP_016786959.2), monkey TP53 (NM_001047151.2 and NP_001040616.1), dog TP53 (NM_001003210.1 and NP_001003210.1), cattle TP53 (NM_174201.2 and NP_776626.1), mouse TP53 (NM_001127233.1 and NP_001120705.1, and NM_011640.3 and NP_035770.2), rat TP53 (NM_030989.3 and NP_112251.2), tropical clawed frog TP53 (NM_001001903.1 and NP_001001903.1), and zebrafish TP53 (NM_001271820.1 and NP_001258749.1, NM_001328587.1 and NP_001315516.1, NM_001328588.1 and NP_001315517.1, and NM_131327.2 and NP_571402.1). Representative sequences of TP53 orthologs are presented below in Table 1.

(122) Anti-TP53 antibodies suitable for detecting TP53 protein are well-known in the art and include, for example, antibodies TA502925 and CF502924 (Origene), antibodies NB200-103 and NB200-171 (Novus Biologicals, Littleton, CO), antibodies ab26 and ab1101 (AbCam, Cambridge, MA), antibody 700439 (ThermoFisher Scientific), antibody 33-856 (ProSci), etc. In addition, reagents are well-known for detecting TP53. Multiple clinical tests of TP53 are available in NIH Genetic Testing Registry (GTR) (e.g., GTR Test ID: GTR000517320.2, offered by Fulgent Clinical Diagnostics Lab (Temple City, CA)). Moreover, multiple siRNA, shRNA, CRISPR constructs for reducing TP53 expression can be found in the commercial product lists of the above-referenced companies, such as siRNA products #sc-29435 and sc-44218, and CRISPR product #sc-416469 from Santa Cruz Biotechnology, RNAi products SR322075 and TL320558V, and CRISPR product KN200003 (Origene), and multiple CRISPR products from GenScript (Piscataway, NJ). Chemical inhibitors of TP53 are also available, including, e.g., Cyclic Pifithrin- hydrobromide, RITA (TOCRIS, MN). It is to be noted that the term can further be used to refer to any combination of features described herein regarding TP53 molecules. For example, any combination of sequence composition, percentage identify, sequence length, domain structure, functional activity, etc. can be used to describe a TP53 molecule encompassed by the present invention.

(123) There is a known and definite correspondence between the amino acid sequence of a particular protein and the nucleotide sequences that can code for the protein, as defined by the genetic code (shown below). Likewise, there is a known and definite correspondence between the nucleotide sequence of a particular nucleic acid and the amino acid sequence encoded by that nucleic acid, as defined by the genetic code.

(124) TABLE-US-00001 GENETIC CODE Alanine (Ala, A) GCA, GCC, GCG, GCT Arginine (Arg, R) AGA, ACG, CGA, CGC, CGG, CGT Asparagine (Asn, N) AAC, AAT Aspartic acid (Asp, D) GAC, GAT Cysteine (Cys, C) TGC, TGT Glutamic acid (Glu, E) GAA, GAG Glutamine (Gln, Q) CAA, CAG Glycine (Gly, G) GGA, GGC, GGG, GGT Histidine (His, H) CAC, CAT Isoleucine (Ile, I) ATA, ATC, ATT Leucine (Leu, L) CTA, CTC, CTG, CTT, TTA, TTG Lysine (Lys, K) AAA, AAG Methionine (Met, M) ATG Phenylalanine (Phe, F) TTC, TTT Proline (Pro, P) CCA, CCC, CCG, CCT Serine (Ser, S) AGC, AGT, TCA, TCC, TCG, TCT Threonine (Thr, T) ACA, ACC, ACG, ACT Tryptophan (Trp, W) TGG Tyrosine (Tyr, Y) TAC, TAT Valine (Val, V) GTA, GTC, GTG, GTT Termination signal (end) TAA, TAG, TGA

(125) An important and well-known feature of the genetic code is its redundancy, whereby, for most of the amino acids used to make proteins, more than one coding nucleotide triplet may be employed (illustrated above). Therefore, a number of different nucleotide sequences may code for a given amino acid sequence. Such nucleotide sequences are considered functionally equivalent since they result in the production of the same amino acid sequence in all organisms (although certain organisms may translate some sequences more efficiently than they do others). Moreover, occasionally, a methylated variant of a purine or pyrimidine may be found in a given nucleotide sequence. Such methylations do not affect the coding relationship between the trinucleotide codon and the corresponding amino acid.

(126) In view of the foregoing, the nucleotide sequence of a DNA or RNA encoding a biomarker nucleic acid (or any portion thereof) can be used to derive the polypeptide amino acid sequence, using the genetic code to translate the DNA or RNA into an amino acid sequence. Likewise, for polypeptide amino acid sequences, corresponding nucleotide sequences that can encode the polypeptide can be deduced from the genetic code (which, because of its redundancy, will produce multiple nucleic acid sequences for any given amino acid sequence). Thus, description and/or disclosure herein of a nucleotide sequence which encodes a polypeptide should be considered to also include description and/or disclosure of the amino acid sequence encoded by the nucleotide sequence. Similarly, description and/or disclosure of a polypeptide amino acid sequence herein should be considered to also include description and/or disclosure of all possible nucleotide sequences that can encode the amino acid sequence.

(127) Finally, nucleic acid and amino acid sequence information for the loci and biomarkers encompassed by the present invention and related biomarkers (e.g., biomarkers listed in Tables 1 and 2) are well known in the art and readily available on publicly available databases, such as the National Center for Biotechnology Information (NCBI). For example, exemplary nucleic acid and amino acid sequences derived from publicly available sequence databases are provided below.

(128) TABLE-US-00002 TABLE1 Smad1 Smad2 Smad3 Smad4 Smad5 Smad9 P53 P63 P73 SEQIDNO:1HumanSmad2transcriptvariant2mRNASequence NM_001003652.4;CDS:127-1530) 1 aggcgggtctacccgcgcggccgcggcggcggagaagcagctcgccagccagcagcccgc 61 cagccgccgggaggttcgatacaagaggctgttttcctagcgtggcttgctgcctttggt 121 aagaacatgtcgtccatcttgccattcacgccgccagttgtgaagagactgctgggatgg 181 aagaagtcagctggtgggtctggaggagcaggcggaggagagcagaatgggcaggaagaa 241 aagtggtgtgagaaagcagtgaaaagtctggtgaagaagctaaagaaaacaggacgatta 301 gatgagcttgagaaagccatcaccactcaaaactgtaatactaaatgtgttaccatacca 361 agcacttgctctgaaatttggggactgagtacaccaaatacgatagatcagtgggataca 421 acaggcctttacagcttctctgaacaaaccaggtctcttgatggtcgtctccaggtatcc 481 catcgaaaaggattgccacatgttatatattgccgattatggcgctggcctgatcttcac 541 agtcatcatgaactcaaggcaattgaaaactgcgaatatgcttttaatcttaaaaaggat 601 gaagtatgtgtaaacccttaccactatcagagagttgagacaccagttttgcctccagta 661 ttagtgccccgacacaccgagatcctaacagaacttccgcctctggatgactatactcac 721 tccattccagaaaacactaacttcccagcaggaattgagccacagagtaattatattcca 781 gaaacgccacctcctggatatatcagtgaagatggagaaacaagtgaccaacagttgaat 841 caaagtatggacacaggctctccagcagaactatctcctactactctttcccctgttaat 901 catagcttggatttacagccagttacttactcagaacctgcattttggtgttcgatagca 961 tattatgaattaaatcagagggttggagaaaccttccatgcatcacagccctcactcact 1021 gtagatggctttacagacccatcaaattcagagaggttctgcttaggtttactctccaat 1081 gttaaccgaaatgccacggtagaaatgacaagaaggcatataggaagaggagtgcgctta 1141 tactacataggtggggaagtttttgctgagtgcctaagtgatagtgcaatctttgtgcag 1201 agccccaattgtaatcagagatatggctggcaccctgcaacagtgtgtaaaattccacca 1261 ggctgtaatctgaagatcttcaacaaccaggaatttgctgctcttctggctcagtctgtt 1321 aatcagggttttgaagccgtctatcagctaactagaatgtgcaccataagaatgagtttt 1381 gtgaaagggtggggagcagaataccgaaggcagacggtaacaagtactccttgctggatt 1441 gaacttcatctgaatggacctctacagtggttggacaaagtattaactcagatgggatcc 1501 ccttcagtgcgttgctcaagcatgtcataaagcttcaccaatcaagtcccatgaaaagac 1561 ttaatgtaacaactcttctgtcatagcattgtgtgtggtccctatggactgtttactatc 1621 caaaagttcaagagagaaaacagcacttgaggtctcatcaattaaagcaccttgtggaat 1681 ctgtttcctatatttgaatattagatgggaaaattagtgtctagaaatactctcccatta 1741 aagaggaagagaagattttaaagacttaatgatgtcttattgggcataaaactgagtgtc 1801 ccaaaggtttattaataacagtagtagttatgtgtacaggtaatgtatcatgatccagta 1861 tcacagtattgtgctgtttatatacatttttagtttgcatagatgaggtgtgtgtgtgcg 1921 ctgcttcttgatctaggcaaacctttataaagttgcagtacctaatctgttattcccact 1981 tctctgttatttttgtgtgtcttttttaatatataatatatatcaagattttcaaattat 2041 ttagaagcagattttcctgtagaaaaactaatttttctgccttttaccaaaaataaactc 2101 ttgggggaagaaaagtggattaacttttgaaatccttgaccttaatgtgttcagtggggc 2161 ttaaacagtcattctttttgtggttttttgtttttttttgtttttttttttaactgctaa 2221 atcttattataaggaaaccatactgaaaacctttccaagcctcttttttccattcccatt 2281 tttgtcctcataatcaaaacagcataacatgacatcatcaccagtaatagttgcattgat 2341 actgctggcaccagttaattctgggatacagtaagaattcatatggagaaagtccctttg 2401 tcttatgcccaaatttcaacaggaataattggcttgtataatctagcagtctgttgattt 2461 atccttccacctcataaaaaatgcataggtggcagtataattattttcagggatatgcta 2521 gaattacttccacatatttatccctttttaaaaaagctaatctataaataccgtttttcc 2581 aaaggtattttacaatatttcaacagcagaccttctgctcttcgagtagtttgatttggt 2641 ttagtaaccagattgcattatgaaatgggccttttgtaaatgtaattgtttctgcaaaat 2701 acctagaaaagtgatgctgaggtaggatcagcagatatgggccatctgtttttaaagtat 2761 gttgtattcagtttataaattgattgttattctacacataattatgaattcagaatttta 2821 aaaattgggggaaaagccatttatttagcaagttttttagcttataagttacctgcagtc 2881 tgagctgttcttaactgatcctggttttgtgattgacaatatttcatgctctgtagtgag 2941 aggagatttccgaaactctgttgctagttcattctgcagcaaataattattatgtctgat 3001 gttgactcattgcagtttaaacatttcttcttgtttgcatcttagtagaaatggaaaata 3061 accactcctggtcgtcttttcataaattttcatatttttgaagctgtctttggtacttgt 3121 tctttgaaatcatatccacctgtctctataggtatcattttcaatactttcaacatttgg 3181 tggttttctattgggtactccccattttcctatatttgtgtgtatatgtatgtgttcatg 3241 taaatttggtatagtaattttttattcattcaacaaatatttattgttcacctgtttgta 3301 ccaggaacttttcttagtctttgggtaaaggtgaacaagacaactacagttcctgccttt 3361 gctgagacagcagttacactaacccttaattatcttacttgtctatgaaggagataaaca 3421 gggtactgtactggagaataacagatgggatgcttcaggtaggacatcaaggaaagcctc 3481 taaggaaaggatgcatgagctaacacctgacattaaagaagcaagccaagtgaggagcca 3541 ggggagataagcattcctggcaaagagaatagcatcaaatgcaaaaaggttcacactaaa 3601 ggaaactcctgattaggtattaatgctttatacagaaacctctatacaaatccaaacttg 3661 aagatcagaatggttctacagttcataacattttgaaggtggccttattttgtgatagtc 3721 tgcttcatgtgattctcactaacatatctccttcctcaacctttgctgtaaaaatttcat 3781 ttgcaccacatcagtactacttaatttaacaagcttttgttgtgtaagctctcactgttt 3841 tagtgccctgctgcttgcttccagactttgtgctgtccagtaattatgtcttccactacc 3901 catcttgtgagcagagtaaatgtcctaggtaataccactatcaggcctgtaggagatact 3961 cagtggagcctctgcccttctttttcttacttgagaacttgtaatggtgttagggaacag 4021 ttgtaggggcagaaaacaactctgaaagtggtagaaggtcctgatcttggtggttactct 4081 tgcattactgtgttaggtcaagcagtgcctactatgctgtttcagtagtggagcgcatct 4141 ctacagttctgatgcgatttttctgtacagtatgaaattgggactcaactctttgaaaac 4201 acctattgagcagttatacctgttgagcagtttacttcctggttgtaattacatttgtgt 4261 gaatgtgtttgatgctttttaacgagatgatgttttttgtattttatctactgtggcctg 4321 attttttttttgttttctgcccctccccccatttataggtgtggttttcatttttctaag 4381 tgatagaatcccctctttgttgaatttttgtctttatttaaattagcaacattacttagg 4441 atttattcttcacaatactgttaattttctaggaatgatgacctgagaaccgaatggcca 4501 tgctttctatcacatttctaagatgagtaatattttttccagtaggttccacagagacac 4561 cttgggggctggcttaggggaggctgttggagttctcactgacttagtggcatatttatt 4621 ctgtactgaagaactgcatggggtttcttttggaaagagtttcattgctttaaaaagaag 4681 ctcagaaagtctttataaccactggtcaacgattagaaaaatataactggatttaggcct 4741 accttctggaataccgctgattgtgctctttttatcctactttaaagaagctttcatgat 4801 tagatttgagctatatcagttataccgattataccttataatacacattcagttagtaaa 4861 catttattgatgcctgttgtttgcccagccactgtgatggatattgaataataaaaagat 4921 gactaggacggggccctgacccttgagctgtgcttggtcttgtagaggttgtgttttttt 4981 tcctcaggacctgtcactttggcagaaggaaatctgcctaatttttcttgaaagctaaat 5041 tttctttgtaagtttttacaaattgtttaatacctagttgtattttttaccttaagccac 5101 attgagttttgcttgatttgtctgtcttttaaacactgtcaaatgctttcccttttgtta 5161 aaattattttaatttcactttttttgtgcccttgtcaatttaagactaagactttgaagg 5221 taaaacaaacaaacaaacatcagtcttagtctcttgctagttgaaatcaaataaaagaaa 5281 atatatacccagttggtttctctacctcttaaaagcttcccatatatacctttaagatcc 5341 ttctcttttttctttaactactaaataggttcagcatttattcagtgttagataccctct 5401 tcgtctgagggtggcgtaggtttatgttgggatataaagtaacacaagacaatcttcact 5461 gtacataaaatatgtcttcatgtacagtctttactttaaaagctgaacattccaatttgc 5521 gccttccctcccaagcccctgcccaccaagtatctctttagatatctagtctgtggacat 5581 gaacaatgaatacttttttcttactctgatcgaaggcattgatacttagacatatcaaac 5641 atttcttcctttcatatgctttactttgctaaatctattatattcattgcctgaatttta 5701 ttcttcctttctacctgacaacacacatccaggtggtacttgctggttatcctctttctt 5761 gttagccttgttttttgttttttttttttttttttgagagggagtctcgctctgttgccc 5821 aacctggagtgcagtggtgcgatcttggttcactgcaagctccgcctcccgggttcacgc 5881 catgcttctgcctcagcctcccaagtagctgggactacaggcgcccaccaccacactcgg 5941 ctaattttttgtatttttagtagagacggggtttcaccgtgttggccaggatggtctcga 6001 tctcctgacctcgtgatctgtccacctcggcttcccaaagtgctgggattacaggcatga 6061 gccaccgcgcccagcctagccatatttttatctgcatatatcagaatgtttctctccttt 6121 gaacttattaacaaaaaaggaacatgcttttcatacctagagtcctaatttcttcatcat 6181 gaaggttgctattcaaattgatcaatcattttaattttacaaatggctcaaaaattctgt 6241 tcagtaaatgtctttgtgactggcaaatggcataaattatgtttaagattatgaactttt 6301 ctgacagttgcagccaatgttttccctacgataccagatttccatcttggggcatattgg 6361 attgttgtatttaagacagtcagaataatgatagtgtgtggtctccagaggtagtcagaa 6421 tcctgctattgagttctttttatatcttccttttcaattttttattaccattttgtttgt 6481 ttagactacactttgtagggattgaggggcaaattatctcttggagtggaattcctgtgt 6541 tttgagccttacaaccaggaaatatgagctatactagatagcctcatgatagcatttacg 6601 ataagaacttatctcgtgtgttcatgtaattttttgagtaggaactgttttatcttgaat 6661 attgtagctaactatatatagcagaactgcctcagtctttttaagaaggaaataaataat 6721 atatgtgtatgaatttatatatacatatacactcatagacaaacttaacagttggggtca 6781 ttctaacagttaaaacaattgttccattgtttaaatctcagatcctggtaaaatgttctt 6841 aatttgtctgtgtacattttcctttcatggacagaccattggagtacattaattttctta 6901 atctgccatttggcagttcatttaatataccattttttggcaacttggtaactaagaatc 6961 acagccaaaatttgttaacatcaaagaaagctctgccatataccccgttactaaattatt 7021 atacatccagcagattctgggatgtactaacttagggttaactttgttgttgttgataat 7081 actagattgctccctctttaattcttcttctggtgcaaggttgctgcttaagttaccctg 7141 ggaaatactactacaaggtcaaattttctagtatcttacagcctgattgaaggtgattca 7201 gatctttgctcaatataaatggattttccaagattctctgggccatccttgacccacagg 7261 tgatctcgctggagtatattaacttaacttcagtgccagttggtttggtgccatgagatc 7321 cataatgaatccagaacttcaccattgcttagatataagagtcccttggaagaataatgc 7381 cactgatgatgggggtcagaaggtgtattaactcaacatagagggcttttagatttttct 7441 tcaaaaaaatttcgagaaaagtattcttttaccctccaaacagttaacagctcttagttt 7501 ctccaaatatgctctttgatttacttatttttaattaaagatggtaatttattgaacaat 7561 gaaatccgtaatatattgatttaaggacaaaagtgaagttttagaattataaaagtactt 7621 aaatattatatattttccatttcataattgttttcctttctctgtggctttaaagttttt 7681 gactattttacaatgttaatcactaggtaacttgccatatttctggttctatattaagtt 7741 ctatcctttataatgctgttattataaagctggtttttagcatttgtctgtagcaataga 7801 aattttactaagtctctgttctcccagtaagttttttcttttctcagtaagtccctaaga 7861 aaacatttgtttgccactcttactattcccaatcttggattgttcgagctgaaaaaaaat 7921 ttgatgagaaacaggaggatccttttctggtgaatataggttcctgctttaagaatgtgg 7981 aaatccattgctttatataactaatatacacacagattaattaaaattgtgagaaataat 8041 tcacacatgacaagtaggtaacatgcatgagttttgaatttttttaaaaacccaactgtt 8101 tgacaaaatatagaacccaaattggtactttcttagaccagtgtaacctcacacctcagt 8161 tttgcttttccaaccctgacttgaaaggcatatttgtatctttttattagtgatagtgaa 8221 gctgtgacactaaccttttatacaaaagagtaaagaaagaaaaactacagcgattaagat 8281 gagaacagttctgcagttgttgaactagatcacagcattgtaggcagaataaaaaatgtt 8341 catatctgagaatattcctttcgccatcttttcccaaggccagacctcctggtggagcac 8401 agttaaaagtaacattctgggcctttgtaatcggagggctgtgtctccagctggcagcct 8461 ttgttttaatatataatgcaggactgtggaaaacagttggcatagaatattttcacctaa 8521 aaaagaaagaaaagacatacaaaactggattaattgcaaaaagagaatacagtaaaatac 8581 catataactggacaaagctagaagaacctttagaagatttgtctgaaaacagatttcaag 8641 agtgagcttttatacactgctcactaatttgcttgattactaccaactcttcttaaagtt 8701 aacacgtttaaggtatttctggacttcctagccttttagcaagcttagaggaactagcca 8761 ttagctagtgatgtaaaaatattttggggactgatgcccttaaaggttatgcccttgaaa 8821 gttcttaccttttctctagtgatattaaggaacgagtgggtagtgttctcagggtgacca 8881 gctgccctaaagtgcctgggattgagggtttccctggatgcgggactttccctggataca 8941 aaacttttagcagagttttgtatatatgtggatttttctgataagtagcacatcagaggc 9001 cttaaccactgcccaaaagcgattctccattgagagtacatatcttgaacttaagaaatt 9061 catttgctctgatttttaatcttgtaaagtttttgctaaactcaaaacaagtcccaggca 9121 caccagaaggagctgaccaccttaggtgttcttgtgatttatccttacttccctatgttg 9181 tcatagttgcttctaaactcagctgcactatggctgtcaacatttctgatacttattggg 9241 atatgtgccatccagtcatttagtactttgaatggaacatgagatttataacacaggtaa 9301 tagctgaaggtaccagtatggtggtgagactcacacttagtgatccagctaaggtaactg 9361 atgttataatggaacagagaagaggccaactagatagctaagttcttctgaacctatgtg 9421 tatatgtaagtacaaatcatgcgtccttatggggttaaacttaatctgaaatttacattt 9481 ttcatagtaaaaggaaaccaattgttgcagatttcttttcttgtgaggaaatacatggcc 9541 tttgatgctctggcgtctactgcatttcccagtctgttctgctcgagaagccagaatgtg 9601 ttgttaacatttttccgtgaatgttgtgttaaaatgattaaatgcatcagccaatggcaa 9661 gtgaaggaattgggtgtcctgatgcagactgagcagtttctctcaattgtagcctcatac 9721 tcataaggtgcttaccagctagaacattgagcacgtgaggtgagattttttttctctgat 9781 ggcattaactttgtaatgcaatatgatggatgcagaccctgttcttgtttccctctggaa 9841 gtccttagtggctgcatccttggtgcactgtgatggagatattaaatgtgttctttgtga 9901 gctttcgttctatgattgtcaaaagtacgatgtggttccttttttatttttattaaacaa 9961 tgagctgaggctttattacagctggttttcaagttaaaattgttgaatactgatgtcttt 10021 ctcccacctacaccaaatattttagtctatttaaagtacaaaaaaagttctgcttaagaa 10081 aacattgcttacatgtcctgtgatttctggtcaatttttatatatatttgtgtgcatcat 10141 ctgtatgtgctttcactttttaccttgtttgctcttacctgtgttaacagccctgtcacc 10201 gttgaaaggtggacagttttcctagcattaaaagaaagccatttgagttgtttaccatgt 10261 tactatgggactaatttttaattgttttaatttttatttaaactgatctttttttatatg 10321 ggattacattttggtgttcactccctaaattatatggaaaccaaaaaaagtgattgtatt 10381 tcacatatggacatatgattttaagagtacatgtttttgtttttttaatttggtgttaca 10441 taaaagattatcctatccccccgggagataaatttatactacttaatataaccccacaac 10501 aggcgcacaccacacactgcacagtgctatttatacatttttatttatttcagagtttgc 10561 ctatgctacattagcgctctaatacataagatctatgctgtaaacaaaaacatcttcaaa 10621 gttgaaatttgctgaaatatacttttaacaaaataacatttttaaggctccattgaaaaa 10681 tactagataagatataatctcatataatcagtatgaataattttaaaaatgagaaatatt 10741 taggtcagccacacttcctttgtgccttgcaagaattcagttctgtggatgaatcagtac 10801 tggttagcagactgttttctgcaaaccattttaaacatgctttagtatgcaacaaaaagg 10861 gacctcaaatgctaaaatacactattttacgtggcattgaatagccttgggactggtgta 10921 gttttatcaacacttttttattaggaagaaacccaagaaaatttactgtaattgctacca 10981 cctgccactgtataaataatctaaaagggacttcccaacattgaacaacaacattgaggg 11041 ctgactcgagatccttctacattgtcacctcagcctggctttgcctgtcactgcttagct 11101 tgaagtagtgacactgttctgtatcaggagatttttataatggccctagcatccataatt 11161 ccacatgttcatcaaatggctgaagagtatgagagaagtattaaggtctatgtttgggct 11221 gtctccccacttggcatattctgtttttccctcttcaaaatagattgaaagcctcttagt 11281 gcaggaagcaggcatcagtatcaaactgatgtcatccaatgtaattattttaagctccag 11341 gtttgtctaagtttgggtgaagaatgttcaggaacatgtttgcaacatacagttatccag 11401 cttaccctttgacagattcacccttctcatcaaaatagtaagcccaacctaaaaattata 11461 agtttacaaataaaggaatagaaaaacccaaaaagctaatttacacataaaaattatctt 11521 ttgctgcaataaataggtatggaaatatttgtagaattggtttaactgattttgtaaaac 11581 aaatgtcatgctattttgccatagtgagacatgcagtaattcttaaaatcacattaatag 11641 aaggcaagaacattgaatcagacttagcagataacagattcagtgataaatgaacaatag 11701 actaagcatacttaggaagctacatgagaacagaatgtattactgtgctcccgtccaaac 11761 tgcatgactttattggttatagaataaatggaatttgagatggggatttgccagttttta 11821 cagtctgtcttcaatagttttgttggctgcctctgcacctttctaaatgttatgtgaaaa 11881 taaaattatttaagttctaaagtagtttaggaaagagatgtgatgacaggaaaaagaagt 11941 taacttctgaacagtttggtccaggaagaagatgggcagaatacagtaagcccagggttg 12001 aagaatacattcaatttggagagatggagaagacctttgaagaaggtcaaaatgagatct 12061 tggaacagaactctcacctgtgtgtctggatatacatgaaaactggacggtgttattgag 12121 ctactgcttatatggtgagcagaaaattgataaccacaagcctggtaggttctgctatga 12181 agcccacatataatcacaaggcctagatagcttggagttaaaagccaaggatagctgtat 12241 agtttgggttccatagtttgcagtgagattgtgcttctgagcagtcatttgggggcagtg 12301 gttctgagattacaagccataacccagccaagaacgggctacctgtggaatgaggatgag 12361 gaagttgctacatataaaccctagtgtgtgtgtgtgtattaagtgaaacttagttaactt 12421 ttttgctcacagccaaagatgattcatctagagaagccattggaattttagcagagtttt 12481 gtatatatgtggatttttctaataagtagcaaatcagaggccttaaccactgcccaacag 12541 cgattctccattgagagtacgtatcttgaacttaagaaattcatttgctctgattttaaa 12601 tcttgtaaagtttttcttcatgagaggtcttgcctctaaactatattgtggcagtatttg 12661 atcaaactacataagtaccatgtaaataagattttaatacaaatgatgactcacttctaa 12721 atggtttgccatttagaaatgtgctgctgtgagaaaaacgaatttttttttttttttttt 12781 ggagacagagtcttgctctgttgcccaggctggggtgcagtggggcgatctcggctcact 12841 gcagcctcgcctcctgggttcaagtgattctcctgccttagcctcctgagtagctgggat 12901 tacaggcacacaccaccacgcccaactactttttgtatttttagtggagacagggtttca 12961 ccatgtttgccaggctggtcttgaactcctgacctcagatgatttgcctgcctcggcctc 13021 ccaaagtgctggaattacaggcgtgagccatcatgcctggctgaaaagtgaaaatttaag 13081 ccagcttaccacctggaataaaaatgttttataggaatgtctaggttgctcttttatatt 13141 gaaaaaaaacttattagtgtctgttttacccaagaaccacaagctacttcatttcaactt 13201 ttaaatcatgaataataacgtgttatcaccacatttaaaaatgtacatcgtcaatcacaa 13261 acacatattctaaggaattgaattttatagagataattgaatgctttcatctgtaaaaga 13321 attagtggcctgcaaaccactgtggattcttgctatgctttgaagttgtcagtgggggaa 13381 tttgctgctgcaagttacttagacttgtaggcaaagggaaattcaaatttttaattctaa 13441 aatgaaaaccactgacaaaattttatactctgaaagtttggttgttagcttagtcattat 13501 tttcctgttctttatcatttcggaattcagatgcttaaatttaacatacaaattatttgt 13561 tggtaaaacataaaacataaaaagctacatttggtaaactaaattttaggattcaaagtc 13621 tctaacaatttctatgtgacatgtcatacggtgcagtttttatttgccaaagtgtctact 13681 tcatactgcctatgcactgcttcccgtttttaatctctctaccccaacccccctataatt 13741 aaataaacccctagaaaactgccttcttttagaatacctaattgattactttaaatattt 13801 tttcagaatcaaaattacaaaagggagagatacctaagaatctggcttgtttatattctt 13861 taaaagatcgcatttgattgaaggtgggtgcatattttttatatccactctttccccatt 13921 tgtatgtgaccattgtaaaagtggatgtgcttttttttttttgctgaggtctagagacaa 13981 tgttttagagatacagaatgaaacatttatgggtaaaatacaatgggtaagacttgcttc 14041 aaaatagtatgtgacagaggaagtagatggaggtatgaatgaataggacattgatggttg 14101 tttgttgggattgggtaagggagctttgttgtattctatttccttttagataagtttgaa 14161 attccttgtagtgaagaaattaaacgtctccatcaggtgcattgccacgtcttctctagg 14221 aagcctccttaacatcctctggtggctcctgaactttttctgttctcattcacagggaag 14281 ctcatggggctgcctggagacttgaggttacatcttgcctagtattaccaaaattgtgat 14341 acttttctccaccccataatagcacagtctttggtctcaacttgaactaaagtctttttt 14401 tttttttttttttttttttttagtatttattgatcattcttgggtgtttctcggagaggg 14461 ggatgtggcagggtcataggacaatagtggagggaaggtcagcagataaacatgtgaaca 14521 agggtctctggttttcctaggcagaggaccctgcggccttctgcagtgtttgtgtccctg 14581 ggtacttgagattaaggagtggtgatgactcttaacgagcatgctgccttcaagcatctg 14641 tttaacaaagcacatcttgcaccgcccttaatccatttaaccctgagtggacacagcaca 14701 tgtttcagagagcacggggttgggggtaaggttatagattaacagcatcccaaggcagaa 14761 gaatttttcctagtacagaacaaaatggagtctcctatgtctacttctttctacacagac 14821 acagcaacaatctgatctctctttcctttccccacatttcccccttttctattcgacaaa 14881 accgccatcgtcatcatggcccgctctcaatgagctgttgggtacacctcccagacaggg 14941 tggcggccgggcagaggggctcctcacttcccagacggggcggctgggcagaggcgcccc 15001 cccacctcccggacggggtggatgctggccgggggctgccccccacctcccgaacggggc 15061 agctggccgggcgggggttgccccccacctcccggacggggcggctggccgagcaggggc 15121 tgccccccacctccctcccagacggggcggctgctgggcggagacgctccttacttcccg 15181 gacggggtggttgctgggcggaggggctcctcacttctcagacggggcggccgggcagag 15241 acgctcctcacctcccagacggggtggcggtcgggcagagacactcctcacatcccagac 15301 ggggcggcggggcagaggcgctccccacatctcagacgatgggcggccgggaagaggcgc 15361 tcctcacttcccagactgggcggccgggctgaggggctcctcacatcccagacgatgggc 15421 agccaggcagagatgctcctcacttcccagacggggtggcggccgggcagaggctgcaat 15481 ctccgcactttgggaggccaaggcaggcggctgggaggtggaggttgtagcgagccgaga 15541 tcgtgccactgcactccagcctgggcaacattgagcactgagtgagcgagactccatctg 15601 caatcccagcacctcgggaggcccaggcgggcagatcatgcgcggtcaggagctggagac 15661 cagcctggccaacacggcgaaaccccgtctccaccaaaaaatacaaaaaccagtcaggcg 15721 tggcggcgcgcgtctgcaatcccaggcactcggcaggctgaggcaggagaatcaggcagg 15781 gaggttgcagtgagccgagatggcggcagtacagtccagccttggctcggcatcagaggg 15841 agacggtggaaagtgggagaccgtagaaagtgggagacggggggagacgggagagggaga 15901 gggatgtgctttttttctaaccgttattgccaccaagtaataatgtcttaattcacaatt 15961 tacatagtgattggctggagagaggtattgagcataaatttttttttaagattcaactgg 16021 gaaatggatgatttacatgattttagtctctttagttgtctgggtatttcttgactggga 16081 atagcaatatcttaaaggccatttttaacaagaatgctaaggatggaacacttgaaggaa 16141 gcagtcctgtacagtcaaatacttcagttaccttggataatagaatgaaaactcaattgc 16201 ctactttgaacaaattttttttttggattttaatggctggacagaataacattctgctaa 16261 ttttaatccttggtcatttccgatgtaatggaaaatgcagtttgactcagaatcggaggc 16321 ctggggtttggaccctgattgtgccaatttatgtgactttagataaatcttttcatcagt 16381 ctaccttaaagttcttcatttcctccagttccctaaaatgaggaagttagtttttagggt 16441 ggttatgagaactaaatgagagcacttgagagatcattcagcctgaagtgggtactcagt 16501 attagatggctaaatctgcacagtctagaataccaggcaaaggttactctgaaggtcttt 16561 gctaataacaaatctttctctaagaaagtttgtaaatgtgatgttaaactcagaaatgtc 16621 acatagaacatattggagcaattattgccgcaaaagtaactcgtagcaaccacaaaaacc 16681 cagtggtgtgcagcaataaacagtttatgaattagataagtgatttcggctagatgtctc 16741 tggagcagttgtagtctttcctcgttcatgagggagttggcctcacctggaaggacttgg 16801 catttttccacatgcctcctatcctccattaaacaagcatgtttttgtggaggttgtaga 16861 aggcaacaacagccaagcccaatcccataactccctttcatgtctgcatgcttcatgcta 16921 actagcattcaccagaaacaagccacatggctaaacccagtgtggaaaggcactacagag 16981 ttattagaccaagggagagaacataggaggggtgaagaattggagccttaaatgcagtca 17041 atctaccacacccttgctttgtatttaacaggttactgtactggtttgccagcaaacaat 17101 ggaaaatgtggagaagctgaagaatgctcaagctgggacttaatagagtggcctatttgg 17161 tttgaaatgttttaacttacagagcattgagtagaagcctaatctaatatacataaggaa 17221 gacaaaagcaaaggattgtgttttctatctaaaggttaatcattgtggttgctcctggcc 17281 attatcacatgactggaagttaacactctccaaacgctgagcctatcctgtacagcacta 17341 gaaagtagaaagaatcactcaattcagggaaaccgttttctcttaatgtgaacatttaca 17401 ttaatgccatttccaaaacctttctgggacttcttaaatgcaaagatgctatctgcttta 17461 cttcatgctgcctgtttttaggagcttggagtgctttaggaagcttcccaatactggttt 17521 agcagtaatttggttgactgatcaaggcatgttttaactttgacactgaaattttaaaaa 17581 gacaacagttatcttgcccggagagtcaagtttctgcttccaaggaggtcaggaattgtt 17641 ctctttggtgatgtggctgtgcttggtagcccttgaaagtggagtcgacagcagtcctca 17701 gcttttgtgtgcctgtcttagtctgttttgtgttactataacaggatagctgaggcaggg 17761 tcacttatgaaggatgctcacagttctacaggctgggaagttcaagggcatggccctggc 17821 ttttggcaagggctttgctgctgcttcatagcttgatggagaaggtcagaggggaagcag 17881 acgtgcaaacaacccacttgttcacaacaaccaaacaagtctctttttaacaacccactc 17941 ctggggactaatctagtcttgagagagtgagaactcattgcaagagcagcaccaagccat 18001 tcatgaagcatctgcctcagtgaaccaaacatctcccactaggccccagctctcaacacc 18061 accacaatgaagataaaatctcatcatacatttgagggacagtttgggagacagaccata 18121 gcagtgctcagtatttctacccaaatgttcaggtaacttaatatatttttccttgaatat 18181 atgtttaaatgggcttcccttccccacgctcatcttgaatggtcccacaacaacttttga 18241 ttatcacgttcctgtaaatacacaaaaatattttgtggtcttttactggcagcccagtgg 18301 atgggactttaaaaaatcacccagattccaacaaccagagaaaacgactggtgtatattt 18361 tttccagtctttatttgtatgtctgtgtatattcaatggaaaatgtttgaagcttcactc 18421 acagcacattccattagagaaagctactaaaatcataaggaaaatctaaaatgcagtaag 18481 ccagtcagcaagccataatgggcatatgaaaacaaagttttttgccatgatttgtggacc 18541 acagaagatctgtgttattagtctatttaagtttggtgtttgaaattaaaaatgttcgac 18601 atactttttatgttttttttaaatatactgtctatatttaaaattgagtatactgtactt 18661 tagtgtgtttggaagcagatatccccaaataaaagtatacagtagaaccaaagaatttta 18721 ttgatcagctagaatttagttttcaggtgtaataactgtcaacctaaataacagaggctt 18781 tctaaaagaaaatgatgtttatttgggaatagggcattgtgaaggcaatatgcatgccat 18841 agtaaactgtgtgtattcaggaaggtaaaggaagacaggtttttaaaggacagataaaga 18901 ttatataattgtcttgaaataattattcttggctacaaggattaataacaaggatgctgc 18961 cagttcgggtttggacaatcggcttctaggcagatgtcccaaaagtattttctgtgtaag 19021 gttgcgaatagtgtttgtgcaagctggcgtggtttcttctgggtctttgaggtagtgcgt 19081 aaaatccctctcttcatggacttccctggctccatttgtcagggcttttggaaacatgac 19141 tcttgattctgacagctttcacctttccctctcttgatgaagatgtttttccgaaagtat 19201 ctatgatgaatcatcttgtagttaggctttgattgtcccttggtgacagaatagaccttt 19261 cccgggttattggtctggtcctgcatcctgcattggcaggagtgattggcaactaaaagt 19321 cagtgttaaaacccttttagccacctttgagggcagggaggctttaagggagtggcactt 19381 aggctaagtccacctggagtctattattaagtccaattttttttccttagtcctttgttg 19441 tcccctcaaagtgctgggctagcattattctgttaggaattgtacttctttctgcagaaa 19501 atttggcaaataacagatacaaagtttaaaaaggaaatacacaaaattaatagtaatgtg 19561 acaatcccagtttgcataatggttttgagccctgaacctaggcttacaggcaaccaattg 19621 aataaatcaaattgtaatacaattcttgctctgatgtcttaggaaaaatgtctacagcct 19681 gaaatcatcaactttttgtcctggtttgcagtttgaatgtctctagctatggcattggtt 19741 ggtatggtgaacttttgtgtgacccatacatcagcatgagacttgctcctttaaaaatta 19801 atcacatcttagcttataggcctcagagcatgggagtagttttttttcttagagagtcat 19861 agccaaatattgaaggaaattaggaggattcaggagcaaatccagtctgcaggtggataa 19921 caggagtttcaaaacggtacagagctgtgatctaataacaggtacatatagctttcttca 19981 gaaacttaaagttaccctgatttttaccaaagatgttcagaataaaacagatttgtaaac 20041 tttatcagattttgtctgcaagaatagtagtatggtcacagtaatctcagatttaaaaac 20101 ctccttgaggctaagaagctaagtcaaggtagactttagattttacctatagttttaagg 20161 ttcctgggcctgccaggaaatgataatttttaattcagtgtaatgctgagaaccattgaa 20221 gccaggcattctacacattctcaaatatgacattttaatcaaagccttggtaatacaacc 20281 agtgtttccaattgtatcctgttataacgagagccgatttttattgaacttaggcaaatc 20341 atattgccttaagagtactcacaaataggctgggcacagtggctcatgcctgtaatccca 20401 gctctttgggaggccaagacaggtggaacacctgaggtcaggagtttgaaaccagcctgg 20461 ccaacatagtgaaacctccccccggccaccgtctctactaaaaaatacaaaaattagctg 20521 ggtgtggtggtgcatgcctgtagtcccagctacttgggaggctgagacagaattgcttga 20581 accctggaggcagaagttgcactgaaacaagatcgtgccactgcattccagctggggcaa 20641 cagagcgagactccgtctcaaaaacaaaaacaaatgaatactcaaaatagtttccaaatt 20701 ggagggatcaagaagaaaggaaaagcaaatatttctacctttgttcacaaaagtattcca 20761 aattgctgtaaactatagatagcatgagagaatttctttaaatatggaaaacaaaacatt 20821 taagtaaaaaaacaataatgcttcaaataaaagtcacagacacatcttcagttacttagt 20881 ctcatgtaactttttttgttgtggttgatcttaattagtagttacatggactcatcagtt 20941 tcttgaagttctgaaaaaatatttagtccattggtattaaagtgattagtaacctgtatt 21001 taaaagtgtgttagcatcttttccatgaatctgattgcaaatgcttttagagaaaaagca 21061 ataactgggaattacaaaaacttagaataaccatgattaaaaatctgatgagagtttacc 21121 ataaccagaaatagacaaagagttttggttatttttgtggcaaacagcataatcagaatt 21181 atgactgatgacatatttctaacggcatcgtacaattttggaacactcatatcaataaca 21241 tactcataaatgtaactgtgtctagtattacatcattagacaatgcttttcatacaattt 21301 aatacatcaaagaagcctaattagctaacatctctaccagatggcatacacatgctctga 21361 ggctttccagaggcccaagtggaaaactcaaaggtaattttaagtcaaaaacacttaatt 21421 tagaacttgagcctagagaagcctgtcaaagatgtcaaaagttcgaaacaggatcacagg 21481 tcactataaaatatttaacaagaatgataatcaaaagacttaagaagcaatgcagaaagt 21541 tacatacatttaaaaaccatcttttcaaagcttcatttttcccaagcaaaaaaaaaactt 21601 aaacacaagaatttatcttgatagaacataaaatttttcttaggccagttgccaaaatgg 21661 taaagaaaaatctcttgcagtgtgactgcctttacttatgggaagcctatttggatatac 21721 tgaaagttgaatctgatgaaaaggtacttgaatttaatcagacacaggaagagtatttcc 21781 aaggttatgagtgtacgccttatagaggaatgtaaataagaaagctagtatgttgaacag 21841 aatacatggctcttggaaaaattacgagaaatttcctgcttgcgtggaacaattcaaaca 21901 tgagaagagccaagaattcagaatcaagttatactggaggaaaacattgcttttctaggc 21961 cttctacagaacatttcagtatcaagttataacagcaagagttagaaccagaggaaaaaa 22021 gttacaggagctaatgaaaaagttaagagttatcacccctgccaaacaaaaagatgtacc 22081 ttcttaaggggagaaagagctaaaggcaatgatgtgtgacctacaaataaggtgcagcaa 22141 gatacagcaaaggttgaacttgtgagatataaatcaggatcttcaagaagaaaactctac 22201 ctcaagaaatgaaatgaccatcttaaatgaaaaaagacagcctttctaacctgaatctag 22261 gggaaattaaacggatctcagaaggaaatatggcagaaatttaaactgtggtttagaaga 22321 tggctgattttagaattaaaaattaaaacctctttcaattttattaagaccagatcctta 22381 aaaagaaccttgttctaacattggggaccaaattttgtgtgtgtgtgtgtgtgtgtgtgt 22441 gtgtgtgtgtgtgtgtgtgtatagtgcatgtatagcatttacactatcgtgtatatacaa 22501 atatatagcatatgtatagaatatactgtattattgtacatatacatatgtacaagtata 22561 tatgtaagctcaatgtcttatgatttcattctgacctattgccaacttcattacacacaa 22621 ctcctttcataaatgtatccttcatgaacatttcatgatctgcacagaccttcagtgaca 22681 tgcttaaactttctgctttgttttatacttccccttaaacaactggtcatcctgctttag 22741 gataaaaagttactatgcaagactcatacagaattattctgttaattttgtaaccttcct 22801 taccaaaggtacattctcacacccattaacttccttcatatttctctcctcctcctactt 22861 agtggttcctttctgtcttgtttccatatttgaaacaacctctaataaactctgaattta 22921 aacaacttttttcccaataaaaagcaatttttatgccttataacttttctcatcaaaaca 22981 tctttttttgggtacactttgtatatggaattgtgtattttcaaattttaacttattaac 23041 cttaatttttagtgaaaacctaggaagcaaaattttgaagtgttatatcagcattttata 23101 aatgagaaccatattataatttttagaaacatgtttccttataactttgtatattaatag 23161 gcccaaatatatttagtctttctataatttaggaagccaagaacaaactaatattttcag 23221 cagtttattgtttttttttggaaatgatccagacatttactgaagattaatttataagat 23281 ttcaaattacatgaaaagttcattaacatcctatttttaaaaacattcttttggtttatt 23341 ttttagagacaatgtcttgctgtgttacccaggctggagttcagtggctgttcacaggca 23401 caattgtagcacactgcagcctcaaactccaactcacacaatcctcctgcctccgtttcc 23461 tgagtagctggaactatagatgcatacctgcataccaccatgtctcacccttgcttatcc 23521 cgtttataatccatccaattcttttttttttttttttttttgagacggagtctcgctctg 23581 tcacccaggctggagtgcagtggcgtgatctcggctcactgcaagctccgccttctgggt 23641 tcatgccattctcctgcctcagcctcccgagtagctgggactacaggcgcccgccaccgc 23701 gcccagccaattttttgtatttttagtagagacgaggtttcaccgtgatctcgatctcct 23761 gacctcgtgatctgcccgccttggcctcccaaagtgctaggattacaggcgtgagccact 23821 gcacctggcccccaattcatttttaacaattattcctagattacttataaaaactgagat 23881 attagacatagctagtcatttcaagttattttcctgttaaccatttttattacctgtgag 23941 tatcatgtgttcaattaagaaccataaaaatgaaatatgtaggtattttgccagtaactc 24001 agaggacacagctgaagtcaataatacaaaattagttcaacttacagttatacaaagatc 24061 attctgtttttaagttgagtttatagttttatgaccttaaaaagtctaacagagacaaat 24121 ataaaactgagtagtaaattcaggcaaaaattttaaagacacttatttttgatttaccaa 24181 ttattttaaaaccagcttatcagatgtttaagttatattaactaaaaggcacttgtgtta 24241 attactatatattttgtattagcactcatttatttgatgaatagaattccttaagggatt 24301 tgtggccaactgccagattttaccacgtagacacaacatacaacatatatatacatatgt 24361 gtaaacacacctaaacatacacatacacaaacatagctttcattttagaattttagtcat 24421 acgatagtaatacaggcttgctggtttataaaagacagttattggattcaaattatattt 24481 ctgagaaagtgggacctgctcagctgggtaaacatgcagaataggtaatcttatgaaagc 24541 tgtgaaccaaaagttttggtaaatagcagtttggatttttaaaaaacctcttaccccacc 24601 tccccaaccccttttttcccttttttcagtttcaaatgagtttaatgttaatatttaaat 24661 gcttacatttttagctaggactggctgaattgtataagaaaaaacaatctccaggtggcc 24721 ttgaatttttagtaacaaatcttttgtttgccattctggtttttttgactagtcagtgca 24781 ggcagggaagcattttagcagttgtggatgaggggtttttgttttgttcttttagccttt 24841 gcatagcaggcaagcaatttttatgctataccagagataccttatattattgccctgagc 24901 tcaagattttgacctgtttgagagcctaatttttatacgtatttatctagttcttttagg 24961 ctattaatcctttaattaactgttccatcaccctaagcagttattaggcaaacctaaatt 25021 tacattaaaagggatacttcttaattctaggtgttggttgccagggaactattataattt 25081 ataaagccattaatttaaggccctttaagacctttttttttctttttgttcttggctgga 25141 atgccgtaaggagtgagtttcatctcaacactggcagaaacagcagatttaaagtaggca 25201 gaaaaaaaattagagagcttagaagactctacatatcaactctatagctgcagtctcttg 25261 gtactaagaataaaaaagcttggggagtttagacaaagcatagacaatctctatgatggt 25321 cattgatccaaaaacatgcatgaggaaaagccacatagctgacctgaagtcccagaaaag 25381 caggcatgccttaatgtttgagaatttccattttgtttcttctcaatctcttaagagcaa 25441 agaaaattctgtaaatcctgacagataagtcaggtgtttggaccagtgttttaactggtg 25501 gcgattgccctagtggctttaaaagagccatcctgtgcccaaaatttagaatgtttattt 25561 ttgctcttgggagatgttcagaaacaggggaaaagagccaaatcatttacagatgcatgt 25621 aaccatatcgaaacgaaaccaaaatcagtgttcccaaaagtgttaacccagtcatgcaga 25681 ttaaaaaataatataaacacagaagaacccaaagtaaatttaccagaaaaggcatgcctc 25741 agaatccagagtactcagccaggcgcagtggcccatgcctgtaatcccagcactttggga 25801 ggccaaggcaggaggatcgcttgagcccatgagttcaagaccagcctcagcagtatagtg 25861 agacactgtctctaaaaaaaaattgtttttaaatccagagtactcaaaccagagggacac 25921 ttgtctttatatcaaaaaggacttgccaggaaagacaaaaagtcttttgtcatcccagga 25981 gggatgtaaagtcctttattaaagtggtcttagaaccaagacaaatccaaagtcaagtca 26041 aaaagcctctgccaaaagtgggaggctctgcctgagaaaagactcactggggcagaacag 26101 acaagctatgtaagcggagagcccaaagggctcctgtgagtactgcatactgattctgag 26161 atcaccacttctctctgaaatgtgtcctacttcaggttctactgctgaacaccatttatg 26221 tcaacacagagagaggctctctaaaagaaaactctatttgggaatacagcattgctgtag 26281 aaatacgcatgtcatgggccgtgcgcggtggcttatgcctgtaatcccagcactttggga 26341 ggctgaggtgggccgatcacgaggtcaggagtttgagaccagcctggccaacatagtgaa 26401 accccctctctactaaaaatacaaaaaattagatgggtgtattggtgggtgcctatgatc 26461 ccgctacttgggaggctgaggcagaagattggcttgaacctgagaagtggaggttgcagt 26521 gagcctagatgtgccactgcactccagcctgggcgacagtgcaaaactacgtctccaaaa 26581 aaaaaaaaaaaagacccatgtcatggtaaactacgtgtgtattcagggaagtaaaggaag 26641 acaaagattttaaagaaaaatgagggttgtataattgttttgaaataattgtcgttggtt 26701 acaaagatcaatagcaagggtggtgccactctgaagttggacaggcagtggctaggcaaa 26761 agtattttgtgggtaacctttgtgaaaggttgcagtttttgtaacacaagctgctttatt 26821 ttcccaaaagctttcacagtacatagaaaatatattggacgtgtattaaatgtgccaaat 26881 tagtcagcaatattacattaaaatatgtgttattacttgttaatgttcttaataagttgt 26941 tcaggcagttataccagactatcttttctcattttccaatttataagtgtattatccaaa 27001 aatgttagttttagggtgaccactgtatattttggtattttttaaagctacccaattgtg 27061 tataatttataaaaatctttttttcataagacctaaaacttctgaacaatacataggtgc 27121 aaataaataaattcctttttatctcaaactcacttccactgccctccctgaagaaagcct 27181 tttgttattgttgtcttgactaaatgtggcatgggagctaacattttcaagggaagctga 27241 tcttatctccgggctctagaagccaagacatgaggtatgtgtttaccgtctcttaggtga 27301 ctctccagaactttcattctcaacctcctccctcactgccagttcctcctcagcttctta 27361 gccaagtggtagaggaaaaatggtattttatgtcaggactaagccatgtgctctgagccc 27421 tgggtaagtctgcaaggcttctctagaactcatacataggtcaattattcctcctctgaa 27481 aacttaaactctggcaccactagctttttcctacagcatacatgggctcagtaaatcctc 27541 tgttaagacaacaggaaaattaagacaatgtccttgcaagccccataactactttctatc 27601 cctgctattcacagccaagtgtgtcgagaccagttcacacaaaccttgttgattttcggt 27661 ttcaccccctccttactaaatcacccctccatttgctgcagttgcccttgcgtgctgtac 27721 tcagacttggaggaagtgatgtcttattcaaggccagtttttgtactagtggttaaataa 27781 atggtttccaaattggagtcagaaggagagcttctaaaatgtaggttccctggcctcaat 27841 tgtgagattctgctttagcaggtctggaattggagcactgggatctgcattttcagaaaa 27901 cccaaaatgattatcagccaggacttaaacctctgctttagaccacattccctgtgggct 27961 ttcagattttctatcaatgttcttccctcttcccagctcccacacattaaaactcagatc 28021 atgcagaaaagaagttacagttccttcatttcacatcaatttctcatgcatcccatctgg 28081 ttttgggaaggtgtgggacgaggtggatggccttaaacttgccaatcaaagataacgttc 28141 tctttcgattcaaatagcctatctcaggcttaaaaccatctctttggataaatgctcagc 28201 ttttcaaaggttcttcctagcttcttcctcatgatggcatctagtgggtgagaacagtca 28261 tctccaggtgacacaggaaagagtttctctaatgtatgtgctgaggtccttgacggtcct 28321 gctgctggtgctcatcctgccatctttgctggatgtcactgagtctactgggtaatgtaa 28381 gtgggtccctggcttttgttcactgctgtcatgccctgctcctgaccacaactctgtcat 28441 tgcctttggtctcaaggtctctaccttaatagcttccatgtcccaactatgggactgtta 28501 atctgctgggctttggagtgggtgggaagggatgatgttggaactttgggatgtactgaa 28561 catcttgctcaagctttgggaagccaacattttctcagactgactagacacctccttcca 28621 ccaatgctgagctagtgctcctgtgccatactgggtaagcctctaagtcatgagtaggac 28681 ttttttgagtggcttgcagtcttccccaggctatgccaggaaagtagttgactaaccctg 28741 ctgctccaagactcgcatacccatcctgaagtttccgtttatttcccaacagggcaattg 28801 caatctcaatcaatctctccctgccctgggagtcattccactcctgcctaatgaagagac 28861 tcttctcacatcgtattctcagtttctcttatccatggttaggagtaaaactcatgttca 28921 gttgtccaagctttgcttttagtatgtgaatggagctcttagcatgtagaactcccttct 28981 cattctcagtaaagtctgactttgaagactacttatcatcttcctagagatgccaaagaa 29041 taatcaagataataaaggcaggctctgagattcacagctgagtagcaactgtgctgttac 29101 tctagtacacaccctctcctttcctgtgactgtcaggcttcagggcttacctttattgga 29161 aagacagcaggggggcatatatgaagaaaatggaatctttaatattgtcaaagtcttgac 29221 ccaatagagacattcttgccccagactctcttgcttcagtgcctttgcctgttctggtcc 29281 taagtaccttgaatatccttctcttgatgccctgatataaaactctttattcctcaaagc 29341 caagttcaggttatcacctccaccacagacttttctttccctccccaaacttcattgcct 29401 cttctcatcactccctttgtaatttgtttatactggtaagagagcattcatcataattag 29461 gcctatctatgcctacctttcttgttaaattatgagctttgttctgccttggatatctct 29521 ctggcttggatatctctctggcctttgctctgcacttccaaatgtatccattattcaaga 29581 cccaggtttccagcctgatcaacatagcaagatcccatctctccaaaaaaaaaaaaaaaa 29641 aaaaattgtggggccgggtacagtggctcatgcctgtaatcccagcactttgggaggccg 29701 aggcaggtggatcatgaggtcacgagtttgagaccagtctggccaacatagtgaaacccc 29761 atctgtactaaaaatgcagaaaattagccgggtgtggtggtgtgtgcctgtaatcccagc 29821 tactcgggaggctgaggcaggagaatcgcatgaacccgggaggcagaggttgcagtgagc 29881 cgagattgcgccactgcactccagcctgggtgacattgcaagactccatctcaaaaaaaa 29941 aaaaaaaaaaaattagctgggcatggtggcaggcacctgtagtcccagctacttgagagg 30001 ctgaggtgggaggattgcttgagcccaggaagtcgaggcttcatgagccatgtttgtgct 30061 actgcactctagcctggatgacaaagtgagatccttttctaaaaataaggacccagttta 30121 ttttatttagttatttagttatttttgagaccaagtttcatcactcaggctggagtgcaa 30181 tggcacagtcttgactcactgcaacctctgcctcctggattcaagcaattcttctgcctc 30241 agcctcttgagtagctgggattgcaggtgcccgccaccacacctggctaatttttgtatt 30301 tttggtagagacagggtttcactatgttggccaggctggtctcaaactcctgacctcagg 30361 tgatccacctgccttggtctcccaaactgctgggattacaggtgtgagtcaccctgcctg 30421 gccagaacccagtttaaattccatcctctctgcagagtcttccttaaccacccctattga 30481 aagttacccctgcttcctacaagaagtggtacttggatgttcatgagatacctgtgcaag 30541 gctcctgtgggggtcctggggagacagtgacatggacactcatgaaaggaaccttggaat 30601 agcgagtgtgtgtgctataaaatgtgctttagatttgattaccaccacttaagttatgag 30661 ctctgatatggtttgggtctccatccccacccaaatctcatcttgaattgtaatccctac 30721 atgttgagggaaggaagtaattgtattatgggggtggttctcccatgctgttctcatgat 30781 agtgaattctcacaggatctgatggttttataaatggtagtttttcctgtactttcacac 30841 actcacactctcttctgccaccttgtgaagaaggtgcctgcttccccttctgccataatt 30901 gtaagtttcctgaggcctccccagctgtattagtctgatctcacgcggctaataaagaga 30961 taccggagactgggtaatttataaaagaggtttaattgactcacagttttacatggctgg 31021 ggaggcctcacaattatggcagaaggtgaagggggagcaagacacatcttacatggcatc 31081 aggcgagagagcttgtgtaggggaactcccctttataaaaccatcagatctcgtgagact 31141 tattcactattacaagagcagcacgggaaagacccacccccatgattcagttacctctca 31201 ctgggtccctcacataatatggggaattatgggagctccaattcaagatgagatttgggt 31261 ggggacacagccaaactatatcaccagccatgtggaactgttgagtcaattaaacctctt 31321 tcctttataaattacccagtctcaggtatttctttatagcagtgtgagaacagactaata 31381 caagcaccttgaggtcagaggctaaaatcactttttcccaaacatttcctttttatatat 31441 gctacatctttgtgtctgcttcaacatttccagcagtgctttatatatggtaggcatgca 31501 ataaatgcttcttgatcgactgacaggtgctcagaagatctaggttggttgattctcttg 31561 tgatgccatcttttcctgagagctcattaatttttaagttgttttccttgaaatgcatgg 31621 tatgtttcctccaccctgctctttgcctttcatagggttccattttgatcagctgctctc 31681 attgtctgttttgtgatcaaaggttctgatgaactttggaatatgtgtatgtttggagtg 31741 aggatggggtctggaggagatgcatggttgaggaccaattcacccaacccagcttacaga 31801 agtaaagcggccccttaggagcactgaagcattgctgtggatttcagaattaccttattt 31861 ctttttcttttttttttttttttttttgagacgaggtctcgctctgtcgcccaggctgga 31921 gtgcagtggcacaatctcagctcactgcaagctccgcctcctgggttcacaccattctcc 31981 tccctcagcctccccagcagctgggactataggtgcacgccgccacgcctggctaatttt 32041 tgtatttttagtggagacagggtttcaccgtgttagccaggatggtctcaatctcctgac 32101 cttgtgatccacccgcctcagcctcccaaagtgctgggattacaggcgtgagccaccgtg 32161 cccagccagcttctttcaaatcagagtaggccttccagtgtggcaggccataagatctga 32221 agttttcaccctgttcctggaagccaagtggacagcaactaatttttactttctttattg 32281 cacatttggggcttgggggatagagtcagatgtgtgtcagttgaaactgtagctactgca 32341 ttccactccttgggggatcgtagtgctcatgccaacagaaaacttcgaggctaataatta 32401 ctgtcttcagagtacaagacaggcacggaagttgttttggcataagaaaaccacgatttg 32461 catcccacagtctaaggaagacgatgctgaattcagaagatggtgcaaaagtgtgacagt 32521 tcagctgtggcggctgttgctgatgcatgggactattttatttacatttcctttcttctt 32581 ttttaacagagacaggatcttgctgtgttgcccagcctggtcttaaactcctgggcccaa 32641 gtgatcctcccacctcagcctcccaacgtgttgggattacaggcatgagccaccatgcct 32701 gggctttatttatatttccaagtcaaatgttagttggtcaatcagtctttttaagcacca 32761 attttgtgcctagccttgtggaaactgtaggaaaaagatactttttatttgggaggacct 32821 tgatttgctgtcacaggtgccactaatgccaattataaggcagtgtggaatcaggtgatt 32881 gaaagcccagtctgtagcataaactgctgcagggttccagtgggggcaattaaggtgggc 32941 agggagggtggatagcatttgactttgacagcataacctgagcagaggcacagtggggat 33001 ggtgagtgtgcagtgggaggagggagagaggtaagtggtagggaagaggtgggaaggggg 33061 caaggagaaggctcaggaggtttggggacagggaaatgacttggttggcgacctcttact 33121 ttcttctcgtgtgtgcaatttggaattcacttggttcttagtatttctgggtcagatgac 33181 ttctttgcagtatgagaaaccatttcccaggctggctacctgggctgtggtatcttccag 33241 tgctcctctgtgattgtactcagatcagctcgtctaggcaggcaggatggcagaagccct 33301 ctgacttcatgtctgaaagagtatgtgtttcaactctgtaattacagcatttaacagacg 33361 atatcagccctctttgggatggcttttggcaaatgggctagaagtctattgtgcatttaa 33421 atgatactgcatcttctctttaaaaggtttctcagtgagtccaccccactctgtatccaa 33481 gtatgtctcaggccatgaggcaaaaggaaatgagtagttctttttggttggagaattaaa 33541 aagaaatctccacccaagtaacaggtacatagtgggaaaaaataacatctgcctgaaagc 33601 ttcatcttcaggcaaagagagggtcagggggcgggagcttagtaatggggaaacctcaga 33661 agatttaaagagaattacagacagacaaggctgaacattggctgtcatccaacaaagctc 33721 ttataagatgggaatcactgcccggttcttgagctccgacctggagggaagaggagtctg 33781 gaagacttggcacaggcctgagtgcttcattgtctttctggttccaagtcctcctcagct 33841 cactaggaaggaggtggggtgggggcaggtaggccactctgcataagtgcacacatctac 33901 actggctagtctacttcacaattcccccacaggttatccttatctctacctggttccagt 33961 tccagattggagggatatagaataccatccccacccctcaccttgcttgctctggcctgg 34021 aaaactgtcattcctttaccaccagctggcatctgccatatgcttcaaggaactgaataa 34081 agaggaaggggaaagaagaaactagagaaactggaatgcttcctatctgacccccaagta 34141 cagggactgcctctttccgtaacggcacagaacgtctccatccctttgacctccacctcc 34201 ccagagatgcccgaggaggacagccttgtttctgtgatctgttgttgagaactgctgctg 34261 agaattcttccttcagcaccgccttaggcaccattggtttttcactaggtccgctgtaga 34321 aaacagccaggaattacttagttgactaccacctgaggtgctgtttggtgttggtaataa 34381 agaataaaggtggaaatgaa SEQIDNO:2HumanSMAD2Isoform1AminoAcidSequence (NP_001003652.1) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkcvtipstcseiwglstpntidqwdttglysfseqtrsldgrlqvshr 121 kglphviycrlwrwpdlhshhelkaienceyafnlkkdevcvnpyhyqrvetpvlppvlv 181 prhteiltelpplddythsipentnfpagiepqsnyipetpppgyisedgetsdqqlnqs 241 mdtgspaelspttlspvnhsldlqpvtysepafwcsiayyelnqrvgetfhasqpsltvd 301 gftdpsnserfclgllsnvnrnatvemtrrhigrgvrlyyiggevfaeclsdsaifvqsp 361 ncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgfeavyqltrmctirmsfvk 421 gwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsvrcssms SEQIDNO:3HumanSMAD2transcriptvariant3mRNASequence (NM_001135937.2;CDS:401-1714) 1 cggccgggaggcggggcgggccgtaggcaaagggaggtggggaggcggtggccggcgact 61 ccccgcgccccgctcgccccccggcccttcccgcggtgctcggcctcgttcctttcctcc 121 tccgctccctccgtcttccatacccgccccgcgcggctttcggccggcgtgcctcgcgcc 181 ctaacgggcggctggaggcgccaatcagcgggcggcagggtgccagccccggggctgcgc 241 cggcgaatcggcggggcccgcggcccagggtggcaggcgggtctacccgcgcggccgcgg 301 cggcggagaagcagctcgccagccagcagcccgccagccgccgggaggttcgatacaaga 361 ggctgttttcctagcgtggcttgctgcctttggtaagaacatgtcgtccatcttgccatt 421 cacgccgccagttgtgaagagactgctgggatggaagaagtcagctggtgggtctggagg 481 agcaggcggaggagagcagaatgggcaggaagaaaagtggtgtgagaaagcagtgaaaag 541 tctggtgaagaagctaaagaaaacaggacgattagatgagcttgagaaagccatcaccac 601 tcaaaactgtaatactaaatgtgttaccataccaaggtctcttgatggtcgtctccaggt 661 atcccatcgaaaaggattgccacatgttatatattgccgattatggcgctggcctgatct 721 tcacagtcatcatgaactcaaggcaattgaaaactgcgaatatgcttttaatcttaaaaa 781 ggatgaagtatgtgtaaacccttaccactatcagagagttgagacaccagttttgcctcc 841 agtattagtgccccgacacaccgagatcctaacagaacttccgcctctggatgactatac 901 tcactccattccagaaaacactaacttcccagcaggaattgagccacagagtaattatat 961 tccagaaacgccacctcctggatatatcagtgaagatggagaaacaagtgaccaacagtt 1021 gaatcaaagtatggacacaggctctccagcagaactatctcctactactctttcccctgt 1081 taatcatagcttggatttacagccagttacttactcagaacctgcattttggtgttcgat 1141 agcatattatgaattaaatcagagggttggagaaaccttccatgcatcacagccctcact 1201 cactgtagatggctttacagacccatcaaattcagagaggttctgcttaggtttactctc 1261 caatgttaaccgaaatgccacggtagaaatgacaagaaggcatataggaagaggagtgcg 1321 cttatactacataggtggggaagtttttgctgagtgcctaagtgatagtgcaatctttgt 1381 gcagagccccaattgtaatcagagatatggctggcaccctgcaacagtgtgtaaaattcc 1441 accaggctgtaatctgaagatcttcaacaaccaggaatttgctgctcttctggctcagtc 1501 tgttaatcagggttttgaagccgtctatcagctaactagaatgtgcaccataagaatgag 1561 ttttgtgaaagggtggggagcagaataccgaaggcagacggtaacaagtactccttgctg 1621 gattgaacttcatctgaatggacctctacagtggttggacaaagtattaactcagatggg 1681 atccccttcagtgcgttgctcaagcatgtcataaagcttcaccaatcaagtcccatgaaa 1741 agacttaatgtaacaactcttctgtcatagcattgtgtgtggtccctatggactgtttac 1801 tatccaaaagttcaagagagaaaacagcacttgaggtctcatcaattaaagcaccttgtg 1861 gaatctgtttcctatatttgaatattagatgggaaaattagtgtctagaaatactctccc 1921 attaaagaggaagagaagattttaaagacttaatgatgtcttattgggcataaaactgag 1981 tgtcccaaaggtttattaataacagtagtagttatgtgtacaggtaatgtatcatgatcc 2041 agtatcacagtattgtgctgtttatatacatttttagtttgcatagatgaggtgtgtgtg 2101 tgcgctgcttcttgatctaggcaaacctttataaagttgcagtacctaatctgttattcc 2161 cacttctctgttatttttgtgtgtcttttttaatatataatatatatcaagattttcaaa 2221 ttatttagaagcagattttcctgtagaaaaactaatttttctgccttttaccaaaaataa 2281 actcttgggggaagaaaagtggattaacttttgaaatccttgaccttaatgtgttcagtg 2341 gggcttaaacagtcattctttttgtggttttttgtttttttttgtttttttttttaactg 2401 ctaaatcttattataaggaaaccatactgaaaacctttccaagcctcttttttccattcc 2461 catttttgtcctcataatcaaaacagcataacatgacatcatcaccagtaatagttgcat 2521 tgatactgctggcaccagttaattctgggatacagtaagaattcatatggagaaagtccc 2581 tttgtcttatgcccaaatttcaacaggaataattggcttgtataatctagcagtctgttg 2641 atttatccttccacctcataaaaaatgcataggtggcagtataattattttcagggatat 2701 gctagaattacttccacatatttatccctttttaaaaaagctaatctataaataccgttt 2761 ttccaaaggtattttacaatatttcaacagcagaccttctgctcttcgagtagtttgatt 2821 tggtttagtaaccagattgcattatgaaatgggccttttgtaaatgtaattgtttctgca 2881 aaatacctagaaaagtgatgctgaggtaggatcagcagatatgggccatctgtttttaaa 2941 gtatgttgtattcagtttataaattgattgttattctacacataattatgaattcagaat 3001 tttaaaaattgggggaaaagccatttatttagcaagttttttagcttataagttacctgc 3061 agtctgagctgttcttaactgatcctggttttgtgattgacaatatttcatgctctgtag 3121 tgagaggagatttccgaaactctgttgctagttcattctgcagcaaataattattatgtc 3181 tgatgttgactcattgcagtttaaacatttcttcttgtttgcatcttagtagaaatggaa 3241 aataaccactcctggtcgtcttttcataaattttcatatttttgaagctgtctttggtac 3301 ttgttctttgaaatcatatccacctgtctctataggtatcattttcaatactttcaacat 3361 ttggtggttttctattgggtactccccattttcctatatttgtgtgtatatgtatgtgtt 3421 catgtaaatttggtatagtaattttttattcattcaacaaatatttattgttcacctgtt 3481 tgtaccaggaacttttcttagtctttgggtaaaggtgaacaagacaactacagttcctgc 3541 ctttgctgagacagcagttacactaacccttaattatcttacttgtctatgaaggagata 3601 aacagggtactgtactggagaataacagatgggatgcttcaggtaggacatcaaggaaag 3661 cctctaaggaaaggatgcatgagctaacacctgacattaaagaagcaagccaagtgagga 3721 gccaggggagataagcattcctggcaaagagaatagcatcaaatgcaaaaaggttcacac 3781 taaaggaaactcctgattaggtattaatgctttatacagaaacctctatacaaatccaaa 3841 cttgaagatcagaatggttctacagttcataacattttgaaggtggccttattttgtgat 3901 agtctgcttcatgtgattctcactaacatatctccttcctcaacctttgctgtaaaaatt 3961 tcatttgcaccacatcagtactacttaatttaacaagcttttgttgtgtaagctctcact 4021 gttttagtgccctgctgcttgcttccagactttgtgctgtccagtaattatgtcttccac 4081 tacccatcttgtgagcagagtaaatgtcctaggtaataccactatcaggcctgtaggaga 4141 tactcagtggagcctctgcccttctttttcttacttgagaacttgtaatggtgttaggga 4201 acagttgtaggggcagaaaacaactctgaaagtggtagaaggtcctgatcttggtggtta 4261 ctcttgcattactgtgttaggtcaagcagtgcctactatgctgtttcagtagtggagcgc 4321 atctctacagttctgatgcgatttttctgtacagtatgaaattgggactcaactctttga 4381 aaacacctattgagcagttatacctgttgagcagtttacttcctggttgtaattacattt 4441 gtgtgaatgtgtttgatgctttttaacgagatgatgttttttgtattttatctactgtgg 4501 cctgattttttttttgttttctgcccctccccccatttataggtgtggttttcatttttc 4561 taagtgatagaatcccctctttgttgaatttttgtctttatttaaattagcaacattact 4621 taggatttattcttcacaatactgttaattttctaggaatgatgacctgagaaccgaatg 4681 gccatgctttctatcacatttctaagatgagtaatattttttccagtaggttccacagag 4741 acaccttgggggctggcttaggggaggctgttggagttctcactgacttagtggcatatt 4801 tattctgtactgaagaactgcatggggtttcttttggaaagagtttcattgctttaaaaa 4861 gaagctcagaaagtctttataaccactggtcaacgattagaaaaatataactggatttag 4921 gcctaccttctggaataccgctgattgtgctctttttatcctactttaaagaagctttca 4981 tgattagatttgagctatatcagttataccgattataccttataatacacattcagttag 5041 taaacatttattgatgcctgttgtttgcccagccactgtgatggatattgaataataaaa 5101 agatgactaggacggggccctgacccttgagctgtgcttggtcttgtagaggttgtgttt 5161 tttttcctcaggacctgtcactttggcagaaggaaatctgcctaatttttcttgaaagct 5221 aaattttctttgtaagtttttacaaattgtttaatacctagttgtattttttaccttaag 5281 ccacattgagttttgcttgatttgtctgtcttttaaacactgtcaaatgctttccctttt 5341 gttaaaattattttaatttcactttttttgtgcccttgtcaatttaagactaagactttg 5401 aaggtaaaacaaacaaacaaacatcagtcttagtctcttgctagttgaaatcaaataaaa 5461 gaaaatatatacccagttggtttctctacctcttaaaagcttcccatatatacctttaag 5521 atccttctcttttttctttaactactaaataggttcagcatttattcagtgttagatacc 5581 ctcttcgtctgagggtggcgtaggtttatgttgggatataaagtaacacaagacaatctt 5641 cactgtacataaaatatgtcttcatgtacagtctttactttaaaagctgaacattccaat 5701 ttgcgccttccctcccaagcccctgcccaccaagtatctctttagatatctagtctgtgg 5761 acatgaacaatgaatacttttttcttactctgatcgaaggcattgatacttagacatatc 5821 aaacatttcttcctttcatatgctttactttgctaaatctattatattcattgcctgaat 5881 tttattcttcctttctacctgacaacacacatccaggtggtacttgctggttatcctctt 5941 tcttgttagccttgttttttgttttttttttttttttttgagagggagtctcgctctgtt 6001 gcccaacctggagtgcagtggtgcgatcttggttcactgcaagctccgcctcccgggttc 6061 acgccatgcttctgcctcagcctcccaagtagctgggactacaggcgcccaccaccacac 6121 tcggctaattttttgtatttttagtagagacggggtttcaccgtgttggccaggatggtc 6181 tcgatctcctgacctcgtgatctgtccacctcggcttcccaaagtgctgggattacaggc 6241 atgagccaccgcgcccagcctagccatatttttatctgcatatatcagaatgtttctctc 6301 ctttgaacttattaacaaaaaaggaacatgcttttcatacctagagtcctaatttcttca 6361 tcatgaaggttgctattcaaattgatcaatcattttaattttacaaatggctcaaaaatt 6421 ctgttcagtaaatgtctttgtgactggcaaatggcataaattatgtttaagattatgaac 6481 ttttctgacagttgcagccaatgttttccctacgataccagatttccatcttggggcata 6541 ttggattgttgtatttaagacagtcagaataatgatagtgtgtggtctccagaggtagtc 6601 agaatcctgctattgagttctttttatatcttccttttcaattttttattaccattttgt 6661 ttgtttagactacactttgtagggattgaggggcaaattatctcttggagtggaattcct 6721 gtgttttgagccttacaaccaggaaatatgagctatactagatagcctcatgatagcatt 6781 tacgataagaacttatctcgtgtgttcatgtaattttttgagtaggaactgttttatctt 6841 gaatattgtagctaactatatatagcagaactgcctcagtctttttaagaaggaaataaa 6901 taatatatgtgtatgaatttatatatacatatacactcatagacaaacttaacagttggg 6961 gtcattctaacagttaaaacaattgttccattgtttaaatctcagatcctggtaaaatgt 7021 tcttaatttgtctgtgtacattttcctttcatggacagaccattggagtacattaatttt 7081 cttaatctgccatttggcagttcatttaatataccattttttggcaacttggtaactaag 7141 aatcacagccaaaatttgttaacatcaaagaaagctctgccatataccccgttactaaat 7201 tattatacatccagcagattctgggatgtactaacttagggttaactttgttgttgttga 7261 taatactagattgctccctctttaattcttcttctggtgcaaggttgctgcttaagttac 7321 cctgggaaatactactacaaggtcaaattttctagtatcttacagcctgattgaaggtga 7381 ttcagatctttgctcaatataaatggattttccaagattctctgggccatccttgaccca 7441 caggtgatctcgctggagtatattaacttaacttcagtgccagttggtttggtgccatga 7501 gatccataatgaatccagaacttcaccattgcttagatataagagtcccttggaagaata 7561 atgccactgatgatgggggtcagaaggtgtattaactcaacatagagggcttttagattt 7621 ttcttcaaaaaaatttcgagaaaagtattcttttaccctccaaacagttaacagctctta 7681 gtttctccaaatatgctctttgatttacttatttttaattaaagatggtaatttattgaa 7741 caatgaaatccgtaatatattgatttaaggacaaaagtgaagttttagaattataaaagt 7801 acttaaatattatatattttccatttcataattgttttcctttctctgtggctttaaagt 7861 ttttgactattttacaatgttaatcactaggtaacttgccatatttctggttctatatta 7921 agttctatcctttataatgctgttattataaagctggtttttagcatttgtctgtagcaa 7981 tagaaattttactaagtctctgttctcccagtaagttttttcttttctcagtaagtccct 8041 aagaaaacatttgtttgccactcttactattcccaatcttggattgttcgagctgaaaaa 8101 aaatttgatgagaaacaggaggatccttttctggtgaatataggttcctgctttaagaat 8161 gtggaaatccattgctttatataactaatatacacacagattaattaaaattgtgagaaa 8221 taattcacacatgacaagtaggtaacatgcatgagttttgaatttttttaaaaacccaac 8281 tgtttgacaaaatatagaacccaaattggtactttcttagaccagtgtaacctcacacct 8341 cagttttgcttttccaaccctgacttgaaaggcatatttgtatctttttattagtgatag 8401 tgaagctgtgacactaaccttttatacaaaagagtaaagaaagaaaaactacagcgatta 8461 agatgagaacagttctgcagttgttgaactagatcacagcattgtaggcagaataaaaaa 8521 tgttcatatctgagaatattcctttcgccatcttttcccaaggccagacctcctggtgga 8581 gcacagttaaaagtaacattctgggcctttgtaatcggagggctgtgtctccagctggca 8641 gcctttgttttaatatataatgcaggactgtggaaaacagttggcatagaatattttcac 8701 ctaaaaaagaaagaaaagacatacaaaactggattaattgcaaaaagagaatacagtaaa 8761 ataccatataactggacaaagctagaagaacctttagaagatttgtctgaaaacagattt 8821 caagagtgagcttttatacactgctcactaatttgcttgattactaccaactcttcttaa 8881 agttaacacgtttaaggtatttctggacttcctagccttttagcaagcttagaggaacta 8941 gccattagctagtgatgtaaaaatattttggggactgatgcccttaaaggttatgccctt 9001 gaaagttcttaccttttctctagtgatattaaggaacgagtgggtagtgttctcagggtg 9061 accagctgccctaaagtgcctgggattgagggtttccctggatgcgggactttccctgga 9121 tacaaaacttttagcagagttttgtatatatgtggatttttctgataagtagcacatcag 9181 aggccttaaccactgcccaaaagcgattctccattgagagtacatatcttgaacttaaga 9241 aattcatttgctctgatttttaatcttgtaaagtttttgctaaactcaaaacaagtccca 9301 ggcacaccagaaggagctgaccaccttaggtgttcttgtgatttatccttacttccctat 9361 gttgtcatagttgcttctaaactcagctgcactatggctgtcaacatttctgatacttat 9421 tgggatatgtgccatccagtcatttagtactttgaatggaacatgagatttataacacag 9481 gtaatagctgaaggtaccagtatggtggtgagactcacacttagtgatccagctaaggta 9541 actgatgttataatggaacagagaagaggccaactagatagctaagttcttctgaaccta 9601 tgtgtatatgtaagtacaaatcatgcgtccttatggggttaaacttaatctgaaatttac 9661 atttttcatagtaaaaggaaaccaattgttgcagatttcttttcttgtgaggaaatacat 9721 ggcctttgatgctctggcgtctactgcatttcccagtctgttctgctcgagaagccagaa 9781 tgtgttgttaacatttttccgtgaatgttgtgttaaaatgattaaatgcatcagccaatg 9841 gcaagtgaaggaattgggtgtcctgatgcagactgagcagtttctctcaattgtagcctc 9901 atactcataaggtgcttaccagctagaacattgagcacgtgaggtgagattttttttctc 9961 tgatggcattaactttgtaatgcaatatgatggatgcagaccctgttcttgtttccctct 10021 ggaagtccttagtggctgcatccttggtgcactgtgatggagatattaaatgtgttcttt 10081 gtgagctttcgttctatgattgtcaaaagtacgatgtggttccttttttatttttattaa 10141 acaatgagctgaggctttattacagctggttttcaagttaaaattgttgaatactgatgt 10201 ctttctcccacctacaccaaatattttagtctatttaaagtacaaaaaaagttctgctta 10261 agaaaacattgcttacatgtcctgtgatttctggtcaatttttatatatatttgtgtgca 10321 tcatctgtatgtgctttcactttttaccttgtttgctcttacctgtgttaacagccctgt 10381 caccgttgaaaggtggacagttttcctagcattaaaagaaagccatttgagttgtttacc 10441 atgttaaaaaaaaaaaaaaaa SEQIDNO:4HumanSMARD2Isoform2AminoAcidSequence NP_001129409.1) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkcvtiprsldgrlqvshrkglphviycrlwrwpdlhshhelkaience 121 yafnlkkdevcvnpyhyqrvetpvlppvlvprhteiltelpplddythsipentnfpagi 181 epqsnyipetpppgyisedgetsdqqlnqsmdtgspaelspttlspvnhsldlqpvtyse 241 pafwcsiayyelnqrvgetfhasqpsltvdgftdpsnserfclgllsnvnrnatvemtrr 301 higrgvrlyyiggevfaeclsdsaifvqspncnqrygwhpatvckippgcnlkifnnqef 361 aallaqsvnqgfeavyqltrmctirmsfvkgwgaeyrrqtvtstpcwielhlngplqwld 421 kvltqmgspsvrcssms SEQIDNO:5HumanSMARD2transcriptvariant1mRNASequence (NM_005901.6;CDS:353-1756) 1 gcgcgcgtcctcaccccctccttccccgcgggcggcggccaggctccctcccctcccctt 61 ccctctcctcccctcccctcccctctcttcccctaccctcccgcgcgcccgggccgccgg 121 ccgggcccgggcctgggggcggggcgggaagacggcggccgggagtgttttcagttccgc 181 ctccaatcgcccattcccctcttcccctcccagccccctccatcccatcggaagaggaag 241 gaacaaaaggtcccggaccccccggatctgacggggcgggacctggcgccaccttgcagg 301 ttcgatacaagaggctgttttcctagcgtggcttgctgcctttggtaagaacatgtcgtc 361 catcttgccattcacgccgccagttgtgaagagactgctgggatggaagaagtcagctgg 421 tgggtctggaggagcaggcggaggagagcagaatgggcaggaagaaaagtggtgtgagaa 481 agcagtgaaaagtctggtgaagaagctaaagaaaacaggacgattagatgagcttgagaa 541 agccatcaccactcaaaactgtaatactaaatgtgttaccataccaagcacttgctctga 601 aatttggggactgagtacaccaaatacgatagatcagtgggatacaacaggcctttacag 661 cttctctgaacaaaccaggtctcttgatggtcgtctccaggtatcccatcgaaaaggatt 721 gccacatgttatatattgccgattatggcgctggcctgatcttcacagtcatcatgaact 781 caaggcaattgaaaactgcgaatatgcttttaatcttaaaaaggatgaagtatgtgtaaa 841 cccttaccactatcagagagttgagacaccagttttgcctccagtattagtgccccgaca 901 caccgagatcctaacagaacttccgcctctggatgactatactcactccattccagaaaa 961 cactaacttcccagcaggaattgagccacagagtaattatattccagaaacgccacctcc 1021 tggatatatcagtgaagatggagaaacaagtgaccaacagttgaatcaaagtatggacac 1081 aggctctccagcagaactatctcctactactctttcccctgttaatcatagcttggattt 1141 acagccagttacttactcagaacctgcattttggtgttcgatagcatattatgaattaaa 1201 tcagagggttggagaaaccttccatgcatcacagccctcactcactgtagatggctttac 1261 agacccatcaaattcagagaggttctgcttaggtttactctccaatgttaaccgaaatgc 1321 cacggtagaaatgacaagaaggcatataggaagaggagtgcgcttatactacataggtgg 1381 ggaagtttttgctgagtgcctaagtgatagtgcaatctttgtgcagagccccaattgtaa 1441 tcagagatatggctggcaccctgcaacagtgtgtaaaattccaccaggctgtaatctgaa 1501 gatcttcaacaaccaggaatttgctgctcttctggctcagtctgttaatcagggttttga 1561 agccgtctatcagctaactagaatgtgcaccataagaatgagttttgtgaaagggtgggg 1621 agcagaataccgaaggcagacggtaacaagtactccttgctggattgaacttcatctgaa 1681 tggacctctacagtggttggacaaagtattaactcagatgggatccccttcagtgcgttg 1741 ctcaagcatgtcataaagcttcaccaatcaagtcccatgaaaagacttaatgtaacaact 1801 cttctgtcatagcattgtgtgtggtccctatggactgtttactatccaaaagttcaagag 1861 agaaaacagcacttgaggtctcatcaattaaagcaccttgtggaatctgtttcctatatt 1921 tgaatattagatgggaaaattagtgtctagaaatactctcccattaaagaggaagagaag 1981 attttaaagacttaatgatgtcttattgggcataaaactgagtgtcccaaaggtttatta 2041 ataacagtagtagttatgtgtacaggtaatgtatcatgatccagtatcacagtattgtgc 2101 tgtttatatacatttttagtttgcatagatgaggtgtgtgtgtgcgctgcttcttgatct 2161 aggcaaacctttataaagttgcagtacctaatctgttattcccacttctctgttattttt 2221 gtgtgtcttttttaatatataatatatatcaagattttcaaattatttagaagcagattt 2281 tcctgtagaaaaactaatttttctgccttttaccaaaaataaactcttgggggaagaaaa 2341 gtggattaacttttgaaatccttgaccttaatgtgttcagtggggcttaaacagtcattc 2401 tttttgtggttttttgtttttttttgtttttttttttaactgctaaatcttattataagg 2461 aaaccatactgaaaacctttccaagcctcttttttccattcccatttttgtcctcataat 2521 caaaacagcataacatgacatcatcaccagtaatagttgcattgatactgctggcaccag 2581 ttaattctgggatacagtaagaattcatatggagaaagtccctttgtcttatgcccaaat 2641 ttcaacaggaataattggcttgtataatctagcagtctgttgatttatccttccacctca 2701 taaaaaatgcataggtggcagtataattattttcagggatatgctagaattacttccaca 2761 tatttatccctttttaaaaaagctaatctataaataccgtttttccaaaggtattttaca 2821 atatttcaacagcagaccttctgctcttcgagtagtttgatttggtttagtaaccagatt 2881 gcattatgaaatgggccttttgtaaatgtaattgtttctgcaaaatacctagaaaagtga 2941 tgctgaggtaggatcagcagatatgggccatctgtttttaaagtatgttgtattcagttt 3001 ataaattgattgttattctacacataattatgaattcagaattttaaaaattgggggaaa 3061 agccatttatttagcaagttttttagcttataagttacctgcagtctgagctgttcttaa 3121 ctgatcctggttttgtgattgacaatatttcatgctctgtagtgagaggagatttccgaa 3181 actctgttgctagttcattctgcagcaaataattattatgtctgatgttgactcattgca 3241 gtttaaacatttcttcttgtttgcatcttagtagaaatggaaaataaccactcctggtcg 3301 tcttttcataaattttcatatttttgaagctgtctttggtacttgttctttgaaatcata 3361 tccacctgtctctataggtatcattttcaatactttcaacatttggtggttttctattgg 3421 gtactccccattttcctatatttgtgtgtatatgtatgtgttcatgtaaatttggtatag 3481 taattttttattcattcaacaaatatttattgttcacctgtttgtaccaggaacttttct 3541 tagtctttgggtaaaggtgaacaagacaactacagttcctgcctttgctgagacagcagt 3601 tacactaacccttaattatcttacttgtctatgaaggagataaacagggtactgtactgg 3661 agaataacagatgggatgcttcaggtaggacatcaaggaaagcctctaaggaaaggatgc 3721 atgagctaacacctgacattaaagaagcaagccaagtgaggagccaggggagataagcat 3781 tcctggcaaagagaatagcatcaaatgcaaaaaggttcacactaaaggaaactcctgatt 3841 aggtattaatgctttatacagaaacctctatacaaatccaaacttgaagatcagaatggt 3901 tctacagttcataacattttgaaggtggccttattttgtgatagtctgcttcatgtgatt 3961 ctcactaacatatctccttcctcaacctttgctgtaaaaatttcatttgcaccacatcag 4021 tactacttaatttaacaagcttttgttgtgtaagctctcactgttttagtgccctgctgc 4081 ttgcttccagactttgtgctgtccagtaattatgtcttccactacccatcttgtgagcag 4141 agtaaatgtcctaggtaataccactatcaggcctgtaggagatactcagtggagcctctg 4201 cccttctttttcttacttgagaacttgtaatggtgttagggaacagttgtaggggcagaa 4261 aacaactctgaaagtggtagaaggtcctgatcttggtggttactcttgcattactgtgtt 4321 aggtcaagcagtgcctactatgctgtttcagtagtggagcgcatctctacagttctgatg 4381 cgatttttctgtacagtatgaaattgggactcaactctttgaaaacacctattgagcagt 4441 tatacctgttgagcagtttacttcctggttgtaattacatttgtgtgaatgtgtttgatg 4501 ctttttaacgagatgatgttttttgtattttatctactgtggcctgattttttttttgtt 4561 ttctgcccctccccccatttataggtgtggttttcatttttctaagtgatagaatcccct 4621 ctttgttgaatttttgtctttatttaaattagcaacattacttaggatttattcttcaca 4681 atactgttaattttctaggaatgatgacctgagaaccgaatggccatgctttctatcaca 4741 tttctaagatgagtaatattttttccagtaggttccacagagacaccttgggggctggct 4801 taggggaggctgttggagttctcactgacttagtggcatatttattctgtactgaagaac 4861 tgcatggggtttcttttggaaagagtttcattgctttaaaaagaagctcagaaagtcttt 4921 ataaccactggtcaacgattagaaaaatataactggatttaggcctaccttctggaatac 4981 cgctgattgtgctctttttatcctactttaaagaagctttcatgattagatttgagctat 5041 atcagttataccgattataccttataatacacattcagttagtaaacatttattgatgcc 5101 tgttgtttgcccagccactgtgatggatattgaataataaaaagatgactaggacggggc 5161 cctgacccttgagctgtgcttggtcttgtagaggttgtgttttttttcctcaggacctgt 5221 cactttggcagaaggaaatctgcctaatttttcttgaaagctaaattttctttgtaagtt 5281 tttacaaattgtttaatacctagttgtattttttaccttaagccacattgagttttgctt 5341 gatttgtctgtcttttaaacactgtcaaatgctttcccttttgttaaaattattttaatt 5401 tcactttttttgtgcccttgtcaatttaagactaagactttgaaggtaaaacaaacaaac 5461 aaacatcagtcttagtctcttgctagttgaaatcaaataaaagaaaatatatacccagtt 5521 ggtttctctacctcttaaaagcttcccatatatacctttaagatccttctcttttttctt 5581 taactactaaataggttcagcatttattcagtgttagataccctcttcgtctgagggtgg 5641 cgtaggtttatgttgggatataaagtaacacaagacaatcttcactgtacataaaatatg 5701 tcttcatgtacagtctttactttaaaagctgaacattccaatttgcgccttccctcccaa 5761 gcccctgcccaccaagtatctctttagatatctagtctgtggacatgaacaatgaatact 5821 tttttcttactctgatcgaaggcattgatacttagacatatcaaacatttcttcctttca 5881 tatgctttactttgctaaatctattatattcattgcctgaattttattcttcctttctac 5941 ctgacaacacacatccaggtggtacttgctggttatcctctttcttgttagccttgtttt 6001 ttgttttttttttttttttttgagagggagtctcgctctgttgcccaacctggagtgcag 6061 tggtgcgatcttggttcactgcaagctccgcctcccgggttcacgccatgcttctgcctc 6121 agcctcccaagtagctgggactacaggcgcccaccaccacactcggctaattttttgtat 6181 ttttagtagagacggggtttcaccgtgttggccaggatggtctcgatctcctgacctcgt 6241 gatctgtccacctcggcttcccaaagtgctgggattacaggcatgagccaccgcgcccag 6301 cctagccatatttttatctgcatatatcagaatgtttctctcctttgaacttattaacaa 6361 aaaaggaacatgcttttcatacctagagtcctaatttcttcatcatgaaggttgctattc 6421 aaattgatcaatcattttaattttacaaatggctcaaaaattctgttcagtaaatgtctt 6481 tgtgactggcaaatggcataaattatgtttaagattatgaacttttctgacagttgcagc 6541 caatgttttccctacgataccagatttccatcttggggcatattggattgttgtatttaa 6601 gacagtcagaataatgatagtgtgtggtctccagaggtagtcagaatcctgctattgagt 6661 tctttttatatcttccttttcaattttttattaccattttgtttgtttagactacacttt 6721 gtagggattgaggggcaaattatctcttggagtggaattcctgtgttttgagccttacaa 6781 ccaggaaatatgagctatactagatagcctcatgatagcatttacgataagaacttatct 6841 cgtgtgttcatgtaattttttgagtaggaactgttttatcttgaatattgtagctaacta 6901 tatatagcagaactgcctcagtctttttaagaaggaaataaataatatatgtgtatgaat 6961 ttatatatacatatacactcatagacaaacttaacagttggggtcattctaacagttaaa 7021 acaattgttccattgtttaaatctcagatcctggtaaaatgttcttaatttgtctgtgta 7081 cattttcctttcatggacagaccattggagtacattaattttcttaatctgccatttggc 7141 agttcatttaatataccattttttggcaacttggtaactaagaatcacagccaaaatttg 7201 ttaacatcaaagaaagctctgccatataccccgttactaaattattatacatccagcaga 7261 ttctgggatgtactaacttagggttaactttgttgttgttgataatactagattgctccc 7321 tctttaattcttcttctggtgcaaggttgctgcttaagttaccctgggaaatactactac 7381 aaggtcaaattttctagtatcttacagcctgattgaaggtgattcagatctttgctcaat 7441 ataaatggattttccaagattctctgggccatccttgacccacaggtgatctcgctggag 7501 tatattaacttaacttcagtgccagttggtttggtgccatgagatccataatgaatccag 7561 aacttcaccattgcttagatataagagtcccttggaagaataatgccactgatgatgggg 7621 gtcagaaggtgtattaactcaacatagagggcttttagatttttcttcaaaaaaatttcg 7681 agaaaagtattcttttaccctccaaacagttaacagctcttagtttctccaaatatgctc 7741 tttgatttacttatttttaattaaagatggtaatttattgaacaatgaaatccgtaatat 7801 attgatttaaggacaaaagtgaagttttagaattataaaagtacttaaatattatatatt 7861 ttccatttcataattgttttcctttctctgtggctttaaagtttttgactattttacaat 7921 gttaatcactaggtaacttgccatatttctggttctatattaagttctatcctttataat 7981 gctgttattataaagctggtttttagcatttgtctgtagcaatagaaattttactaagtc 8041 tctgttctcccagtaagttttttcttttctcagtaagtccctaagaaaacatttgtttgc 8101 cactcttactattcccaatcttggattgttcgagctgaaaaaaaatttgatgagaaacag 8161 gaggatccttttctggtgaatataggttcctgctttaagaatgtggaaatccattgcttt 8221 atataactaatatacacacagattaattaaaattgtgagaaataattcacacatgacaag 8281 taggtaacatgcatgagttttgaatttttttaaaaacccaactgtttgacaaaatataga 8341 acccaaattggtactttcttagaccagtgtaacctcacacctcagttttgcttttccaac 8401 cctgacttgaaaggcatatttgtatctttttattagtgatagtgaagctgtgacactaac 8461 cttttatacaaaagagtaaagaaagaaaaactacagcgattaagatgagaacagttctgc 8521 agttgttgaactagatcacagcattgtaggcagaataaaaaatgttcatatctgagaata 8581 ttcctttcgccatcttttcccaaggccagacctcctggtggagcacagttaaaagtaaca 8641 ttctgggcctttgtaatcggagggctgtgtctccagctggcagcctttgttttaatatat 8701 aatgcaggactgtggaaaacagttggcatagaatattttcacctaaaaaagaaagaaaag 8761 acatacaaaactggattaattgcaaaaagagaatacagtaaaataccatataactggaca 8821 aagctagaagaacctttagaagatttgtctgaaaacagatttcaagagtgagcttttata 8881 cactgctcactaatttgcttgattactaccaactcttcttaaagttaacacgtttaaggt 8941 atttctggacttcctagccttttagcaagcttagaggaactagccattagctagtgatgt 9001 aaaaatattttggggactgatgcccttaaaggttatgcccttgaaagttcttaccttttc 9061 tctagtgatattaaggaacgagtgggtagtgttctcagggtgaccagctgccctaaagtg 9121 cctgggattgagggtttccctggatgcgggactttccctggatacaaaacttttagcaga 9181 gttttgtatatatgtggatttttctgataagtagcacatcagaggccttaaccactgccc 9241 aaaagcgattctccattgagagtacatatcttgaacttaagaaattcatttgctctgatt 9301 tttaatcttgtaaagtttttgctaaactcaaaacaagtcccaggcacaccagaaggagct 9361 gaccaccttaggtgttcttgtgatttatccttacttccctatgttgtcatagttgcttct 9421 aaactcagctgcactatggctgtcaacatttctgatacttattgggatatgtgccatcca 9481 gtcatttagtactttgaatggaacatgagatttataacacaggtaatagctgaaggtacc 9541 agtatggtggtgagactcacacttagtgatccagctaaggtaactgatgttataatggaa 9601 cagagaagaggccaactagatagctaagttcttctgaacctatgtgtatatgtaagtaca 9661 aatcatgcgtccttatggggttaaacttaatctgaaatttacatttttcatagtaaaagg 9721 aaaccaattgttgcagatttcttttcttgtgaggaaatacatggcctttgatgctctggc 9781 gtctactgcatttcccagtctgttctgctcgagaagccagaatgtgttgttaacattttt 9841 ccgtgaatgttgtgttaaaatgattaaatgcatcagccaatggcaagtgaaggaattggg 9901 tgtcctgatgcagactgagcagtttctctcaattgtagcctcatactcataaggtgctta 9961 ccagctagaacattgagcacgtgaggtgagattttttttctctgatggcattaactttgt 10021 aatgcaatatgatggatgcagaccctgttcttgtttccctctggaagtccttagtggctg 10081 catccttggtgcactgtgatggagatattaaatgtgttctttgtgagctttcgttctatg 10141 attgtcaaaagtacgatgtggttccttttttatttttattaaacaatgagctgaggcttt 10201 attacagctggttttcaagttaaaattgttgaatactgatgtctttctcccacctacacc 10261 aaatattttagtctatttaaagtacaaaaaaagttctgcttaagaaaacattgcttacat 10321 gtcctgtgatttctggtcaatttttatatatatttgtgtgcatcatctgtatgtgctttc 10381 actttttaccttgtttgctcttacctgtgttaacagccctgtcaccgttgaaaggtggac 10441 agttttcctagcattaaaagaaagccatttgagttgtttaccatgttactatgggactaa 10501 tttttaattgttttaatttttatttaaactgatctttttttatatgggattacattttgg 10561 tgttcactccctaaattatatggaaaccaaaaaaagtgattgtatttcacatatggacat 10621 atgattttaagagtacatgtttttgtttttttaatttggtgttacataaaagattatcct 10681 atccccccgggagataaatttatactacttaatataaccccacaacaggcgcacaccaca 10741 cactgcacagtgctatttatacatttttatttatttcagagtttgcctatgctacattag 10801 cgctctaatacataagatctatgctgtaaacaaaaacatcttcaaagttgaaatttgctg 10861 aaatatacttttaacaaaataacatttttaaggctccattgaaaaatactagataagata 10921 taatctcatataatcagtatgaataattttaaaaatgagaaatatttaggtcagccacac 10981 ttcctttgtgccttgcaagaattcagttctgtggatgaatcagtactggttagcagactg 11041 ttttctgcaaaccattttaaacatgctttagtatgcaacaaaaagggacctcaaatgcta 11101 aaatacactattttacgtggcattgaatagccttgggactggtgtagttttatcaacact 11161 tttttattaggaagaaacccaagaaaatttactgtaattgctaccacctgccactgtata 11221 aataatctaaaagggacttcccaacattgaacaacaacattgagggctgactcgagatcc 11281 ttctacattgtcacctcagcctggctttgcctgtcactgcttagcttgaagtagtgacac 11341 tgttctgtatcaggagatttttataatggccctagcatccataattccacatgttcatca 11401 aatggctgaagagtatgagagaagtattaaggtctatgtttgggctgtctccccacttgg 11461 catattctgtttttccctcttcaaaatagattgaaagcctcttagtgcaggaagcaggca 11521 tcagtatcaaactgatgtcatccaatgtaattattttaagctccaggtttgtctaagttt 11581 gggtgaagaatgttcaggaacatgtttgcaacatacagttatccagcttaccctttgaca 11641 gattcacccttctcatcaaaatagtaagcccaacctaaaaattataagtttacaaataaa 11701 ggaatagaaaaacccaaaaagctaatttacacataaaaattatcttttgctgcaataaat 11761 aggtatggaaatatttgtagaattggtttaactgattttgtaaaacaaatgtcatgctat 11821 tttgccatagtgagacatgcagtaattcttaaaatcacattaatagaaggcaagaacatt 11881 gaatcagacttagcagataacagattcagtgataaatgaacaatagactaagcatactta 11941 ggaagctacatgagaacagaatgtattactgtgctcccgtccaaactgcatgactttatt 12001 ggttatagaataaatggaatttgagatggggatttgccagtttttacagtctgtcttcaa 12061 tagttttgttggctgcctctgcacctttctaaatgttatgtgaaaataaaattatttaag 12121 ttctaaagtagtttaggaaagagatgtgatgacaggaaaaagaagttaacttctgaacag 12181 tttggtccaggaagaagatgggcagaatacagtaagcccagggttgaagaatacattcaa 12241 tttggagagatggagaagacctttgaagaaggtcaaaatgagatcttggaacagaactct 12301 cacctgtgtgtctggatatacatgaaaactggacggtgttattgagctactgcttatatg 12361 gtgagcagaaaattgataaccacaagcctggtaggttctgctatgaagcccacatataat 12421 cacaaggcctagatagcttggagttaaaagccaaggatagctgtatagtttgggttccat 12481 agtttgcagtgagattgtgcttctgagcagtcatttgggggcagtggttctgagattaca 12541 agccataacccagccaagaacgggctacctgtggaatgaggatgaggaagttgctacata 12601 taaaccctagtgtgtgtgtgtgtattaagtgaaacttagttaacttttttgctcacagcc 12661 aaagatgattcatctagagaagccattggaattttagcagagttttgtatatatgtggat 12721 ttttctaataagtagcaaatcagaggccttaaccactgcccaacagcgattctccattga 12781 gagtacgtatcttgaacttaagaaattcatttgctctgattttaaatcttgtaaagtttt 12841 tcttcatgagaggtcttgcctctaaactatattgtggcagtatttgatcaaactacataa 12901 gtaccatgtaaataagattttaatacaaatgatgactcacttctaaatggtttgccattt 12961 agaaatgtgctgctgtgagaaaaacgaattttttttttttttttttggagacagagtctt 13021 gctctgttgcccaggctggggtgcagtggggcgatctcggctcactgcagcctcgcctcc 13081 tgggttcaagtgattctcctgccttagcctcctgagtagctgggattacaggcacacacc 13141 accacgcccaactactttttgtatttttagtggagacagggtttcaccatgtttgccagg 13201 ctggtcttgaactcctgacctcagatgatttgcctgcctcggcctcccaaagtgctggaa 13261 ttacaggcgtgagccatcatgcctggctgaaaagtgaaaatttaagccagcttaccacct 13321 ggaataaaaatgttttataggaatgtctaggttgctcttttatattgaaaaaaaacttat 13381 tagtgtctgttttacccaagaaccacaagctacttcatttcaacttttaaatcatgaata 13441 ataacgtgttatcaccacatttaaaaatgtacatcgtcaatcacaaacacatattctaag 13501 gaattgaattttatagagataattgaatgctttcatctgtaaaagaattagtggcctgca 13561 aaccactgtggattcttgctatgctttgaagttgtcagtgggggaatttgctgctgcaag 13621 ttacttagacttgtaggcaaagggaaattcaaatttttaattctaaaatgaaaaccactg 13681 acaaaattttatactctgaaagtttggttgttagcttagtcattattttcctgttcttta 13741 tcatttcggaattcagatgcttaaatttaacatacaaattatttgttggtaaaacataaa 13801 acataaaaagctacatttggtaaactaaattttaggattcaaagtctctaacaatttcta 13861 tgtgacatgtcatacggtgcagtttttatttgccaaagtgtctacttcatactgcctatg 13921 cactgcttcccgtttttaatctctctaccccaacccccctataattaaataaacccctag 13981 aaaactgccttcttttagaatacctaattgattactttaaatattttttcagaatcaaaa 14041 ttacaaaagggagagatacctaagaatctggcttgtttatattctttaaaagatcgcatt 14101 tgattgaaggtgggtgcatattttttatatccactctttccccatttgtatgtgaccatt 14161 gtaaaagtggatgtgcttttttttttttgctgaggtctagagacaatgttttagagatac 14221 agaatgaaacatttatgggtaaaatacaatgggtaagacttgcttcaaaatagtatgtga 14281 cagaggaagtagatggaggtatgaatgaataggacattgatggttgtttgttgggattgg 14341 gtaagggagctttgttgtattctatttccttttagataagtttgaaattccttgtagtga 14401 agaaattaaacgtctccatcaggtgcattgccacgtcttctctaggaagcctccttaaca 14461 tcctctggtggctcctgaactttttctgttctcattcacagggaagctcatggggctgcc 14521 tggagacttgaggttacatcttgcctagtattaccaaaattgtgatacttttctccaccc 14581 cataatagcacagtctttggtctcaacttgaactaaagtctttttttttttttttttttt 14641 tttttttagtatttattgatcattcttgggtgtttctcggagagggggatgtggcagggt 14701 cataggacaatagtggagggaaggtcagcagataaacatgtgaacaagggtctctggttt 14761 tcctaggcagaggaccctgcggccttctgcagtgtttgtgtccctgggtacttgagatta 14821 aggagtggtgatgactcttaacgagcatgctgccttcaagcatctgtttaacaaagcaca 14881 tcttgcaccgcccttaatccatttaaccctgagtggacacagcacatgtttcagagagca 14941 cggggttgggggtaaggttatagattaacagcatcccaaggcagaagaatttttcctagt 15001 acagaacaaaatggagtctcctatgtctacttctttctacacagacacagcaacaatctg 15061 atctctctttcctttccccacatttcccccttttctattcgacaaaaccgccatcgtcat 15121 catggcccgctctcaatgagctgttgggtacacctcccagacagggtggcggccgggcag 15181 aggggctcctcacttcccagacggggcggctgggcagaggcgcccccccacctcccggac 15241 ggggtggatgctggccgggggctgccccccacctcccgaacggggcagctggccgggcgg 15301 gggttgccccccacctcccggacggggcggctggccgagcaggggctgccccccacctcc 15361 ctcccagacggggcggctgctgggcggagacgctccttacttcccggacggggtggttgc 15421 tgggcggaggggctcctcacttctcagacggggcggccgggcagagacgctcctcacctc 15481 ccagacggggtggcggtcgggcagagacactcctcacatcccagacggggcggcggggca 15541 gaggcgctccccacatctcagacgatgggcggccgggaagaggcgctcctcacttcccag 15601 actgggcggccgggctgaggggctcctcacatcccagacgatgggcagccaggcagagat 15661 gctcctcacttcccagacggggtggcggccgggcagaggctgcaatctccgcactttggg 15721 aggccaaggcaggcggctgggaggtggaggttgtagcgagccgagatcgtgccactgcac 15781 tccagcctgggcaacattgagcactgagtgagcgagactccatctgcaatcccagcacct 15841 cgggaggcccaggcgggcagatcatgcgcggtcaggagctggagaccagcctggccaaca 15901 cggcgaaaccccgtctccaccaaaaaatacaaaaaccagtcaggcgtggcggcgcgcgtc 15961 tgcaatcccaggcactcggcaggctgaggcaggagaatcaggcagggaggttgcagtgag 16021 ccgagatggcggcagtacagtccagccttggctcggcatcagagggagacggtggaaagt 16081 gggagaccgtagaaagtgggagacggggggagacgggagagggagagggatgtgcttttt 16141 ttctaaccgttattgccaccaagtaataatgtcttaattcacaatttacatagtgattgg 16201 ctggagagaggtattgagcataaatttttttttaagattcaactgggaaatggatgattt 16261 acatgattttagtctctttagttgtctgggtatttcttgactgggaatagcaatatctta 16321 aaggccatttttaacaagaatgctaaggatggaacacttgaaggaagcagtcctgtacag 16381 tcaaatacttcagttaccttggataatagaatgaaaactcaattgcctactttgaacaaa 16441 ttttttttttggattttaatggctggacagaataacattctgctaattttaatccttggt 16501 catttccgatgtaatggaaaatgcagtttgactcagaatcggaggcctggggtttggacc 16561 ctgattgtgccaatttatgtgactttagataaatcttttcatcagtctaccttaaagttc 16621 ttcatttcctccagttccctaaaatgaggaagttagtttttagggtggttatgagaacta 16681 aatgagagcacttgagagatcattcagcctgaagtgggtactcagtattagatggctaaa 16741 tctgcacagtctagaataccaggcaaaggttactctgaaggtctttgctaataacaaatc 16801 tttctctaagaaagtttgtaaatgtgatgttaaactcagaaatgtcacatagaacatatt 16861 ggagcaattattgccgcaaaagtaactcgtagcaaccacaaaaacccagtggtgtgcagc 16921 aataaacagtttatgaattagataagtgatttcggctagatgtctctggagcagttgtag 16981 tctttcctcgttcatgagggagttggcctcacctggaaggacttggcatttttccacatg 17041 cctcctatcctccattaaacaagcatgtttttgtggaggttgtagaaggcaacaacagcc 17101 aagcccaatcccataactccctttcatgtctgcatgcttcatgctaactagcattcacca 17161 gaaacaagccacatggctaaacccagtgtggaaaggcactacagagttattagaccaagg 17221 gagagaacataggaggggtgaagaattggagccttaaatgcagtcaatctaccacaccct 17281 tgctttgtatttaacaggttactgtactggtttgccagcaaacaatggaaaatgtggaga 17341 agctgaagaatgctcaagctgggacttaatagagtggcctatttggtttgaaatgtttta 17401 acttacagagcattgagtagaagcctaatctaatatacataaggaagacaaaagcaaagg 17461 attgtgttttctatctaaaggttaatcattgtggttgctcctggccattatcacatgact 17521 ggaagttaacactctccaaacgctgagcctatcctgtacagcactagaaagtagaaagaa 17581 tcactcaattcagggaaaccgttttctcttaatgtgaacatttacattaatgccatttcc 17641 aaaacctttctgggacttcttaaatgcaaagatgctatctgctttacttcatgctgcctg 17701 tttttaggagcttggagtgctttaggaagcttcccaatactggtttagcagtaatttggt 17761 tgactgatcaaggcatgttttaactttgacactgaaattttaaaaagacaacagttatct 17821 tgcccggagagtcaagtttctgcttccaaggaggtcaggaattgttctctttggtgatgt 17881 ggctgtgcttggtagcccttgaaagtggagtcgacagcagtcctcagcttttgtgtgcct 17941 gtcttagtctgttttgtgttactataacaggatagctgaggcagggtcacttatgaagga 18001 tgctcacagttctacaggctgggaagttcaagggcatggccctggcttttggcaagggct 18061 ttgctgctgcttcatagcttgatggagaaggtcagaggggaagcagacgtgcaaacaacc 18121 cacttgttcacaacaaccaaacaagtctctttttaacaacccactcctggggactaatct 18181 agtcttgagagagtgagaactcattgcaagagcagcaccaagccattcatgaagcatctg 18241 cctcagtgaaccaaacatctcccactaggccccagctctcaacaccaccacaatgaagat 18301 aaaatctcatcatacatttgagggacagtttgggagacagaccatagcagtgctcagtat 18361 ttctacccaaatgttcaggtaacttaatatatttttccttgaatatatgtttaaatgggc 18421 ttcccttccccacgctcatcttgaatggtcccacaacaacttttgattatcacgttcctg 18481 taaatacacaaaaatattttgtggtcttttactggcagcccagtggatgggactttaaaa 18541 aatcacccagattccaacaaccagagaaaacgactggtgtatattttttccagtctttat 18601 ttgtatgtctgtgtatattcaatggaaaatgtttgaagcttcactcacagcacattccat 18661 tagagaaagctactaaaatcataaggaaaatctaaaatgcagtaagccagtcagcaagcc 18721 ataatgggcatatgaaaacaaagttttttgccatgatttgtggaccacagaagatctgtg 18781 ttattagtctatttaagtttggtgtttgaaattaaaaatgttcgacatactttttatgtt 18841 ttttttaaatatactgtctatatttaaaattgagtatactgtactttagtgtgtttggaa 18901 gcagatatccccaaataaaagtatacagtagaaccaaagaattttattgatcagctagaa 18961 tttagttttcaggtgtaataactgtcaacctaaataacagaggctttctaaaagaaaatg 19021 atgtttatttgggaatagggcattgtgaaggcaatatgcatgccatagtaaactgtgtgt 19081 attcaggaaggtaaaggaagacaggtttttaaaggacagataaagattatataattgtct 19141 tgaaataattattcttggctacaaggattaataacaaggatgctgccagttcgggtttgg 19201 acaatcggcttctaggcagatgtcccaaaagtattttctgtgtaaggttgcgaatagtgt 19261 ttgtgcaagctggcgtggtttcttctgggtctttgaggtagtgcgtaaaatccctctctt 19321 catggacttccctggctccatttgtcagggcttttggaaacatgactcttgattctgaca 19381 gctttcacctttccctctcttgatgaagatgtttttccgaaagtatctatgatgaatcat 19441 cttgtagttaggctttgattgtcccttggtgacagaatagacctttcccgggttattggt 19501 ctggtcctgcatcctgcattggcaggagtgattggcaactaaaagtcagtgttaaaaccc 19561 ttttagccacctttgagggcagggaggctttaagggagtggcacttaggctaagtccacc 19621 tggagtctattattaagtccaattttttttccttagtcctttgttgtcccctcaaagtgc 19681 tgggctagcattattctgttaggaattgtacttctttctgcagaaaatttggcaaataac 19741 agatacaaagtttaaaaaggaaatacacaaaattaatagtaatgtgacaatcccagtttg 19801 cataatggttttgagccctgaacctaggcttacaggcaaccaattgaataaatcaaattg 19861 taatacaattcttgctctgatgtcttaggaaaaatgtctacagcctgaaatcatcaactt 19921 tttgtcctggtttgcagtttgaatgtctctagctatggcattggttggtatggtgaactt 19981 ttgtgtgacccatacatcagcatgagacttgctcctttaaaaattaatcacatcttagct 20041 tataggcctcagagcatgggagtagttttttttcttagagagtcatagccaaatattgaa 20101 ggaaattaggaggattcaggagcaaatccagtctgcaggtggataacaggagtttcaaaa 20161 cggtacagagctgtgatctaataacaggtacatatagctttcttcagaaacttaaagtta 20221 ccctgatttttaccaaagatgttcagaataaaacagatttgtaaactttatcagattttg 20281 tctgcaagaatagtagtatggtcacagtaatctcagatttaaaaacctccttgaggctaa 20341 gaagctaagtcaaggtagactttagattttacctatagttttaaggttcctgggcctgcc 20401 aggaaatgataatttttaattcagtgtaatgctgagaaccattgaagccaggcattctac 20461 acattctcaaatatgacattttaatcaaagccttggtaatacaaccagtgtttccaattg 20521 tatcctgttataacgagagccgatttttattgaacttaggcaaatcatattgccttaaga 20581 gtactcacaaataggctgggcacagtggctcatgcctgtaatcccagctctttgggaggc 20641 caagacaggtggaacacctgaggtcaggagtttgaaaccagcctggccaacatagtgaaa 20701 cctccccccggccaccgtctctactaaaaaatacaaaaattagctgggtgtggtggtgca 20761 tgcctgtagtcccagctacttgggaggctgagacagaattgcttgaaccctggaggcaga 20821 agttgcactgaaacaagatcgtgccactgcattccagctggggcaacagagcgagactcc 20881 gtctcaaaaacaaaaacaaatgaatactcaaaatagtttccaaattggagggatcaagaa 20941 gaaaggaaaagcaaatatttctacctttgttcacaaaagtattccaaattgctgtaaact 21001 atagatagcatgagagaatttctttaaatatggaaaacaaaacatttaagtaaaaaaaca 21061 ataatgcttcaaataaaagtcacagacacatcttcagttacttagtctcatgtaactttt 21121 tttgttgtggttgatcttaattagtagttacatggactcatcagtttcttgaagttctga 21181 aaaaatatttagtccattggtattaaagtgattagtaacctgtatttaaaagtgtgttag 21241 catcttttccatgaatctgattgcaaatgcttttagagaaaaagcaataactgggaatta 21301 caaaaacttagaataaccatgattaaaaatctgatgagagtttaccataaccagaaatag 21361 acaaagagttttggttatttttgtggcaaacagcataatcagaattatgactgatgacat 21421 atttctaacggcatcgtacaattttggaacactcatatcaataacatactcataaatgta 21481 actgtgtctagtattacatcattagacaatgcttttcatacaatttaatacatcaaagaa 21541 gcctaattagctaacatctctaccagatggcatacacatgctctgaggctttccagaggc 21601 ccaagtggaaaactcaaaggtaattttaagtcaaaaacacttaatttagaacttgagcct 21661 agagaagcctgtcaaagatgtcaaaagttcgaaacaggatcacaggtcactataaaatat 21721 ttaacaagaatgataatcaaaagacttaagaagcaatgcagaaagttacatacatttaaa 21781 aaccatcttttcaaagcttcatttttcccaagcaaaaaaaaaacttaaacacaagaattt 21841 atcttgatagaacataaaatttttcttaggccagttgccaaaatggtaaagaaaaatctc 21901 ttgcagtgtgactgcctttacttatgggaagcctatttggatatactgaaagttgaatct 21961 gatgaaaaggtacttgaatttaatcagacacaggaagagtatttccaaggttatgagtgt 22021 acgccttatagaggaatgtaaataagaaagctagtatgttgaacagaatacatggctctt 22081 ggaaaaattacgagaaatttcctgcttgcgtggaacaattcaaacatgagaagagccaag 22141 aattcagaatcaagttatactggaggaaaacattgcttttctaggccttctacagaacat 22201 ttcagtatcaagttataacagcaagagttagaaccagaggaaaaaagttacaggagctaa 22261 tgaaaaagttaagagttatcacccctgccaaacaaaaagatgtaccttcttaaggggaga 22321 aagagctaaaggcaatgatgtgtgacctacaaataaggtgcagcaagatacagcaaaggt 22381 tgaacttgtgagatataaatcaggatcttcaagaagaaaactctacctcaagaaatgaaa 22441 tgaccatcttaaatgaaaaaagacagcctttctaacctgaatctaggggaaattaaacgg 22501 atctcagaaggaaatatggcagaaatttaaactgtggtttagaagatggctgattttaga 22561 attaaaaattaaaacctctttcaattttattaagaccagatccttaaaaagaaccttgtt 22621 ctaacattggggaccaaattttgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgt 22681 gtgtgtatagtgcatgtatagcatttacactatcgtgtatatacaaatatatagcatatg 22741 tatagaatatactgtattattgtacatatacatatgtacaagtatatatgtaagctcaat 22801 gtcttatgatttcattctgacctattgccaacttcattacacacaactcctttcataaat 22861 gtatccttcatgaacatttcatgatctgcacagaccttcagtgacatgcttaaactttct 22921 gctttgttttatacttccccttaaacaactggtcatcctgctttaggataaaaagttact 22981 atgcaagactcatacagaattattctgttaattttgtaaccttccttaccaaaggtacat 23041 tctcacacccattaacttccttcatatttctctcctcctcctacttagtggttcctttct 23101 gtcttgtttccatatttgaaacaacctctaataaactctgaatttaaacaacttttttcc 23161 caataaaaagcaatttttatgccttataacttttctcatcaaaacatctttttttgggta 23221 cactttgtatatggaattgtgtattttcaaattttaacttattaaccttaatttttagtg 23281 aaaacctaggaagcaaaattttgaagtgttatatcagcattttataaatgagaaccatat 23341 tataatttttagaaacatgtttccttataactttgtatattaataggcccaaatatattt 23401 agtctttctataatttaggaagccaagaacaaactaatattttcagcagtttattgtttt 23461 tttttggaaatgatccagacatttactgaagattaatttataagatttcaaattacatga 23521 aaagttcattaacatcctatttttaaaaacattcttttggtttattttttagagacaatg 23581 tcttgctgtgttacccaggctggagttcagtggctgttcacaggcacaattgtagcacac 23641 tgcagcctcaaactccaactcacacaatcctcctgcctccgtttcctgagtagctggaac 23701 tatagatgcatacctgcataccaccatgtctcacccttgcttatcccgtttataatccat 23761 ccaattcttttttttttttttttttttgagacggagtctcgctctgtcacccaggctgga 23821 gtgcagtggcgtgatctcggctcactgcaagctccgccttctgggttcatgccattctcc 23881 tgcctcagcctcccgagtagctgggactacaggcgcccgccaccgcgcccagccaatttt 23941 ttgtatttttagtagagacgaggtttcaccgtgatctcgatctcctgacctcgtgatctg 24001 cccgccttggcctcccaaagtgctaggattacaggcgtgagccactgcacctggccccca 24061 attcatttttaacaattattcctagattacttataaaaactgagatattagacatagcta 24121 gtcatttcaagttattttcctgttaaccatttttattacctgtgagtatcatgtgttcaa 24181 ttaagaaccataaaaatgaaatatgtaggtattttgccagtaactcagaggacacagctg 24241 aagtcaataatacaaaattagttcaacttacagttatacaaagatcattctgtttttaag 24301 ttgagtttatagttttatgaccttaaaaagtctaacagagacaaatataaaactgagtag 24361 taaattcaggcaaaaattttaaagacacttatttttgatttaccaattattttaaaacca 24421 gcttatcagatgtttaagttatattaactaaaaggcacttgtgttaattactatatattt 24481 tgtattagcactcatttatttgatgaatagaattccttaagggatttgtggccaactgcc 24541 agattttaccacgtagacacaacatacaacatatatatacatatgtgtaaacacacctaa 24601 acatacacatacacaaacatagctttcattttagaattttagtcatacgatagtaataca 24661 ggcttgctggtttataaaagacagttattggattcaaattatatttctgagaaagtggga 24721 cctgctcagctgggtaaacatgcagaataggtaatcttatgaaagctgtgaaccaaaagt 24781 tttggtaaatagcagtttggatttttaaaaaacctcttaccccacctccccaaccccttt 24841 tttcccttttttcagtttcaaatgagtttaatgttaatatttaaatgcttacatttttag 24901 ctaggactggctgaattgtataagaaaaaacaatctccaggtggccttgaatttttagta 24961 acaaatcttttgtttgccattctggtttttttgactagtcagtgcaggcagggaagcatt 25021 ttagcagttgtggatgaggggtttttgttttgttcttttagcctttgcatagcaggcaag 25081 caatttttatgctataccagagataccttatattattgccctgagctcaagattttgacc 25141 tgtttgagagcctaatttttatacgtatttatctagttcttttaggctattaatccttta 25201 attaactgttccatcaccctaagcagttattaggcaaacctaaatttacattaaaaggga 25261 tacttcttaattctaggtgttggttgccagggaactattataatttataaagccattaat 25321 ttaaggccctttaagacctttttttttctttttgttcttggctggaatgccgtaaggagt 25381 gagtttcatctcaacactggcagaaacagcagatttaaagtaggcagaaaaaaaattaga 25441 gagcttagaagactctacatatcaactctatagctgcagtctcttggtactaagaataaa 25501 aaagcttggggagtttagacaaagcatagacaatctctatgatggtcattgatccaaaaa 25561 catgcatgaggaaaagccacatagctgacctgaagtcccagaaaagcaggcatgccttaa 25621 tgtttgagaatttccattttgtttcttctcaatctcttaagagcaaagaaaattctgtaa 25681 atcctgacagataagtcaggtgtttggaccagtgttttaactggtggcgattgccctagt 25741 ggctttaaaagagccatcctgtgcccaaaatttagaatgtttatttttgctcttgggaga 25801 tgttcagaaacaggggaaaagagccaaatcatttacagatgcatgtaaccatatcgaaac 25861 gaaaccaaaatcagtgttcccaaaagtgttaacccagtcatgcagattaaaaaataatat 25921 aaacacagaagaacccaaagtaaatttaccagaaaaggcatgcctcagaatccagagtac 25981 tcagccaggcgcagtggcccatgcctgtaatcccagcactttgggaggccaaggcaggag 26041 gatcgcttgagcccatgagttcaagaccagcctcagcagtatagtgagacactgtctcta 26101 aaaaaaaattgtttttaaatccagagtactcaaaccagagggacacttgtctttatatca 26161 aaaaggacttgccaggaaagacaaaaagtcttttgtcatcccaggagggatgtaaagtcc 26221 tttattaaagtggtcttagaaccaagacaaatccaaagtcaagtcaaaaagcctctgcca 26281 aaagtgggaggctctgcctgagaaaagactcactggggcagaacagacaagctatgtaag 26341 cggagagcccaaagggctcctgtgagtactgcatactgattctgagatcaccacttctct 26401 ctgaaatgtgtcctacttcaggttctactgctgaacaccatttatgtcaacacagagaga 26461 ggctctctaaaagaaaactctatttgggaatacagcattgctgtagaaatacgcatgtca 26521 tgggccgtgcgcggtggcttatgcctgtaatcccagcactttgggaggctgaggtgggcc 26581 gatcacgaggtcaggagtttgagaccagcctggccaacatagtgaaaccccctctctact 26641 aaaaatacaaaaaattagatgggtgtattggtgggtgcctatgatcccgctacttgggag 26701 gctgaggcagaagattggcttgaacctgagaagtggaggttgcagtgagcctagatgtgc 26761 cactgcactccagcctgggcgacagtgcaaaactacgtctccaaaaaaaaaaaaaaaaga 26821 cccatgtcatggtaaactacgtgtgtattcagggaagtaaaggaagacaaagattttaaa 26881 gaaaaatgagggttgtataattgttttgaaataattgtcgttggttacaaagatcaatag 26941 caagggtggtgccactctgaagttggacaggcagtggctaggcaaaagtattttgtgggt 27001 aacctttgtgaaaggttgcagtttttgtaacacaagctgctttattttcccaaaagcttt 27061 cacagtacatagaaaatatattggacgtgtattaaatgtgccaaattagtcagcaatatt 27121 acattaaaatatgtgttattacttgttaatgttcttaataagttgttcaggcagttatac 27181 cagactatcttttctcattttccaatttataagtgtattatccaaaaatgttagttttag 27241 ggtgaccactgtatattttggtattttttaaagctacccaattgtgtataatttataaaa 27301 atctttttttcataagacctaaaacttctgaacaatacataggtgcaaataaataaattc 27361 ctttttatctcaaactcacttccactgccctccctgaagaaagccttttgttattgttgt 27421 cttgactaaatgtggcatgggagctaacattttcaagggaagctgatcttatctccgggc 27481 tctagaagccaagacatgaggtatgtgtttaccgtctcttaggtgactctccagaacttt 27541 cattctcaacctcctccctcactgccagttcctcctcagcttcttagccaagtggtagag 27601 gaaaaatggtattttatgtcaggactaagccatgtgctctgagccctgggtaagtctgca 27661 aggcttctctagaactcatacataggtcaattattcctcctctgaaaacttaaactctgg 27721 caccactagctttttcctacagcatacatgggctcagtaaatcctctgttaagacaacag 27781 gaaaattaagacaatgtccttgcaagccccataactactttctatccctgctattcacag 27841 ccaagtgtgtcgagaccagttcacacaaaccttgttgattttcggtttcaccccctcctt 27901 actaaatcacccctccatttgctgcagttgcccttgcgtgctgtactcagacttggagga 27961 agtgatgtcttattcaaggccagtttttgtactagtggttaaataaatggtttccaaatt 28021 ggagtcagaaggagagcttctaaaatgtaggttccctggcctcaattgtgagattctgct 28081 ttagcaggtctggaattggagcactgggatctgcattttcagaaaacccaaaatgattat 28141 cagccaggacttaaacctctgctttagaccacattccctgtgggctttcagattttctat 28201 caatgttcttccctcttcccagctcccacacattaaaactcagatcatgcagaaaagaag 28261 ttacagttccttcatttcacatcaatttctcatgcatcccatctggttttgggaaggtgt 28321 gggacgaggtggatggccttaaacttgccaatcaaagataacgttctctttcgattcaaa 28381 tagcctatctcaggcttaaaaccatctctttggataaatgctcagcttttcaaaggttct 28441 tcctagcttcttcctcatgatggcatctagtgggtgagaacagtcatctccaggtgacac 28501 aggaaagagtttctctaatgtatgtgctgaggtccttgacggtcctgctgctggtgctca 28561 tcctgccatctttgctggatgtcactgagtctactgggtaatgtaagtgggtccctggct 28621 tttgttcactgctgtcatgccctgctcctgaccacaactctgtcattgcctttggtctca 28681 aggtctctaccttaatagcttccatgtcccaactatgggactgttaatctgctgggcttt 28741 ggagtgggtgggaagggatgatgttggaactttgggatgtactgaacatcttgctcaagc 28801 tttgggaagccaacattttctcagactgactagacacctccttccaccaatgctgagcta 28861 gtgctcctgtgccatactgggtaagcctctaagtcatgagtaggacttttttgagtggct 28921 tgcagtcttccccaggctatgccaggaaagtagttgactaaccctgctgctccaagactc 28981 gcatacccatcctgaagtttccgtttatttcccaacagggcaattgcaatctcaatcaat 29041 ctctccctgccctgggagtcattccactcctgcctaatgaagagactcttctcacatcgt 29101 attctcagtttctcttatccatggttaggagtaaaactcatgttcagttgtccaagcttt 29161 gcttttagtatgtgaatggagctcttagcatgtagaactcccttctcattctcagtaaag 29221 tctgactttgaagactacttatcatcttcctagagatgccaaagaataatcaagataata 29281 aaggcaggctctgagattcacagctgagtagcaactgtgctgttactctagtacacaccc 29341 tctcctttcctgtgactgtcaggcttcagggcttacctttattggaaagacagcaggggg 29401 gcatatatgaagaaaatggaatctttaatattgtcaaagtcttgacccaatagagacatt 29461 cttgccccagactctcttgcttcagtgcctttgcctgttctggtcctaagtaccttgaat 29521 atccttctcttgatgccctgatataaaactctttattcctcaaagccaagttcaggttat 29581 cacctccaccacagacttttctttccctccccaaacttcattgcctcttctcatcactcc 29641 ctttgtaatttgtttatactggtaagagagcattcatcataattaggcctatctatgcct 29701 acctttcttgttaaattatgagctttgttctgccttggatatctctctggcttggatatc 29761 tctctggcctttgctctgcacttccaaatgtatccattattcaagacccaggtttccagc 29821 ctgatcaacatagcaagatcccatctctccaaaaaaaaaaaaaaaaaaaaattgtggggc 29881 cgggtacagtggctcatgcctgtaatcccagcactttgggaggccgaggcaggtggatca 29941 tgaggtcacgagtttgagaccagtctggccaacatagtgaaaccccatctgtactaaaaa 30001 tgcagaaaattagccgggtgtggtggtgtgtgcctgtaatcccagctactcgggaggctg 30061 aggcaggagaatcgcatgaacccgggaggcagaggttgcagtgagccgagattgcgccac 30121 tgcactccagcctgggtgacattgcaagactccatctcaaaaaaaaaaaaaaaaaaaatt 30181 agctgggcatggtggcaggcacctgtagtcccagctacttgagaggctgaggtgggagga 30241 ttgcttgagcccaggaagtcgaggcttcatgagccatgtttgtgctactgcactctagcc 30301 tggatgacaaagtgagatccttttctaaaaataaggacccagtttattttatttagttat 30361 ttagttatttttgagaccaagtttcatcactcaggctggagtgcaatggcacagtcttga 30421 ctcactgcaacctctgcctcctggattcaagcaattcttctgcctcagcctcttgagtag 30481 ctgggattgcaggtgcccgccaccacacctggctaatttttgtatttttggtagagacag 30541 ggtttcactatgttggccaggctggtctcaaactcctgacctcaggtgatccacctgcct 30601 tggtctcccaaactgctgggattacaggtgtgagtcaccctgcctggccagaacccagtt 30661 taaattccatcctctctgcagagtcttccttaaccacccctattgaaagttacccctgct 30721 tcctacaagaagtggtacttggatgttcatgagatacctgtgcaaggctcctgtgggggt 30781 cctggggagacagtgacatggacactcatgaaaggaaccttggaatagcgagtgtgtgtg 30841 ctataaaatgtgctttagatttgattaccaccacttaagttatgagctctgatatggttt 30901 gggtctccatccccacccaaatctcatcttgaattgtaatccctacatgttgagggaagg 30961 aagtaattgtattatgggggtggttctcccatgctgttctcatgatagtgaattctcaca 31021 ggatctgatggttttataaatggtagtttttcctgtactttcacacactcacactctctt 31081 ctgccaccttgtgaagaaggtgcctgcttccccttctgccataattgtaagtttcctgag 31141 gcctccccagctgtattagtctgatctcacgcggctaataaagagataccggagactggg 31201 taatttataaaagaggtttaattgactcacagttttacatggctggggaggcctcacaat 31261 tatggcagaaggtgaagggggagcaagacacatcttacatggcatcaggcgagagagctt 31321 gtgtaggggaactcccctttataaaaccatcagatctcgtgagacttattcactattaca 31381 agagcagcacgggaaagacccacccccatgattcagttacctctcactgggtccctcaca 31441 taatatggggaattatgggagctccaattcaagatgagatttgggtggggacacagccaa 31501 actatatcaccagccatgtggaactgttgagtcaattaaacctctttcctttataaatta 31561 cccagtctcaggtatttctttatagcagtgtgagaacagactaatacaagcaccttgagg 31621 tcagaggctaaaatcactttttcccaaacatttcctttttatatatgctacatctttgtg 31681 tctgcttcaacatttccagcagtgctttatatatggtaggcatgcaataaatgcttcttg 31741 atcgactgacaggtgctcagaagatctaggttggttgattctcttgtgatgccatctttt 31801 cctgagagctcattaatttttaagttgttttccttgaaatgcatggtatgtttcctccac 31861 cctgctctttgcctttcatagggttccattttgatcagctgctctcattgtctgttttgt 31921 gatcaaaggttctgatgaactttggaatatgtgtatgtttggagtgaggatggggtctgg 31981 aggagatgcatggttgaggaccaattcacccaacccagcttacagaagtaaagcggcccc 32041 ttaggagcactgaagcattgctgtggatttcagaattaccttatttctttttcttttttt 32101 tttttttttttttgagacgaggtctcgctctgtcgcccaggctggagtgcagtggcacaa 32161 tctcagctcactgcaagctccgcctcctgggttcacaccattctcctccctcagcctccc 32221 cagcagctgggactataggtgcacgccgccacgcctggctaatttttgtatttttagtgg 32281 agacagggtttcaccgtgttagccaggatggtctcaatctcctgaccttgtgatccaccc 32341 gcctcagcctcccaaagtgctgggattacaggcgtgagccaccgtgcccagccagcttct 32401 ttcaaatcagagtaggccttccagtgtggcaggccataagatctgaagttttcaccctgt 32461 tcctggaagccaagtggacagcaactaatttttactttctttattgcacatttggggctt 32521 gggggatagagtcagatgtgtgtcagttgaaactgtagctactgcattccactccttggg 32581 ggatcgtagtgctcatgccaacagaaaacttcgaggctaataattactgtcttcagagta 32641 caagacaggcacggaagttgttttggcataagaaaaccacgatttgcatcccacagtcta 32701 aggaagacgatgctgaattcagaagatggtgcaaaagtgtgacagttcagctgtggcggc 32761 tgttgctgatgcatgggactattttatttacatttcctttcttcttttttaacagagaca 32821 ggatcttgctgtgttgcccagcctggtcttaaactcctgggcccaagtgatcctcccacc 32881 tcagcctcccaacgtgttgggattacaggcatgagccaccatgcctgggctttatttata 32941 tttccaagtcaaatgttagttggtcaatcagtctttttaagcaccaattttgtgcctagc 33001 cttgtggaaactgtaggaaaaagatactttttatttgggaggaccttgatttgctgtcac 33061 aggtgccactaatgccaattataaggcagtgtggaatcaggtgattgaaagcccagtctg 33121 tagcataaactgctgcagggttccagtgggggcaattaaggtgggcagggagggtggata 33181 gcatttgactttgacagcataacctgagcagaggcacagtggggatggtgagtgtgcagt 33241 gggaggagggagagaggtaagtggtagggaagaggtgggaagggggcaaggagaaggctc 33301 aggaggtttggggacagggaaatgacttggttggcgacctcttactttcttctcgtgtgt 33361 gcaatttggaattcacttggttcttagtatttctgggtcagatgacttctttgcagtatg 33421 agaaaccatttcccaggctggctacctgggctgtggtatcttccagtgctcctctgtgat 33481 tgtactcagatcagctcgtctaggcaggcaggatggcagaagccctctgacttcatgtct 33541 gaaagagtatgtgtttcaactctgtaattacagcatttaacagacgatatcagccctctt 33601 tgggatggcttttggcaaatgggctagaagtctattgtgcatttaaatgatactgcatct 33661 tctctttaaaaggtttctcagtgagtccaccccactctgtatccaagtatgtctcaggcc 33721 atgaggcaaaaggaaatgagtagttctttttggttggagaattaaaaagaaatctccacc 33781 caagtaacaggtacatagtgggaaaaaataacatctgcctgaaagcttcatcttcaggca 33841 aagagagggtcagggggcgggagcttagtaatggggaaacctcagaagatttaaagagaa 33901 ttacagacagacaaggctgaacattggctgtcatccaacaaagctcttataagatgggaa 33961 tcactgcccggttcttgagctccgacctggagggaagaggagtctggaagacttggcaca 34021 ggcctgagtgcttcattgtctttctggttccaagtcctcctcagctcactaggaaggagg 34081 tggggtgggggcaggtaggccactctgcataagtgcacacatctacactggctagtctac 34141 ttcacaattcccccacaggttatccttatctctacctggttccagttccagattggaggg 34201 atatagaataccatccccacccctcaccttgcttgctctggcctggaaaactgtcattcc 34261 tttaccaccagctggcatctgccatatgcttcaaggaactgaataaagaggaaggggaaa 34321 gaagaaactagagaaactggaatgcttcctatctgacccccaagtacagggactgcctct 34381 ttccgtaacggcacagaacgtctccatccctttgacctccacctccccagagatgcccga 34441 ggaggacagccttgtttctgtgatctgttgttgagaactgctgctgagaattcttccttc 34501 agcaccgccttaggcaccattggtttttcactaggtccgctgtagaaaacagccaggaat 34561 tacttagttgactaccacctgaggtgctgtttggtgttggtaataaagaataaaggtgga 34621 aatgaa SEQIDNO:6FkananSMARD2Isoform1AminoAcidSequence(NP_005892.1) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkcvtipstcseiwglstpntidqwdttglysfseqtrsldgrlqvshr 121 kglphviycrlwrwpdlhshhelkaienceyafnlkkdevcvnpyhyqrvetpvlppvlv 181 prhteiltelpplddythsipentnfpagiepqsnyipetpppgyisedgetsdqqlnqs 241 mdtgspaelspttlspvnhsldlqpvtysepafwcsiayyelnqrvgetfhasqpsltvd 301 gftdpsnserfclgllsnvnrnatvemtrrhigrgvrlyyiggevfaeclsdsaifvqsp 361 ncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgfeavyqltrmctirmsfvk 421 gwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsvrcssms SEQIDNO:7MouseSmad2transcriptvariant2mRNASequence NM_001252481.1;(CDS:443-1846) 1 ggttaaaataactatctgagatttgttttgctgttgttgttgtttaaggaaaattaaggt 61 agtaccatatcttaaatcattgcaacaagaggcagtattgctacttataaaagtaaataa 121 tagtgtataaaattgtgtttcaaccgaatcttactggcatctttctctctttcttggaaa 181 cactccatgaaacaatagatgcagtagatcaggatgatggggacgggaatgggggcacta 241 ctacactactatactactacactctaggatgcgaggctgcatgcagagttaacaacagtc 301 agctgactgtttacctgaaagactggcatagaataggaaaatttggtgccaagtgcataa 361 aaataagcaaatgaaaagacattaattctgggtagatttaccgggctttttctgagtgtg 421 gattgttacctttggtaagaaaatgtcgtccatcttgccattcactccgccagtggtgaa 481 gagacttctgggatggaaaaaatcagccggtgggtctggaggagcaggtggtggagagca 541 gaatggacaggaagaaaagtggtgtgaaaaagcagtgaaaagtctggtgaaaaagctaaa 601 gaaaacaggacggttagatgagcttgagaaagccatcaccactcagaattgcaatactaa 661 atgtgtcaccataccaagcacttgctctgaaatttggggactgagtacagcaaatacggt 721 agatcagtgggacacaacaggcctttacagcttctctgaacaaaccaggtctcttgatgg 781 ccgtcttcaggtttcacaccggaaagggttgccacatgttatatattgccggctctggcg 841 ctggccggaccttcacagtcatcatgagctcaaggcaatcgaaaactgcgaatatgcttt 901 taatctgaaaaaagatgaagtgtgtgtaaatccgtaccactaccagagagttgagacccc 961 agtcttgcctccagtcttagtgcctcggcacacggagattctaacagaactgccgcccct 1021 ggatgactacacccactccattccagaaaacacaaatttcccagcaggaattgagccaca 1081 gagtaattacatcccagaaacaccaccacctggatatatcagtgaagatggagaaacaag 1141 tgaccaacagttgaaccaaagtatggacacaggctctccggctgaactgtctcctactac 1201 tctctctcctgttaatcacagcttggatttgcagccagttacttactcggaacctgcatt 1261 ctggtgttcaatcgcatactatgaactaaaccagagggttggagagaccttccatgcgtc 1321 acagccctcgctcactgtagacggcttcacagacccatcaaactcggagaggttctgctt 1381 aggcttgctctccaacgttaaccgaaatgccactgtagaaatgacaagaagacatatagg 1441 aaggggagtgcgcttgtattacataggtggggaagtgtttgctgagtgcctaagtgatag 1501 tgcaatctttgtgcagagccccaactgtaaccagagatacggctggcaccctgcaacagt 1561 gtgtaagatcccaccaggctgtaacctgaagatcttcaacaaccaagaatttgctgctct 1621 tctggctcagtctgtcaaccagggttttgaagccgtttatcagctaacccgaatgtgcac 1681 cataagaatgagttttgtgaagggctggggagcagaatatcggaggcagacagtaacaag 1741 tactccttgctggattgaacttcatctgaatggccctctgcagtggctggacaaagtatt 1801 aactcagatgggatccccttcagtgcgatgctcaagcatgtcgtaaacccatcaaagact 1861 cgctgtaacagctcctccgtcgtagtattcatgtatgatcccgtggactgtttgctatcc 1921 aaaaattccagagcaaaaacagcacttgaggtctcatcagttaaagcaccttgtggaatc 1981 tgtttcctatatttgaatattagatgggaaaattagtgtctagaaatgccctccccagcg 2041 gggaaaaagaagacttaaagacttaatgatgtcttgttgggcataagacagtatcccaaa 2101 ggttattaataacagtagtagttgtgtacaggtaatgtgtccagacccagtattgcagta 2161 ctatgctgtttgtatacattcttagtttgcataaatgaggtgtgtgtgctgcttcttggt 2221 ctaggcaagcctttataaaattacagtatctaatctgttattcccacttctccgttattt 2281 ttgtgtcttttttaatatataatatatatatatcaagattttcaaattatcatttagaag 2341 cagattttccttgtagaaactaatttttctgccttttaccaaaaataaacaaactcttgg 2401 gggaagacaagtggattaacttggaagtccttgaccttcatgtgtccagtggatcttagc 2461 agtcgttcttttgtgagccttttctcctgagttgcattagaaggaaaccttactggaacc 2521 gtccaggctcctcatcccattcctgttctggttcagagcagtacagcagaatgacgtcgt 2581 gctaaacagttgcactgctggcttctgggttagttgtttctgagtccaggaaaggtttgt 2641 gtgggcagtaagtccttttgtctaataaccagacttcagcagatgataactgatgtgtat 2701 aaccagttgttctgttgattaacttttgtctcaaacatgcacaggtggcagtataattat 2761 tttcagggctattctagaatcatctcagtctgtttccttcttccaaagccagtctaataa 2821 taaagtacctttctgtaaaggcagccgaccttttgcctcattttacttttactaccaggt 2881 tgtattacagaacagaccttttgtaaatgtgttagagtgacgctgaggtcttgtcagcag 2941 atagggccatctgtttttaaagtgtattgtatgtaatttataagtagaatgttattttac 3001 ctagcttcaaaggtttaaatattgtgagctaagccatttagcaagatttctagcccgcag 3061 ttagctgtggacttagctcttcctgacttaccctgggtgtgtggtttgctgacctttcag 3121 ctctgcaggaaggagatcccagctgtcctttggtcctcccttctgcagcacacgacagtc 3181 atgtccagtgttgactcctttctcgtttgcaactccgtacaaatgcctggtctccttttt 3241 gtaaactttcatatttttgcagacaaatacttttggtacttactctttgagaccattctc 3301 acatgtatgtacagtaatcatttttgatgcttttcaacattggttgttttctatttgata 3361 tttctcattttcctatatttgtgtttgtatgttatgtgttcatgtaaatttggtatagta 3421 atttttattcaaatatttattgttcacctgttaatgtgccatgaacttccttaacttttg 3481 ggtgaaggtgaacaagatagctatagttcctgcctttgctaagagcagttggtttaaccc 3541 atactcaagtgtctgcataggaggtaaacagggtatactttgagaatggcagagacgatg 3601 cttttggtaggatattaggaaggcatctggagagtgatgtgtaagctaacccctgaccta 3661 ggaagagaaagccatgtgaagagccaagggcaatttaacactgctggaacattatcagca 3721 tccaaaggctcaggctcatagagactcactgtcaggtatcatgattgtgcacacacctgc 3781 acacacccacacgtggtgatgaaaatgcttgttcagtttagaatttgttgaaggtgggac 3841 tgctttgtgacaggctgcttctgtcatctcactgtaatctattcctcagaccttgtacag 3901 ctttcttacaccaggtcagtgccacttaatttaacaactcccgttacgtaaatgctcacc 3961 agtctggagcctccctgcttgcttctggacgtgttgctgcatatcggctatcactgcttc 4021 ccttccgctgcccatcttgtgatagagcaattgtcctgtgcattattgctgttgagccta 4081 ctggagatccttgtacataaactgccccttctctggaagtttccacagactagaaaactt 4141 gagctgttgggacagttctggggcagaggacagctttgaaagtggtaggaggttatcaga 4201 catgttaaagtgttgccaacagtgagacacagctccatggttggggttcaggaataggtt 4261 ttctataccaccgagcgtgaacaagtcaccgtgtaaactcatgtgaaaagaattcagtgc 4321 ttatctttgcttttcaccggaatgctgtgggcatgcgctactgtcacctagattttgttg 4381 atttcacctcttttgcaagactgatttttgttccagatgattcctacggcctctcttggt 4441 tgatttatattgatttaatttctccacattatttagcatcatgtctcagcagtaatttga 4501 aagcctttctaccagattcaaacatttggttgtattaggccagtcttttggaatgccact 4561 aaactgggctgtgacttaaggaccctttcctgctagggtctgagccacaccagttagact 4621 tactatccatcgttatatacatttagtcagcatagttcctgcctattgtttacccagcca 4681 atgtgattctgggaccatgtcctggctctggagttgggcttagtcctgtgagagttcctg 4741 ttgttttcagggcctatgactttgccagaaggaatttgcatatgttttcttgagagctga 4801 atcttctaattgtgtacatatatgtatgtatatgtacagagttccttctttgtttcttta 4861 atttcaccttcatcacgccttggttgtcagttcatcccgactaagagtccaagtcagtca 4921 ggttagtaggcttttgctggttgaagtcaaagaaagcagatgcccagttgccttccctac 4981 ctctgccaagagctgcccgtatgtgtttttaagccctccccctttttttaagattaacta 5041 cttggaacagttgttctcttaggtgtcctctttgctggagagtagttgatttggtggtga 5101 ggtataaagtaaggagacaatctaagttgacccttccagcttgcctgtgtgttgcacctc 5161 tctgtgcaactatctcaggtatgtcttcacagggcagccaagggcctttccccatactgt 5221 ggcttaaggctttggtgtcctgatagatcagacttattacttgtcatgcttttgcctgag 5281 cactttgctaaacccaggcttccttgcaccttaccctccccagtcaatcagctctatttt 5341 tttttctgaatgcattctgtattcttcccttagtgcgatgcatttccctgcaggcaagct 5401 agtattgttcattcctggaccgttgttggagtctttcaaatgactctggaatttttgccc 5461 agttaaaatgtccctgtgactgacaagtagcaaactcaacattatttatcatagtttaga 5521 tggtaacagcatctccatcacagtttggggacagtctagatcagcggtgtgaccctttag 5581 tgcagttcctcatgttgtggtgacccccagccataaaattattttattgctacttcatta 5641 ctgtaattttgctactgttatgaatcataatgtaaatatctttgatttttgatggtctta 5701 ggtgacccctgtgaaaaggttgtttgaccacccctcccccaaggggttgcaacccacagg 5761 ttgagaaaccactgttgtaaagtgtccgatttattccagtgatggtggtctgtggtctgc 5821 agaggtagacctctgccattggctcctcttctgttttccagcttgcttgattattttact 5881 tgttcagactaccttttgtccagggagattgagggacaagttatttcttggattatagtt 5941 tatgtgtttaaatacttggagccagaaaatgctgagttaatctcatgagtgcttttgcga 6001 taagaattggcctcatgtgttatatcttgaatagagacttttaccttggccattataggt 6061 agcttatatacatgagagttgcctcaaacattttagttttagtgtatatgtgtgtgtgtg 6121 ttcaagtgtacacacatgtaccctcagaaaacaaacggtggggttatcttaacaatgatg 6181 aaagatacattgtttaaatctcagatctcagtaaagagatcccatttgcttgtagactca 6241 tgacacaatcagtgtatttaaaatgaaattaccagtccttatttgacagtgcagctggta 6301 tgctggtgttcgggcactggtgaaaatcataagaaatcaattaccgccaataaagctttc 6361 catatacctcatccctaaactacacccagcactgagggttaacttgaaaatctgtctctt 6421 cttcatttgggtctccccatgaaattccagagacccgggaagtacctccatgaagtcaga 6481 gtcccacacctaatgctactctaaaggaaggtagttcaggcctgtcttggcagtgaacta 6541 ccaagaaatgattttccaagacttcttagaacctctgtatactaaccacctatgtgttca 6601 ttggctagcttctgagtcttagagtggaccccaggtttcacaaatgctagagatgtagga 6661 tcccttgggaaaaggggtgttttttggtttgctattttgggatggaaggtaaggatttgt 6721 accttttttctgtcttgaagtaatttttaaacaaccaaatacgcaacataagaacagata 6781 caaagctttagcgtgttggaaaacgctctgattagtgtacaacttccaaaccagctgtta 6841 cccttcctctctctggctttaaggttcctggctggttgcagtggtaaacactaagtaact 6901 ttatgtttctaaggctgtattaaattgtgcccttcacagtgttgtgtcatagggggttgg 6961 ctttggggagctgagaagaaacctgccttgaagggccagtgcctagctggttgcacattt 7021 gtccttgcctctgtagggtggtggattattggcttatagaggtagtttacagagactggt 7081 ttaaatcacgagaataactaaccaacccctggcctctgaaccatgtatgtacatataccg 7141 atccagcctatttcttggtaaaatgcagaattcaaattgggcacacattagaccagcttt 7201 accttcgacttcatttacgcttttattgactctgacataaggtgtgagtatttgactttc 7261 tttgttggtggcagtgatctgtaacactcagcactttctaggtgagctaaaccaagaaaa 7321 tccacagtgactggctaaggctgcaacttcattggaaggcaagtgaaaaagcatcagagg 7381 cctcctgcctcaaggctggcctcctgggagctcagtacacagtagtgtggctctgggcct 7441 ctgcaagggccttcaagcttggctgtcctcatacacgaaattagaatgtgggagtagttg 7501 gcgttgaaggtcttcacatttaaagggatataaaacgatacatgaaactagaatattcat 7561 ttagctcagaaaatctcaacacgtggtaggtaagatgctatgtaacttacgggaacagga 7621 gactcgggacgtcttgtctgaaagtgggtttcaagagtgaagtctgatacactaccacta 7681 aatgtacttggtctgagttaaataaccttaaggtatttcccagcttccagctggttagcc 7741 tttagcaagagagctacaagtgcattgtccttaaggagccttatgtacacagacgttctt 7801 ttctctgcacgtgtcaagggaaggtgaccagtcccagccatgcctgggacaagggtccca 7861 gatatgcaatgctaagtgccaaccaaagtgagtcctaggggtcctgggaggagttgtccc 7921 cttaggtgtcctcaggacttattctcatactgatgtcatcctagctgataactgtgttgg 7981 gttatgccatggctgtcaatatttttaggactcaacccctgtattctgtattcattactg 8041 tggatgcaacctaagatttacaataaataacacaaagaacaatggagttgagtatggaat 8101 gaaaagaggcaacgagctagggatgatctgtgtaggtgtaagtacactttgtgtccttag 8161 gagttcttgtaacagaaaccgtgtgaaactatagatgtcttctcctataagggaaaacat 8221 ggtgtttgatgctttggtctctatttcccagtctgtcctgcttaagaagccagaatgtgg 8281 tttctatttggtggatgctgtcttaaaattactaaatgtgtcatccggaagcaggtaaag 8341 gagtcagtatccctgtggagttctgtcctactctcacggtgcttaccagctaagctgagc 8401 tcaggagccaagggaaaccctgctcctgctctctggtggtcctcagtggctgatgcagtg 8461 cactgtgatggagatactaaaacaagtgtgttatttgtaagtcttctctcagtgattgtc 8521 agacaactgtggtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgagaaacag 8581 tgagctgaggctttattatagctgatttccagttaaaattgtgaaatacgtatttcttgt 8641 ccacaccaaatatttcagtctatttaatgtattaaagaaatagttctgcttaagaaaatg 8701 ttgcttaaatgttctgtgatttctggtgcatttttatacagatctgtgtgtgtctgtgca 8761 ttcactttctgcctttgctctctgtgttaactgtcctgttgccctcggaaggtggacact 8821 attcgtagcattaaaaagaaatatttgagttatttaccatgtc SEQIDNO:8MouseSmad2Isoform1AminoAcidSequence(NP_001239410.1) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkavtipstcseiwglstantvdqwdttglysfseqtrsldgrlqvshr 121 kglphviycrlwrwpdlhshhelkaienceyafnlkkdevcvnpyhyqrvetpvlppvlv 181 prhteiltelpplddythsipentnfpagiepqsnyipetpppgyisedgetsdqqlnqs 241 mdtgspaelspttlspvnhsldlqpvtysepafwcsiayyelnqrvgetfhasqpsltvd 301 gftdpsnserfclgllsnvnrnatvemtrrhigrgvrlyyiggevfaeclsdsaifvqsp 361 ncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgfeavyqltrmctirmsfvk 421 gwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsvrcssms SEQIDNO:9MouseSmad2transcriptvariant3mRNASequence (NM_001311070.1;CDS:48-1361) 1 atttaccgggctttttctgagtgtggattgttacctttggtaagaaaatgtcgtccatct 61 tgccattcactccgccagtggtgaagagacttctgggatggaaaaaatcagccggtgggt 121 ctggaggagcaggtggtggagagcagaatggacaggaagaaaagtggtgtgaaaaagcag 181 tgaaaagtctggtgaaaaagctaaagaaaacaggacggttagatgagcttgagaaagcca 241 tcaccactcagaattgcaatactaaatgtgtcaccataccaaggtctcttgatggccgtc 301 ttcaggtttcacaccggaaagggttgccacatgttatatattgccggctctggcgctggc 361 cggaccttcacagtcatcatgagctcaaggcaatcgaaaactgcgaatatgcttttaatc 421 tgaaaaaagatgaagtgtgtgtaaatccgtaccactaccagagagttgagaccccagtct 481 tgcctccagtcttagtgcctcggcacacggagattctaacagaactgccgcccctggatg 541 actacacccactccattccagaaaacacaaatttcccagcaggaattgagccacagagta 601 attacatcccagaaacaccaccacctggatatatcagtgaagatggagaaacaagtgacc 661 aacagttgaaccaaagtatggacacaggctctccggctgaactgtctcctactactctct 721 ctcctgttaatcacagcttggatttgcagccagttacttactcggaacctgcattctggt 781 gttcaatcgcatactatgaactaaaccagagggttggagagaccttccatgcgtcacagc 841 cctcgctcactgtagacggcttcacagacccatcaaactcggagaggttctgcttaggct 901 tgctctccaacgttaaccgaaatgccactgtagaaatgacaagaagacatataggaaggg 961 gagtgcgcttgtattacataggtggggaagtgtttgctgagtgcctaagtgatagtgcaa 1021 tctttgtgcagagccccaactgtaaccagagatacggctggcaccctgcaacagtgtgta 1081 agatcccaccaggctgtaacctgaagatcttcaacaaccaagaatttgctgctcttctgg 1141 ctcagtctgtcaaccagggttttgaagccgtttatcagctaacccgaatgtgcaccataa 1201 gaatgagttttgtgaagggctggggagcagaatatcggaggcagacagtaacaagtactc 1261 cttgctggattgaacttcatctgaatggccctctgcagtggctggacaaagtattaactc 1321 agatgggatccccttcagtgcgatgctcaagcatgtcgtaaacccatcaaagactcgctg 1381 taacagctcctccgtcgtagtattcatgtatgatcccgtggactgtttgctatccaaaaa 1441 ttccagagcaaaaacagcacttgaggtctcatcagttaaagcaccttgtggaatctgttt 1501 cctatatttgaatattagatgggaaaattagtgtctagaaatgccctccccagcggggaa 1561 aaagaagacttaaagacttaatgatgtcttgttgggcataagacagtatcccaaaggtta 1621 ttaataacagtagtagttgtgtacaggtaatgtgtccagacccagtattgcagtactatg 1681 ctgtttgtatacattcttagtttgcataaatgaggtgtgtgtgctgcttcttggtctagg 1741 caagcctttataaaattacagtatctaatctgttattcccacttctccgttatttttgtg 1801 tcttttttaatatataatatatatatatcaagattttcaaattatcatttagaagcagat 1861 tttccttgtagaaactaatttttctgccttttaccaaaaataaacaaactcttgggggaa 1921 gacaagtggattaacttggaagtccttgaccttcatgtgtccagtggatcttagcagtcg 1981 ttcttttgtgagccttttctcctgagttgcattagaaggaaaccttactggaaccgtcca 2041 ggctcctcatcccattcctgttctggttcagagcagtacagcagaatgacgtcgtgctaa 2101 acagttgcactgctggcttctgggttagttgtttctgagtccaggaaaggtttgtgtggg 2161 cagtaagtccttttgtctaataaccagacttcagcagatgataactgatgtgtataacca 2221 gttgttctgttgattaacttttgtctcaaacatgcacaggtggcagtataattattttca 2281 gggctattctagaatcatctcagtctgtttccttcttccaaagccagtctaataataaag 2341 tacctttctgtaaaggcagccgaccttttgcctcattttacttttactaccaggttgtat 2401 tacagaacagaccttttgtaaatgtgttagagtgacgctgaggtcttgtcagcagatagg 2461 gccatctgtttttaaagtgtattgtatgtaatttataagtagaatgttattttacctagc 2521 ttcaaaggtttaaatattgtgagctaagccatttagcaagatttctagcccgcagttagc 2581 tgtggacttagctcttcctgacttaccctgggtgtgtggtttgctgacctttcagctctg 2641 caggaaggagatcccagctgtcctttggtcctcccttctgcagcacacgacagtcatgtc 2701 cagtgttgactcctttctcgtttgcaactccgtacaaatgcctggtctcctttttgtaaa 2761 ctttcatatttttgcagacaaatacttttggtacttactctttgagaccattctcacatg 2821 tatgtacagtaatcatttttgatgcttttcaacattggttgttttctatttgatatttct 2881 cattttcctatatttgtgtttgtatgttatgtgttcatgtaaatttggtatagtaatttt 2941 tattcaaatatttattgttcacctgttaatgtgccatgaacttccttaacttttgggtga 3001 aggtgaacaagatagctatagttcctgcctttgctaagagcagttggtttaacccatact 3061 caagtgtctgcataggaggtaaacagggtatactttgagaatggcagagacgatgctttt 3121 ggtaggatattaggaaggcatctggagagtgatgtgtaagctaacccctgacctaggaag 3181 agaaagccatgtgaagagccaagggcaatttaacactgctggaacattatcagcatccaa 3241 aggctcaggctcatagagactcactgtcaggtatcatgattgtgcacacacctgcacaca 3301 cccacacgtggtgatgaaaatgcttgttcagtttagaatttgttgaaggtgggactgctt 3361 tgtgacaggctgcttctgtcatctcactgtaatctattcctcagaccttgtacagctttc 3421 ttacaccaggtcagtgccacttaatttaacaactcccgttacgtaaatgctcaccagtct 3481 ggagcctccctgcttgcttctggacgtgttgctgcatatcggctatcactgcttcccttc 3541 cgctgcccatcttgtgatagagcaattgtcctgtgcattattgctgttgagcctactgga 3601 gatccttgtacataaactgccccttctctggaagtttccacagactagaaaacttgagct 3661 gttgggacagttctggggcagaggacagctttgaaagtggtaggaggttatcagacatgt 3721 taaagtgttgccaacagtgagacacagctccatggttggggttcaggaataggttttcta 3781 taccaccgagcgtgaacaagtcaccgtgtaaactcatgtgaaaagaattcagtgcttatc 3841 tttgcttttcaccggaatgctgtgggcatgcgctactgtcacctagattttgttgatttc 3901 acctcttttgcaagactgatttttgttccagatgattcctacggcctctcttggttgatt 3961 tatattgatttaatttctccacattatttagcatcatgtctcagcagtaatttgaaagcc 4021 tttctaccagattcaaacatttggttgtattaggccagtcttttggaatgccactaaact 4081 gggctgtgacttaaggaccctttcctgctagggtctgagccacaccagttagacttacta 4141 tccatcgttatatacatttagtcagcatagttcctgcctattgtttacccagccaatgtg 4201 attctgggaccatgtcctggctctggagttgggcttagtcctgtgagagttcctgttgtt 4261 ttcagggcctatgactttgccagaaggaatttgcatatgttttcttgagagctgaatctt 4321 ctaattgtgtacatatatgtatgtatatgtacagagttccttctttgtttctttaatttc 4381 accttcatcacgccttggttgtcagttcatcccgactaagagtccaagtcagtcaggtta 4441 gtaggcttttgctggttgaagtcaaagaaagcagatgcccagttgccttccctacctctg 4501 ccaagagctgcccgtatgtgtttttaagccctccccctttttttaagattaactacttgg 4561 aacagttgttctcttaggtgtcctctttgctggagagtagttgatttggtggtgaggtat 4621 aaagtaaggagacaatctaagttgacccttccagcttgcctgtgtgttgcacctctctgt 4681 gcaactatctcaggtatgtcttcacagggcagccaagggcctttccccatactgtggctt 4741 aaggctttggtgtcctgatagatcagacttattacttgtcatgcttttgcctgagcactt 4801 tgctaaacccaggcttccttgcaccttaccctccccagtcaatcagctctattttttttt 4861 ctgaatgcattctgtattcttcccttagtgcgatgcatttccctgcaggcaagctagtat 4921 tgttcattcctggaccgttgttggagtctttcaaatgactctggaatttttgcccagtta 4981 aaatgtccctgtgactgacaagtagcaaactcaacattatttatcatagtttagatggta 5041 acagcatctccatcacagtttggggacagtctagatcagcggtgtgaccctttagtgcag 5101 ttcctcatgttgtggtgacccccagccataaaattattttattgctacttcattactgta 5161 attttgctactgttatgaatcataatgtaaatatctttgatttttgatggtcttaggtga 5221 cccctgtgaaaaggttgtttgaccacccctcccccaaggggttgcaacccacaggttgag 5281 aaaccactgttgtaaagtgtccgatttattccagtgatggtggtctgtggtctgcagagg 5341 tagacctctgccattggctcctcttctgttttccagcttgcttgattattttacttgttc 5401 agactaccttttgtccagggagattgagggacaagttatttcttggattatagtttatgt 5461 gtttaaatacttggagccagaaaatgctgagttaatctcatgagtgcttttgcgataaga 5521 attggcctcatgtgttatatcttgaatagagacttttaccttggccattataggtagctt 5581 atatacatgagagttgcctcaaacattttagttttagtgtatatgtgtgtgtgtgttcaa 5641 gtgtacacacatgtaccctcagaaaacaaacggtggggttatcttaacaatgatgaaaga 5701 tacattgtttaaatctcagatctcagtaaagagatcccatttgcttgtagactcatgaca 5761 caatcagtgtatttaaaatgaaattaccagtccttatttgacagtgcagctggtatgctg 5821 gtgttcgggcactggtgaaaatcataagaaatcaattaccgccaataaagctttccatat 5881 acctcatccctaaactacacccagcactgagggttaacttgaaaatctgtctcttcttca 5941 tttgggtctccccatgaaattccagagacccgggaagtacctccatgaagtcagagtccc 6001 acacctaatgctactctaaaggaaggtagttcaggcctgtcttggcagtgaactaccaag 6061 aaatgattttccaagacttcttagaacctctgtatactaaccacctatgtgttcattggc 6121 tagcttctgagtcttagagtggaccccaggtttcacaaatgctagagatgtaggatccct 6181 tgggaaaaggggtgttttttggtttgctattttgggatggaaggtaaggatttgtacctt 6241 ttttctgtcttgaagtaatttttaaacaaccaaatacgcaacataagaacagatacaaag 6301 ctttagcgtgttggaaaacgctctgattagtgtacaacttccaaaccagctgttaccctt 6361 cctctctctggctttaaggttcctggctggttgcagtggtaaacactaagtaactttatg 6421 tttctaaggctgtattaaattgtgcccttcacagtgttgtgtcatagggggttggctttg 6481 gggagctgagaagaaacctgccttgaagggccagtgcctagctggttgcacatttgtcct 6541 tgcctctgtagggtggtggattattggcttatagaggtagtttacagagactggtttaaa 6601 tcacgagaataactaaccaacccctggcctctgaaccatgtatgtacatataccgatcca 6661 gcctatttcttggtaaaatgcagaattcaaattgggcacacattagaccagctttacctt 6721 cgacttcatttacgcttttattgactctgacataaggtgtgagtatttgactttctttgt 6781 tggtggcagtgatctgtaacactcagcactttctaggtgagctaaaccaagaaaatccac 6841 agtgactggctaaggctgcaacttcattggaaggcaagtgaaaaagcatcagaggcctcc 6901 tgcctcaaggctggcctcctgggagctcagtacacagtagtgtggctctgggcctctgca 6961 agggccttcaagcttggctgtcctcatacacgaaattagaatgtgggagtagttggcgtt 7021 gaaggtcttcacatttaaagggatataaaacgatacatgaaactagaatattcatttagc 7081 tcagaaaatctcaacacgtggtaggtaagatgctatgtaacttacgggaacaggagactc 7141 gggacgtcttgtctgaaagtgggtttcaagagtgaagtctgatacactaccactaaatgt 7201 acttggtctgagttaaataaccttaaggtatttcccagcttccagctggttagcctttag 7261 caagagagctacaagtgcattgtccttaaggagccttatgtacacagacgttcttttctc 7321 tgcacgtgtcaagggaaggtgaccagtcccagccatgcctgggacaagggtcccagatat 7381 gcaatgctaagtgccaaccaaagtgagtcctaggggtcctgggaggagttgtccccttag 7441 gtgtcctcaggacttattctcatactgatgtcatcctagctgataactgtgttgggttat 7501 gccatggctgtcaatatttttaggactcaacccctgtattctgtattcattactgtggat 7561 gcaacctaagatttacaataaataacacaaagaacaatggagttgagtatggaatgaaaa 7621 gaggcaacgagctagggatgatctgtgtaggtgtaagtacactttgtgtccttaggagtt 7681 cttgtaacagaaaccgtgtgaaactatagatgtcttctcctataagggaaaacatggtgt 7741 ttgatgctttggtctctatttcccagtctgtcctgcttaagaagccagaatgtggtttct 7801 atttggtggatgctgtcttaaaattactaaatgtgtcatccggaagcaggtaaaggagtc 7861 agtatccctgtggagttctgtcctactctcacggtgcttaccagctaagctgagctcagg 7921 agccaagggaaaccctgctcctgctctctggtggtcctcagtggctgatgcagtgcactg 7981 tgatggagatactaaaacaagtgtgttatttgtaagtcttctctcagtgattgtcagaca 8041 actgtggtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgagaaacagtgagc 8101 tgaggctttattatagctgatttccagttaaaattgtgaaatacgtatttcttgtccaca 8161 ccaaatatttcagtctatttaatgtattaaagaaatagttctgcttaagaaaatgttgct 8221 taaatgttctgtgatttctggtgcatttttatacagatctgtgtgtgtctgtgcattcac 8281 tttctgcctttgctctctgtgttaactgtcctgttgccctcggaaggtggacactattcg 8341 tagcattaaaaagaaatatttgagttatttaccatgtc SEQIDNO:10MouseSmad2Isoform2AminoAcidSequence(NP_001297999.1) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkcvtiprsldgrlqvshrkglphviycrlwrwpdlhshhelkaience 121 yafnlkkdevcvnpyhyqrvetpvlppvlvprhteiltelpplddythsipentnfpagi 181 epqsnyipetpppgyisedgetsdqqlnqsmdtgspaelspttlspvnhsldlqpvtyse 241 pafwcsiayyelnqrvgetfhasqpsltvdgftdpsnserfclgllsnvnrnatvemtrr 301 higrgvrlyyiggevfaeclsdsaifvqspncnqrygwhpatvckippgcnlkifnnqef 361 aallaqsvnqgfeavyqltrmctirmsfvkgwgaeyrrqtvtstpcwielhlngplqwld 421 kvltqmgspsvrcssms SEQIDNO:11MouseSmad2transcriptvariant1Sequence(NM_010754.5;CDS: 332-1735) 1 cgccccgctcggcccccggccctgcccgcggcgcccggcctccttccgtccctgccgtgc 61 tccctccgtcttccgtgcgcgcccgctcggccggcgtgcctcacgcctaacgggcggccg 121 cgggcgccaatcagcgggcggcagggtgccagcccggggctgcgccggcgaatcggcggg 181 gtccgcggctcggggagggaggcggggctaccgcgcgcggcggtggaggagcagctcgcc 241 aagcctgcagctcgcgagcgccgagcgagcctcccggagggtagatttaccgggcttttt 301 ctgagtgtggattgttacctttggtaagaaaatgtcgtccatcttgccattcactccgcc 361 agtggtgaagagacttctgggatggaaaaaatcagccggtgggtctggaggagcaggtgg 421 tggagagcagaatggacaggaagaaaagtggtgtgaaaaagcagtgaaaagtctggtgaa 481 aaagctaaagaaaacaggacggttagatgagcttgagaaagccatcaccactcagaattg 541 caatactaaatgtgtcaccataccaagcacttgctctgaaatttggggactgagtacagc 601 aaatacggtagatcagtgggacacaacaggcctttacagcttctctgaacaaaccaggtc 661 tcttgatggccgtcttcaggtttcacaccggaaagggttgccacatgttatatattgccg 721 gctctggcgctggccggaccttcacagtcatcatgagctcaaggcaatcgaaaactgcga 781 atatgcttttaatctgaaaaaagatgaagtgtgtgtaaatccgtaccactaccagagagt 841 tgagaccccagtcttgcctccagtcttagtgcctcggcacacggagattctaacagaact 901 gccgcccctggatgactacacccactccattccagaaaacacaaatttcccagcaggaat 961 tgagccacagagtaattacatcccagaaacaccaccacctggatatatcagtgaagatgg 1021 agaaacaagtgaccaacagttgaaccaaagtatggacacaggctctccggctgaactgtc 1081 tcctactactctctctcctgttaatcacagcttggatttgcagccagttacttactcgga 1141 acctgcattctggtgttcaatcgcatactatgaactaaaccagagggttggagagacctt 1201 ccatgcgtcacagccctcgctcactgtagacggcttcacagacccatcaaactcggagag 1261 gttctgcttaggcttgctctccaacgttaaccgaaatgccactgtagaaatgacaagaag 1321 acatataggaaggggagtgcgcttgtattacataggtggggaagtgtttgctgagtgcct 1381 aagtgatagtgcaatctttgtgcagagccccaactgtaaccagagatacggctggcaccc 1441 tgcaacagtgtgtaagatcccaccaggctgtaacctgaagatcttcaacaaccaagaatt 1501 tgctgctcttctggctcagtctgtcaaccagggttttgaagccgtttatcagctaacccg 1561 aatgtgcaccataagaatgagttttgtgaagggctggggagcagaatatcggaggcagac 1621 agtaacaagtactccttgctggattgaacttcatctgaatggccctctgcagtggctgga 1681 caaagtattaactcagatgggatccccttcagtgcgatgctcaagcatgtcgtaaaccca 1741 tcaaagactcgctgtaacagctcctccgtcgtagtattcatgtatgatcccgtggactgt 1801 ttgctatccaaaaattccagagcaaaaacagcacttgaggtctcatcagttaaagcacct 1861 tgtggaatctgtttcctatatttgaatattagatgggaaaattagtgtctagaaatgccc 1921 tccccagcggggaaaaagaagacttaaagacttaatgatgtcttgttgggcataagacag 1981 tatcccaaaggttattaataacagtagtagttgtgtacaggtaatgtgtccagacccagt 2041 attgcagtactatgctgtttgtatacattcttagtttgcataaatgaggtgtgtgtgctg 2101 cttcttggtctaggcaagcctttataaaattacagtatctaatctgttattcccacttct 2161 ccgttatttttgtgtcttttttaatatataatatatatatatcaagattttcaaattatc 2221 atttagaagcagattttccttgtagaaactaatttttctgccttttaccaaaaataaaca 2281 aactcttgggggaagacaagtggattaacttggaagtccttgaccttcatgtgtccagtg 2341 gatcttagcagtcgttcttttgtgagccttttctcctgagttgcattagaaggaaacctt 2401 actggaaccgtccaggctcctcatcccattcctgttctggttcagagcagtacagcagaa 2461 tgacgtcgtgctaaacagttgcactgctggcttctgggttagttgtttctgagtccagga 2521 aaggtttgtgtgggcagtaagtccttttgtctaataaccagacttcagcagatgataact 2581 gatgtgtataaccagttgttctgttgattaacttttgtctcaaacatgcacaggtggcag 2641 tataattattttcagggctattctagaatcatctcagtctgtttccttcttccaaagcca 2701 gtctaataataaagtacctttctgtaaaggcagccgaccttttgcctcattttactttta 2761 ctaccaggttgtattacagaacagaccttttgtaaatgtgttagagtgacgctgaggtct 2821 tgtcagcagatagggccatctgtttttaaagtgtattgtatgtaatttataagtagaatg 2881 ttattttacctagcttcaaaggtttaaatattgtgagctaagccatttagcaagatttct 2941 agcccgcagttagctgtggacttagctcttcctgacttaccctgggtgtgtggtttgctg 3001 acctttcagctctgcaggaaggagatcccagctgtcctttggtcctcccttctgcagcac 3061 acgacagtcatgtccagtgttgactcctttctcgtttgcaactccgtacaaatgcctggt 3121 ctcctttttgtaaactttcatatttttgcagacaaatacttttggtacttactctttgag 3181 accattctcacatgtatgtacagtaatcatttttgatgcttttcaacattggttgttttc 3241 tatttgatatttctcattttcctatatttgtgtttgtatgttatgtgttcatgtaaattt 3301 ggtatagtaatttttattcaaatatttattgttcacctgttaatgtgccatgaacttcct 3361 taacttttgggtgaaggtgaacaagatagctatagttcctgcctttgctaagagcagttg 3421 gtttaacccatactcaagtgtctgcataggaggtaaacagggtatactttgagaatggca 3481 gagacgatgcttttggtaggatattaggaaggcatctggagagtgatgtgtaagctaacc 3541 cctgacctaggaagagaaagccatgtgaagagccaagggcaatttaacactgctggaaca 3601 ttatcagcatccaaaggctcaggctcatagagactcactgtcaggtatcatgattgtgca 3661 cacacctgcacacacccacacgtggtgatgaaaatgcttgttcagtttagaatttgttga 3721 aggtgggactgctttgtgacaggctgcttctgtcatctcactgtaatctattcctcagac 3781 cttgtacagctttcttacaccaggtcagtgccacttaatttaacaactcccgttacgtaa 3841 atgctcaccagtctggagcctccctgcttgcttctggacgtgttgctgcatatcggctat 3901 cactgcttcccttccgctgcccatcttgtgatagagcaattgtcctgtgcattattgctg 3961 ttgagcctactggagatccttgtacataaactgccccttctctggaagtttccacagact 4021 agaaaacttgagctgttgggacagttctggggcagaggacagctttgaaagtggtaggag 4081 gttatcagacatgttaaagtgttgccaacagtgagacacagctccatggttggggttcag 4141 gaataggttttctataccaccgagcgtgaacaagtcaccgtgtaaactcatgtgaaaaga 4201 attcagtgcttatctttgcttttcaccggaatgctgtgggcatgcgctactgtcacctag 4261 attttgttgatttcacctcttttgcaagactgatttttgttccagatgattcctacggcc 4321 tctcttggttgatttatattgatttaatttctccacattatttagcatcatgtctcagca 4381 gtaatttgaaagcctttctaccagattcaaacatttggttgtattaggccagtcttttgg 4441 aatgccactaaactgggctgtgacttaaggaccctttcctgctagggtctgagccacacc 4501 agttagacttactatccatcgttatatacatttagtcagcatagttcctgcctattgttt 4561 acccagccaatgtgattctgggaccatgtcctggctctggagttgggcttagtcctgtga 4621 gagttcctgttgttttcagggcctatgactttgccagaaggaatttgcatatgttttctt 4681 gagagctgaatcttctaattgtgtacatatatgtatgtatatgtacagagttccttcttt 4741 gtttctttaatttcaccttcatcacgccttggttgtcagttcatcccgactaagagtcca 4801 agtcagtcaggttagtaggcttttgctggttgaagtcaaagaaagcagatgcccagttgc 4861 cttccctacctctgccaagagctgcccgtatgtgtttttaagccctccccctttttttaa 4921 gattaactacttggaacagttgttctcttaggtgtcctctttgctggagagtagttgatt 4981 tggtggtgaggtataaagtaaggagacaatctaagttgacccttccagcttgcctgtgtg 5041 ttgcacctctctgtgcaactatctcaggtatgtcttcacagggcagccaagggcctttcc 5101 ccatactgtggcttaaggctttggtgtcctgatagatcagacttattacttgtcatgctt 5161 ttgcctgagcactttgctaaacccaggcttccttgcaccttaccctccccagtcaatcag 5221 ctctatttttttttctgaatgcattctgtattcttcccttagtgcgatgcatttccctgc 5281 aggcaagctagtattgttcattcctggaccgttgttggagtctttcaaatgactctggaa 5341 tttttgcccagttaaaatgtccctgtgactgacaagtagcaaactcaacattatttatca 5401 tagtttagatggtaacagcatctccatcacagtttggggacagtctagatcagcggtgtg 5461 accctttagtgcagttcctcatgttgtggtgacccccagccataaaattattttattgct 5521 acttcattactgtaattttgctactgttatgaatcataatgtaaatatctttgatttttg 5581 atggtcttaggtgacccctgtgaaaaggttgtttgaccacccctcccccaaggggttgca 5641 acccacaggttgagaaaccactgttgtaaagtgtccgatttattccagtgatggtggtct 5701 gtggtctgcagaggtagacctctgccattggctcctcttctgttttccagcttgcttgat 5761 tattttacttgttcagactaccttttgtccagggagattgagggacaagttatttcttgg 5821 attatagtttatgtgtttaaatacttggagccagaaaatgctgagttaatctcatgagtg 5881 cttttgcgataagaattggcctcatgtgttatatcttgaatagagacttttaccttggcc 5941 attataggtagcttatatacatgagagttgcctcaaacattttagttttagtgtatatgt 6001 gtgtgtgtgttcaagtgtacacacatgtaccctcagaaaacaaacggtggggttatctta 6061 acaatgatgaaagatacattgtttaaatctcagatctcagtaaagagatcccatttgctt 6121 gtagactcatgacacaatcagtgtatttaaaatgaaattaccagtccttatttgacagtg 6181 cagctggtatgctggtgttcgggcactggtgaaaatcataagaaatcaattaccgccaat 6241 aaagctttccatatacctcatccctaaactacacccagcactgagggttaacttgaaaat 6301 ctgtctcttcttcatttgggtctccccatgaaattccagagacccgggaagtacctccat 6361 gaagtcagagtcccacacctaatgctactctaaaggaaggtagttcaggcctgtcttggc 6421 agtgaactaccaagaaatgattttccaagacttcttagaacctctgtatactaaccacct 6481 atgtgttcattggctagcttctgagtcttagagtggaccccaggtttcacaaatgctaga 6541 gatgtaggatcccttgggaaaaggggtgttttttggtttgctattttgggatggaaggta 6601 aggatttgtaccttttttctgtcttgaagtaatttttaaacaaccaaatacgcaacataa 6661 gaacagatacaaagctttagcgtgttggaaaacgctctgattagtgtacaacttccaaac 6721 cagctgttacccttcctctctctggctttaaggttcctggctggttgcagtggtaaacac 6781 taagtaactttatgtttctaaggctgtattaaattgtgcccttcacagtgttgtgtcata 6841 gggggttggctttggggagctgagaagaaacctgccttgaagggccagtgcctagctggt 6901 tgcacatttgtccttgcctctgtagggtggtggattattggcttatagaggtagtttaca 6961 gagactggtttaaatcacgagaataactaaccaacccctggcctctgaaccatgtatgta 7021 catataccgatccagcctatttcttggtaaaatgcagaattcaaattgggcacacattag 7081 accagctttaccttcgacttcatttacgcttttattgactctgacataaggtgtgagtat 7141 ttgactttctttgttggtggcagtgatctgtaacactcagcactttctaggtgagctaaa 7201 ccaagaaaatccacagtgactggctaaggctgcaacttcattggaaggcaagtgaaaaag 7261 catcagaggcctcctgcctcaaggctggcctcctgggagctcagtacacagtagtgtggc 7321 tctgggcctctgcaagggccttcaagcttggctgtcctcatacacgaaattagaatgtgg 7381 gagtagttggcgttgaaggtcttcacatttaaagggatataaaacgatacatgaaactag 7441 aatattcatttagctcagaaaatctcaacacgtggtaggtaagatgctatgtaacttacg 7501 ggaacaggagactcgggacgtcttgtctgaaagtgggtttcaagagtgaagtctgataca 7561 ctaccactaaatgtacttggtctgagttaaataaccttaaggtatttcccagcttccagc 7621 tggttagcctttagcaagagagctacaagtgcattgtccttaaggagccttatgtacaca 7681 gacgttcttttctctgcacgtgtcaagggaaggtgaccagtcccagccatgcctgggaca 7741 agggtcccagatatgcaatgctaagtgccaaccaaagtgagtcctaggggtcctgggagg 7801 agttgtccccttaggtgtcctcaggacttattctcatactgatgtcatcctagctgataa 7861 ctgtgttgggttatgccatggctgtcaatatttttaggactcaacccctgtattctgtat 7921 tcattactgtggatgcaacctaagatttacaataaataacacaaagaacaatggagttga 7981 gtatggaatgaaaagaggcaacgagctagggatgatctgtgtaggtgtaagtacactttg 8041 tgtccttaggagttcttgtaacagaaaccgtgtgaaactatagatgtcttctcctataag 8101 ggaaaacatggtgtttgatgctttggtctctatttcccagtctgtcctgcttaagaagcc 8161 agaatgtggtttctatttggtggatgctgtcttaaaattactaaatgtgtcatccggaag 8221 caggtaaaggagtcagtatccctgtggagttctgtcctactctcacggtgcttaccagct 8281 aagctgagctcaggagccaagggaaaccctgctcctgctctctggtggtcctcagtggct 8341 gatgcagtgcactgtgatggagatactaaaacaagtgtgttatttgtaagtcttctctca 8401 gtgattgtcagacaactgtggtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgt 8461 gagaaacagtgagctgaggctttattatagctgatttccagttaaaattgtgaaatacgt 8521 atttcttgtccacaccaaatatttcagtctatttaatgtattaaagaaatagttctgctt 8581 aagaaaatgttgcttaaatgttctgtgatttctggtgcatttttatacagatctgtgtgt 8641 gtctgtgcattcactttctgcctttgctctctgtgttaactgtcctgttgccctcggaag 8701 gtggacactattcgtagcattaaaaagaaatatttgagttatttaccatgtc SEQIDNO:12MouseSmad2Isoform1AminoAcidSequence(NP_034884.2) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkcvtipstcseiwglstantvdqwdttglysfseqtrsldgrlqvshr 121 kglphviycrlwrwpdlhshhelkaienceyafnlkkdevcvnpyhyqrvetpvlppvlv 181 prhteiltelpplddythsipentnfpagiepqsnyipetpppgyisedgetsdqqlnqs 241 mdtgspaelspttlspvnhsldlqpvtysepafwcsiayyelnqrvgetfhasqpsltvd 301 gftdpsnserfclgllsnvnrnatvemtrrhigrgvrlyyiggevfaeclsdsaifvqsp 361 ncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgfeavyqltrmctirmsfvk 421 gwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsvrcssms SEQIDNO:13RatSmad2transcriptvariant2Sequence(NM_001277450.1;CDS: 210-1613) 1 gggcgccaatcagcgggcggcagggtgccagcccggggctgcgccggcgaatcggcgggg 61 cccgcggctcggggagggaggcggggctaccgcgcgcggcggtggaggagcagctcgctc 121 gcctgcagctcgcgagcgctgagcgagccgcccgaagggtagatttaccaggctgtttct 181 gagtgtggattgttacccttggtaagaaaatgtcgtccatcttgccattcactccgccag 241 tggtgaagagacttctgggatggaaaaaatcagccggtgggtctggaggagcaggtggtg 301 gagaacagaatggacaggaagaaaagtggtgtgaaaaagcagtgaaaagtctggtgaaaa 361 agctaaagaaaacaggacgattagatgagcttgagaaagccatcaccactcagaattgca 421 atactaagtgtgtcaccataccaagcacttgctctgaaatttggggactgagtacagcaa 481 atacggtagatcagtgggacacaacaggcctttacagcttctctgaacaaaccaggtctc 541 ttgatggtcgtcttcaggtgtctcatcggaaagggctgccacatgttatatattgccggc 601 tgtggcgctggccagaccttcacagccatcatgagctcaaggcgatcgagaactgcgaat 661 acgctttcagtctgaaaaaagatgaagtgtgtgtgaacccttaccactaccagagggtgg 721 agacaccagtcttgcctccagtcttggtgcctcggcacacagagattctaacagaactgc 781 cgcctctggatgactatacccactccattccagaaaacacaaatttcccagcaggaattg 841 agccacagagtaattacatcccagaaacaccaccacctggatatatcagtgaagatggag 901 aaactagtgaccaacagttgaaccaaagtatggacacaggctctccggctgaactgtctc 961 ctaccactctctcccctgtcaatcacagcttggatttgcagccagttacttattcagaac 1021 ctgcattttggtgttcaatcgcatattatgaactaaaccagagggttggagagaccttcc 1081 atgcgtcacagccctcactcactgtagacggctttacagatccatcgaactcggagaggt 1141 tctgcttaggtttgctctccaacgttaacagaaacgctactgtagaaatgaccagaaggc 1201 atataggaaggggagtgcgcttgtattacataggtggggaagtgtttgccgagtgcctaa 1261 gtgatagtgcgatctttgtgcagagccccaactgtaaccagagatacggctggcaccccg 1321 cgacagtgtgcaaaatcccaccaggctgtaacctgaagatcttcaacaaccaagaatttg 1381 ctgctcttctggctcagtctgttaaccagggttttgaggccgtttatcagctgactcgaa 1441 tgtgcaccataagaatgagcttcgtgaaggggtggggagcagaataccggaggcagacag 1501 taacaagtactccttgctggattgaacttcatctgaatggccccctgcagtggttggaca 1561 aagtattaactcagatgggatccccgtcagtgcgatgctcaagcatgtcctaaagtccgt 1621 cagcagtggagctcattggaagacttaacgtaccaactcctccgccacagtactcgtgtg 1681 tgatcccgtggactgtgctagtcaaaacccagagcgaaaacagcacttgaggtctcatca 1741 gttaaagcaccttgtggagtctgtttcctacatttgaattttagatgggaaattagtgtc 1801 tagaaatgccctccccagaggggacaaagaagacttaaagacttaatgatgtctcgttgg 1861 gcataagacagtgtcccaaaggttattaataccagtagtagttgtgtacagtaatgtgtc 1921 cagacccagtattgcagtgctctgctgtttgtataccttcttagtgtgcataaatgaggt 1981 gtgtgctgctgcttggtctaggcaagcctttataaaattacagtacctaatctgttattc 2041 ccacttctccgttatttttgtgtcttttttaatatataatatatatatcgagattttcaa 2101 attatcatttagaagcagattttccttgtagaaactaatttttctgccttttaccaaaaa 2161 taaactcgtgggggaagaaaagtggattaacttggaagtccttgaccttaatgtgtccag 2221 tgggtcttagcattctttctgtgatcattttctgctgaattgcattagaaggaaaccttg 2281 ttggaaacttccaggctctttgtgccatttctgttctgattcaaagcagtgcagcatgat 2341 gtcattgtggtaaatagttgcactgatggcttctgggttagttacttctgagtccagtaa 2401 aggattgtgtgagcagtaagtccttttgtcttctaaccagacttcagcagatgataacca 2461 gttgttccattgattaacttttgtctcaaacgtgcacaggtgacagtataattattttca 2521 gggctattctagaatcatctcagtatgtttccttcttccaacgccagtctgataataaag 2581 tatctttctgtaaaggca SEQIDNO:14RatSmad2AminoAcidSequence(NP_001264379.1) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkcvtipstcseiwglstantvdqwdttglysfseqtrsldgrlqvshr 121 kglphviycrlwrwpdlhshhelkaienceyafslkkdevcvnpyhyqrvetpvlppvlv 181 prhteiltelpplddythsipentnfpagiepqsnyipetpppgyisedgetsdqqlnqs 241 mdtgspaelspttlspvnhsldlqpvtysepafwcsiayyelnqrvgetfhasqpsltvd 301 gftdpsnserfclgllsnvnrnatvemtrrhigrgvrlyyiggevfaeclsdsaifvqsp 361 ncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgfeavyqltrmctirmsfvk 421 gwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsvrcssms SEQIDNO:15RatSmad2transcriptvariant1Sequence(NM_019191.2;CDS:238- 1641) 1 tggagcaggcggctccctccccagccggccgcggtgagcgcgggcctgggggcggggcgg 61 gggcccgcggcgcagttccgcctgcgcgcgcccactcctccggcagcgcggagcccgtcg 121 gaagaggaaggaacaaaaggtccggggcccggctcggacgggccgggaccaggcgctggg 181 tgcagggtagatttaccaggctgtttctgagtgtggattgttacccttggtaagaaaatg 241 tcgtccatcttgccattcactccgccagtggtgaagagacttctgggatggaaaaaatca 301 gccggtgggtctggaggagcaggtggtggagaacagaatggacaggaagaaaagtggtgt 361 gaaaaagcagtgaaaagtctggtgaaaaagctaaagaaaacaggacgattagatgagctt 421 gagaaagccatcaccactcagaattgcaatactaagtgtgtcaccataccaagcacttgc 481 tctgaaatttggggactgagtacagcaaatacggtagatcagtgggacacaacaggcctt 541 tacagcttctctgaacaaaccaggtctcttgatggtcgtcttcaggtgtctcatcggaaa 601 gggctgccacatgttatatattgccggctgtggcgctggccagaccttcacagccatcat 661 gagctcaaggcgatcgagaactgcgaatacgctttcagtctgaaaaaagatgaagtgtgt 721 gtgaacccttaccactaccagagggtggagacaccagtcttgcctccagtcttggtgcct 781 cggcacacagagattctaacagaactgccgcctctggatgactatacccactccattcca 841 gaaaacacaaatttcccagcaggaattgagccacagagtaattacatcccagaaacacca 901 ccacctggatatatcagtgaagatggagaaactagtgaccaacagttgaaccaaagtatg 961 gacacaggctctccggctgaactgtctcctaccactctctcccctgtcaatcacagcttg 1021 gatttgcagccagttacttattcagaacctgcattttggtgttcaatcgcatattatgaa 1081 ctaaaccagagggttggagagaccttccatgcgtcacagccctcactcactgtagacggc 1141 tttacagatccatcgaactcggagaggttctgcttaggtttgctctccaacgttaacaga 1201 aacgctactgtagaaatgaccagaaggcatataggaaggggagtgcgcttgtattacata 1261 ggtggggaagtgtttgccgagtgcctaagtgatagtgcgatctttgtgcagagccccaac 1321 tgtaaccagagatacggctggcaccccgcgacagtgtgcaaaatcccaccaggctgtaac 1381 ctgaagatcttcaacaaccaagaatttgctgctcttctggctcagtctgttaaccagggt 1441 tttgaggccgtttatcagctgactcgaatgtgcaccataagaatgagcttcgtgaagggg 1501 tggggagcagaataccggaggcagacagtaacaagtactccttgctggattgaacttcat 1561 ctgaatggccccctgcagtggttggacaaagtattaactcagatgggatccccgtcagtg 1621 cgatgctcaagcatgtcctaaagtccgtcagcagtggagctcattggaagacttaacgta 1681 ccaactcctccgccacagtactcgtgtgtgatcccgtggactgtgctagtcaaaacccag 1741 agcgaaaacagcacttgaggtctcatcagttaaagcaccttgtggagtctgtttcctaca 1801 tttgaattttagatgggaaattagtgtctagaaatgccctccccagaggggacaaagaag 1861 acttaaagacttaatgatgtctcgttgggcataagacagtgtcccaaaggttattaatac 1921 cagtagtagttgtgtacagtaatgtgtccagacccagtattgcagtgctctgctgtttgt 1981 ataccttcttagtgtgcataaatgaggtgtgtgctgctgcttggtctaggcaagccttta 2041 taaaattacagtacctaatctgttattcccacttctccgttatttttgtgtcttttttaa 2101 tatataatatatatatcgagattttcaaattatcatttagaagcagattttccttgtaga 2161 aactaatttttctgccttttaccaaaaataaactcgtgggggaagaaaagtggattaact 2221 tggaagtccttgaccttaatgtgtccagtgggtcttagcattctttctgtgatcattttc 2281 tgctgaattgcattagaaggaaaccttgttggaaacttccaggctctttgtgccatttct 2341 gttctgattcaaagcagtgcagcatgatgtcattgtggtaaatagttgcactgatggctt 2401 ctgggttagttacttctgagtccagtaaaggattgtgtgagcagtaagtccttttgtctt 2461 ctaaccagacttcagcagatgataaccagttgttccattgattaacttttgtctcaaacg 2521 tgcacaggtgacagtataattattttcagggctattctagaatcatctcagtatgtttcc 2581 ttcttccaacgccagtctgataataaagtatctttctgtaaaggca SEQIDNO:16RatSmad2AminoAcidSequence(NP_062064.1) 1 mssilpftppvvkrllgwkksaggsggagggeqngqeekwcekavkslvkklkktgrlde 61 lekaittqncntkcvtipstcseiwglstantvdqwdttglysfseqtrsldgrlqvshr 121 kglphviycrlwrwpdlhshhelkaienceyafslkkdevcvnpyhyqrvetpvlppvlv 181 prhteiltelpplddythsipentnfpagiepqsnyipetpppgyisedgetsdqqlnqs 241 mdtgspaelspttlspvnhsldlqpvtysepafwcsiayyelnqrvgetfhasqpsltvd 301 gftdpsnserfclgllsnvnrnatvemtrrhigrgvrlyyiggevfaeclsdsaifvqsp 361 ncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgfeavyqltrmctirmsfvk 421 gwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsvrcssms SEQIDNO:17Humanp63transcriptvariant1mRNASequence(NM_003722.5; CDS:128-2170) 1 ctatgtctgatagcatttgaccctattgcttttagcctcccggctttatatctatatata 61 cacaggtatatgtgtatattttatataattgttctccgttcgttgatatcaaagacagtt 121 gaaggaaatgaattttgaaacttcacggtgtgccaccctacagtactgccctgaccctta 181 catccagcgtttcgtagaaaccccagctcatttctcttggaaagaaagttattaccgatc 241 caccatgtcccagagcacacagacaaatgaattcctcagtccagaggttttccagcatat 301 ctgggattttctggaacagcctatatgttcagttcagcccattgacttgaactttgtgga 361 tgaaccatcagaagatggtgcgacaaacaagattgagattagcatggactgtatccgcat 421 gcaggactcggacctgagtgaccccatgtggccacagtacacgaacctggggctcctgaa 481 cagcatggaccagcagattcagaacggctcctcgtccaccagtccctataacacagacca 541 cgcgcagaacagcgtcacggcgccctcgccctacgcacagcccagctccaccttcgatgc 601 tctctctccatcacccgccatcccctccaacaccgactacccaggcccgcacagtttcga 661 cgtgtccttccagcagtcgagcaccgccaagtcggccacctggacgtattccactgaact 721 gaagaaactctactgccaaattgcaaagacatgccccatccagatcaaggtgatgacccc 781 acctcctcagggagctgttatccgcgccatgcctgtctacaaaaaagctgagcacgtcac 841 ggaggtggtgaagcggtgccccaaccatgagctgagccgtgaattcaacgagggacagat 901 tgcccctcctagtcatttgattcgagtagaggggaacagccatgcccagtatgtagaaga 961 tcccatcacaggaagacagagtgtgctggtaccttatgagccaccccaggttggcactga 1021 attcacgacagtcttgtacaatttcatgtgtaacagcagttgtgttggagggatgaaccg 1081 ccgtccaattttaatcattgttactctggaaaccagagatgggcaagtcctgggccgacg 1141 ctgctttgaggcccggatctgtgcttgcccaggaagagacaggaaggcggatgaagatag 1201 catcagaaagcagcaagtttcggacagtacaaagaacggtgatggtacgaagcgcccgtt 1261 tcgtcagaacacacatggtatccagatgacatccatcaagaaacgaagatccccagatga 1321 tgaactgttatacttaccagtgaggggccgtgagacttatgaaatgctgttgaagatcaa 1381 agagtccctggaactcatgcagtaccttcctcagcacacaattgaaacgtacaggcaaca 1441 gcaacagcagcagcaccagcacttacttcagaaacagacctcaatacagtctccatcttc 1501 atatggtaacagctccccacctctgaacaaaatgaacagcatgaacaagctgccttctgt 1561 gagccagcttatcaaccctcagcagcgcaacgccctcactcctacaaccattcctgatgg 1621 catgggagccaacattcccatgatgggcacccacatgccaatggctggagacatgaatgg 1681 actcagccccacccaggcactccctcccccactctccatgccatccacctcccactgcac 1741 acccccacctccgtatcccacagattgcagcattgtcagtttcttagcgaggttgggctg 1801 ttcatcatgtctggactatttcacgacccaggggctgaccaccatctatcagattgagca 1861 ttactccatggatgatctggcaagtctgaaaatccctgagcaatttcgacatgcgatctg 1921 gaagggcatcctggaccaccggcagctccacgaattctcctccccttctcatctcctgcg 1981 gaccccaagcagtgcctctacagtcagtgtgggctccagtgagacccggggtgagcgtgt 2041 tattgatgctgtgcgattcaccctccgccagaccatctctttcccaccccgagatgagtg 2101 gaatgacttcaactttgacatggatgctcgccgcaataagcaacagcgcatcaaagagga 2161 gggggagtgagcctcaccatgtgagctcttcctatccctctcctaactgccagcccccta 2221 aaagcactcctgcttaatcttcaaagccttctccctagctcctccccttcctcttgtctg 2281 atttcttaggggaaggagaagtaagaggctacctcttacctaacatctgacctggcatct 2341 aattctgattctggctttaagccttcaaaactatagcttgcagaactgtagctgccatgg 2401 ctaggtagaagtgagcaaaaaagagttgggtgtctccttaagctgcagagatttctcatt 2461 gacttttataaagcatgttcacccttatagtctaagactatatatataaatgtataaata 2521 tacagtatagatttttgggtggggggcattgagtattgtttaaaatgtaatttaaatgaa 2581 agaaaattgagttgcacttattgaccattttttaatttacttgttttggatggcttgtct 2641 atactccttcccttaaggggtatcatgtatggtgataggtatctagagcttaatgctaca 2701 tgtgagtgacgatgatgtacagattctttcagttctttggattctaaatacatgccacat 2761 caaacctttgagtagatccatttccattgcttattatgtaggtaagactgtagatatgta 2821 ttcttttctcagtgttggtatattttatattactgacatttcttctagtgatgatggttc 2881 acgttggggtgatttaatccagttataagaagaagttcatgtccaaacgtcctctttagt 2941 ttttggttgggaatgaggaaaattcttaaaaggcccatagcagccagttcaaaaacaccc 3001 gacgtcatgtatttgagcatatcagtaacccccttaaatttaataccagataccttatct 3061 tacaatattgattgggaaaacatttgctgccattacagaggtattaaaactaaatttcac 3121 tactagattgactaactcaaatacacatttgctactgttgtaagaattctgattgatttg 3181 attgggatgaatgccatctatctagttctaacagtgaagttttactgtctattaatattc 3241 agggtaaataggaatcattcagaaatgttgagtctgtactaaacagtaagatatctcaat 3301 gaaccataaattcaactttgtaaaaatcttttgaagcatagataatattgtttggtaaat 3361 gtttcttttgtttggtaaatgtttcttttaaagaccctcctattctataaaactctgcat 3421 gtagaggcttgtttacctttctctctctaaggtttacaataggagtggtgatttgaaaaa 3481 tataaaattatgagattggttttcctgtggcataaattgcatcactgtatcattttcttt 3541 tttaaccggtaagagtttcagtttgttggaaagtaactgtgagaacccagtttcccgtcc 3601 atctcccttagggactacccatagacatgaaaggtccccacagagcaagagataagtctt 3661 tcatggctgctgttgcttaaaccacttaaacgaagagttcccttgaaactttgggaaaac 3721 atgttaatgacaatattccagatctttcagaaatataacacatttttttgcatgcatgca 3781 aatgagctctgaaatcttcccatgcattctggtcaagggctgtcattgcacataagcttc 3841 cattttaattttaaagtgcaaaagggccagcgtggctctaaaaggtaatgtgtggattgc 3901 ctctgaaaagtgtgtatatattttgtgtgaaattgcatactttgtattttgattattttt 3961 tttttcttcttgggatagtgggatttccagaaccacacttgaaacctttttttatcgttt 4021 ttgtattttcatgaaaataccatttagtaagaataccacatcaaataagaaataatgcta 4081 caattttaagaggggagggaagggaaagtttttttttattatttttttaaaattttgtat 4141 gttaaagagaatgagtccttgatttcaaagttttgttgtacttaaatggtaataagcact 4201 gtaaacttctgcaacaagcatgcagctttgcaaacccattaaggggaagaatgaaagctg 4261 ttccttggtcctagtaagaagacaaactgcttcccttactttgctgagggtttgaataaa 4321 cctaggacttccgagctatgtcagtactattcaggtaacactagggccttggaaattcct 4381 gtactgtgtctcatggatttggcactagccaaagcgaggcacccttactggcttacctcc 4441 tcatggcagcctactctccttgagtgtatgagtagccagggtaaggggtaaaaggatagt 4501 aagcatagaaaccactagaaagtgggcttaatggagttcttgtggcctcagctcaatgca 4561 gttagctgaagaattgaaaagtttttgtttggagacgtttataaacagaaatggaaagca 4621 gagttttcattaaatccttttaccttttttttttcttggtaatcccctaaaataacagta 4681 tgtgggatattgaatgttaaagggatatttttttctattatttttataattgtacaaaat 4741 taagcaaatgttaaaagttttatatgctttattaatgttttcaaaaggtattatacatgt 4801 gatacattttttaagcttcagttgcttgtcttctggtactttctgttatgggcttttggg 4861 gagccagaagccaatctacaatctctttttgtttgccaggacatgcaataaaatttaaaa 4921 aataaataaaaactaattaagaaa SEQIDNO:18Humanp63Isoform1AminoAcidSequence(NP_003713.3) 1 mnfetsrcatlqycpdpyiqrfvetpahfswkesyyrstmsqstqtneflspevfqhiwd 61 fleqpicsvqpidlnfvdepsedgatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdstkngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkqtsiqspssygnsspplnkmnsmnklpsvsq 481 linpqqrnaltpttipdgmganipmmgthmpmagdmnglsptqalppplsmpstshctpp 541 ppyptdcsivsflarlgcsscldyfttqglttiyqiehysmddlaslkipeqfrhaiwkg 601 ildhrqlhefsspshllrtpssastvsvgssetrgervidavrftlrqtisfpprdewnd 661 fnfdmdarrnkqqrikeege SEQIDNO:19Humanp63transcriptvariant2mRNASequence NM_001114978.2;CDS:128-1795) 1 ctatgtctgatagcatttgaccctattgcttttagcctcccggctttatatctatatata 61 cacaggtatatgtgtatattttatataattgttctccgttcgttgatatcaaagacagtt 121 gaaggaaatgaattttgaaacttcacggtgtgccaccctacagtactgccctgaccctta 181 catccagcgtttcgtagaaaccccagctcatttctcttggaaagaaagttattaccgatc 241 caccatgtcccagagcacacagacaaatgaattcctcagtccagaggttttccagcatat 301 ctgggattttctggaacagcctatatgttcagttcagcccattgacttgaactttgtgga 361 tgaaccatcagaagatggtgcgacaaacaagattgagattagcatggactgtatccgcat 421 gcaggactcggacctgagtgaccccatgtggccacagtacacgaacctggggctcctgaa 481 cagcatggaccagcagattcagaacggctcctcgtccaccagtccctataacacagacca 541 cgcgcagaacagcgtcacggcgccctcgccctacgcacagcccagctccaccttcgatgc 601 tctctctccatcacccgccatcccctccaacaccgactacccaggcccgcacagtttcga 661 cgtgtccttccagcagtcgagcaccgccaagtcggccacctggacgtattccactgaact 721 gaagaaactctactgccaaattgcaaagacatgccccatccagatcaaggtgatgacccc 781 acctcctcagggagctgttatccgcgccatgcctgtctacaaaaaagctgagcacgtcac 841 ggaggtggtgaagcggtgccccaaccatgagctgagccgtgaattcaacgagggacagat 901 tgcccctcctagtcatttgattcgagtagaggggaacagccatgcccagtatgtagaaga 961 tcccatcacaggaagacagagtgtgctggtaccttatgagccaccccaggttggcactga 1021 attcacgacagtcttgtacaatttcatgtgtaacagcagttgtgttggagggatgaaccg 1081 ccgtccaattttaatcattgttactctggaaaccagagatgggcaagtcctgggccgacg 1141 ctgctttgaggcccggatctgtgcttgcccaggaagagacaggaaggcggatgaagatag 1201 catcagaaagcagcaagtttcggacagtacaaagaacggtgatggtacgaagcgcccgtt 1261 tcgtcagaacacacatggtatccagatgacatccatcaagaaacgaagatccccagatga 1321 tgaactgttatacttaccagtgaggggccgtgagacttatgaaatgctgttgaagatcaa 1381 agagtccctggaactcatgcagtaccttcctcagcacacaattgaaacgtacaggcaaca 1441 gcaacagcagcagcaccagcacttacttcagaaacagacctcaatacagtctccatcttc 1501 atatggtaacagctccccacctctgaacaaaatgaacagcatgaacaagctgccttctgt 1561 gagccagcttatcaaccctcagcagcgcaacgccctcactcctacaaccattcctgatgg 1621 catgggagccaacattcccatgatgggcacccacatgccaatggctggagacatgaatgg 1681 actcagccccacccaggcactccctcccccactctccatgccatccacctcccactgcac 1741 acccccacctccgtatcccacagattgcagcattgtcaggatctggcaagtctgaaaatc 1801 cctgagcaatttcgacatgcgatctggaagggcatcctggaccaccggcagctccacgaa 1861 ttctcctccccttctcatctcctgcggaccccaagcagtgcctctacagtcagtgtgggc 1921 tccagtgagacccggggtgagcgtgttattgatgctgtgcgattcaccctccgccagacc 1981 atctctttcccaccccgagatgagtggaatgacttcaactttgacatggatgctcgccgc 2041 aataagcaacagcgcatcaaagaggagggggagtgagcctcaccatgtgagctcttccta 2101 tccctctcctaactgccagccccctaaaagcactcctgcttaatcttcaaagccttctcc 2161 ctagctcctccccttcctcttgtctgatttcttaggggaaggagaagtaagaggctacct 2221 cttacctaacatctgacctggcatctaattctgattctggctttaagccttcaaaactat 2281 agcttgcagaactgtagctgccatggctaggtagaagtgagcaaaaaagagttgggtgtc 2341 tccttaagctgcagagatttctcattgacttttataaagcatgttcacccttatagtcta 2401 agactatatatataaatgtataaatatacagtatagatttttgggtggggggcattgagt 2461 attgtttaaaatgtaatttaaatgaaagaaaattgagttgcacttattgaccatttttta 2521 atttacttgttttggatggcttgtctatactccttcccttaaggggtatcatgtatggtg 2581 ataggtatctagagcttaatgctacatgtgagtgacgatgatgtacagattctttcagtt 2641 ctttggattctaaatacatgccacatcaaacctttgagtagatccatttccattgcttat 2701 tatgtaggtaagactgtagatatgtattcttttctcagtgttggtatattttatattact 2761 gacatttcttctagtgatgatggttcacgttggggtgatttaatccagttataagaagaa 2821 gttcatgtccaaacgtcctctttagtttttggttgggaatgaggaaaattcttaaaaggc 2881 ccatagcagccagttcaaaaacacccgacgtcatgtatttgagcatatcagtaaccccct 2941 taaatttaataccagataccttatcttacaatattgattgggaaaacatttgctgccatt 3001 acagaggtattaaaactaaatttcactactagattgactaactcaaatacacatttgcta 3061 ctgttgtaagaattctgattgatttgattgggatgaatgccatctatctagttctaacag 3121 tgaagttttactgtctattaatattcagggtaaataggaatcattcagaaatgttgagtc 3181 tgtactaaacagtaagatatctcaatgaaccataaattcaactttgtaaaaatcttttga 3241 agcatagataatattgtttggtaaatgtttcttttgtttggtaaatgtttcttttaaaga 3301 ccctcctattctataaaactctgcatgtagaggcttgtttacctttctctctctaaggtt 3361 tacaataggagtggtgatttgaaaaatataaaattatgagattggttttcctgtggcata 3421 aattgcatcactgtatcattttcttttttaaccggtaagagtttcagtttgttggaaagt 3481 aactgtgagaacccagtttcccgtccatctcccttagggactacccatagacatgaaagg 3541 tccccacagagcaagagataagtctttcatggctgctgttgcttaaaccacttaaacgaa 3601 gagttcccttgaaactttgggaaaacatgttaatgacaatattccagatctttcagaaat 3661 ataacacatttttttgcatgcatgcaaatgagctctgaaatcttcccatgcattctggtc 3721 aagggctgtcattgcacataagcttccattttaattttaaagtgcaaaagggccagcgtg 3781 gctctaaaaggtaatgtgtggattgcctctgaaaagtgtgtatatattttgtgtgaaatt 3841 gcatactttgtattttgattattttttttttcttcttgggatagtgggatttccagaacc 3901 acacttgaaacctttttttatcgtttttgtattttcatgaaaataccatttagtaagaat 3961 accacatcaaataagaaataatgctacaattttaagaggggagggaagggaaagtttttt 4021 tttattatttttttaaaattttgtatgttaaagagaatgagtccttgatttcaaagtttt 4081 gttgtacttaaatggtaataagcactgtaaacttctgcaacaagcatgcagctttgcaaa 4141 cccattaaggggaagaatgaaagctgttccttggtcctagtaagaagacaaactgcttcc 4201 cttactttgctgagggtttgaataaacctaggacttccgagctatgtcagtactattcag 4261 gtaacactagggccttggaaattcctgtactgtgtctcatggatttggcactagccaaag 4321 cgaggcacccttactggcttacctcctcatggcagcctactctccttgagtgtatgagta 4381 gccagggtaaggggtaaaaggatagtaagcatagaaaccactagaaagtgggcttaatgg 4441 agttcttgtggcctcagctcaatgcagttagctgaagaattgaaaagtttttgtttggag 4501 acgtttataaacagaaatggaaagcagagttttcattaaatccttttacctttttttttt 4561 cttggtaatcccctaaaataacagtatgtgggatattgaatgttaaagggatattttttt 4621 ctattatttttataattgtacaaaattaagcaaatgttaaaagttttatatgctttatta 4681 atgttttcaaaaggtattatacatgtgatacattttttaagcttcagttgcttgtcttct 4741 ggtactttctgttatgggcttttggggagccagaagccaatctacaatctctttttgttt 4801 gccaggacatgcaataaaatttaaaaaataaataaaaactaattaagaaa SEQIDNO:20Humanp63Isoform2AminoAcidSequence(NP_001108450.1) 1 mnfetsrcatlqycpdpyiqrfvetpahfswkesyyrstmsqstqtneflspevfqhiwd 61 fleqpicsvqpidlnfvdepsedgatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdstkngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhliqkqtsiqspssygnsspplnkmnsmnklpsvsq 481 linpqqrnaltpttipdgmganipmmgthmpmagdmnglsptqalppplsmpstshctpp 541 ppyptdcsivriwqv SEQIDNO:21Humanp63transcriptvariant3mRNASequence (NM_001114979.2;CDS:128-1591) 1 ctatgtctgatagcatttgaccctattgcttttagcctcccggctttatatctatatata 61 cacaggtatatgtgtatattttatataattgttctccgttcgttgatatcaaagacagtt 121 gaaggaaatgaattttgaaacttcacggtgtgccaccctacagtactgccctgaccctta 181 catccagcgtttcgtagaaaccccagctcatttctcttggaaagaaagttattaccgatc 241 caccatgtcccagagcacacagacaaatgaattcctcagtccagaggttttccagcatat 301 ctgggattttctggaacagcctatatgttcagttcagcccattgacttgaactttgtgga 361 tgaaccatcagaagatggtgcgacaaacaagattgagattagcatggactgtatccgcat 421 gcaggactcggacctgagtgaccccatgtggccacagtacacgaacctggggctcctgaa 481 cagcatggaccagcagattcagaacggctcctcgtccaccagtccctataacacagacca 541 cgcgcagaacagcgtcacggcgccctcgccctacgcacagcccagctccaccttcgatgc 601 tctctctccatcacccgccatcccctccaacaccgactacccaggcccgcacagtttcga 661 cgtgtccttccagcagtcgagcaccgccaagtcggccacctggacgtattccactgaact 721 gaagaaactctactgccaaattgcaaagacatgccccatccagatcaaggtgatgacccc 781 acctcctcagggagctgttatccgcgccatgcctgtctacaaaaaagctgagcacgtcac 841 ggaggtggtgaagcggtgccccaaccatgagctgagccgtgaattcaacgagggacagat 901 tgcccctcctagtcatttgattcgagtagaggggaacagccatgcccagtatgtagaaga 961 tcccatcacaggaagacagagtgtgctggtaccttatgagccaccccaggttggcactga 1021 attcacgacagtcttgtacaatttcatgtgtaacagcagttgtgttggagggatgaaccg 1081 ccgtccaattttaatcattgttactctggaaaccagagatgggcaagtcctgggccgacg 1141 ctgctttgaggcccggatctgtgcttgcccaggaagagacaggaaggcggatgaagatag 1201 catcagaaagcagcaagtttcggacagtacaaagaacggtgatggtacgaagcgcccgtt 1261 tcgtcagaacacacatggtatccagatgacatccatcaagaaacgaagatccccagatga 1321 tgaactgttatacttaccagtgaggggccgtgagacttatgaaatgctgttgaagatcaa 1381 agagtccctggaactcatgcagtaccttcctcagcacacaattgaaacgtacaggcaaca 1441 gcaacagcagcagcaccagcacttacttcagaaacatctcctttcagcctgcttcaggaa 1501 tgagcttgtggagccccggagagaaactccaaaacaatctgacgtcttctttagacattc 1561 caagcccccaaaccgatcagtgtacccatagagccctatctctatattttaagtgtgtgt 1621 gttgtatttccatgtgtatatgtgagtgtgtgtgtgtgtatgtgtgtgcgtgtgtatcta 1681 gccctcataaacaggacttgaagacactttggctcagagacccaactgctcaaaggcaca 1741 aagccactagtgagagaatcttttgaagggactcaaacctttacaagaaaggatgttttc 1801 tgcagattttgtatccttagaccggccattggtgggtgaggaaccactgtgtttgtctgt 1861 gagctttctgttgtttcctgggagggaggggtcaggtggggaaaggggcattaagatgtt 1921 tattggaacccttttctgtcttcttctgttgtttttctaaaattcacagggaagcttttg 1981 agcaggtctcaaacttaagatgtctttttaagaaaaggagaaaaaagttgttattgtctg 2041 tgcataagtaagttgtaggtgactgagagactcagtcagacccttttaatgctggtcatg 2101 taataatattgcaagtagtaagaaacgaaggtgtcaagtgtactgctgggcagcgaggtg 2161 atcattaccaaaagtaatcaactttgtgggtggagagttctttgtgagaacttgcattat 2221 ttgtgtcctcccctcatgtgtaggtagaacatttcttaatgctgtgtacctgcctctgcc 2281 actgtatgttggcatctgttatgctaaagtttttcttgtacatgaaaccctggaagacct 2341 actacaaaaaaactgttgtttggcccccatagcaggtgaactcattttgtgcttttaata 2401 gaaagacaaatccaccccagtaatattgcccttacgtagttgtttaccattattcaaagc 2461 tcaaaatagaatttgaagccctctcacaaaatctgtgattaatttgcttaattagagctt 2521 ctatccctcaagcctacctaccataaaaccagccatattactgatactgttcagtgcatt 2581 tagccaggagacttacgttttgagtaagtgagatccaagcagacgtgttaaaatcagcac 2641 tcctggactggaaattaaagattgaaagggtagactacttttcttttttttactcaaaag 2701 tttagagaatctctgtttctttccattttaaaaacatattttaagataatagcataaaga 2761 ctttaaaaatgttcctcccctccatcttcccacacccagtcaccagcactgtattttctg 2821 tcaccaagacaatgatttcttgttattgaggctgttgcttttgtggatgtgtgattttaa 2881 ttttcaataaacttttgcatcttggtttatcttgca SEQIDNO:22Humanp63Isoform3AminoAcidSequence(NP_001108451.1) 1 mnfetsrcatlqycpdpyiqrfvetpahfswkesyyrstmsqstqtneflspevfqhiwd 61 fleqpicsvqpidlnfvdepsedgatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdstkngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkhllsacfrnelveprretpkqsdvffrhskp 481 pnrsvyp SEQIDNO:23Humanp63transcriptvariant4mRNASequence (NM_001114980.2;CDS:143-1903) 1 cagagagagaaagagagagagggacttgagttctgttatcttcttaagtagattcatatt 61 gtaagggtctcggggtgggggggttggcaaaatcctggagccagaagaaaggacagcagc 121 attgatcaatcttacagctaacatgttgtacctggaaaacaatgcccagactcaatttag 181 tgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaacgg 241 ctcctcgtccaccagtccctataacacagaccacgcgcagaacagcgtcacggcgccctc 301 gccctacgcacagcccagctccaccttcgatgctctctctccatcacccgccatcccctc 361 caacaccgactacccaggcccgcacagtttcgacgtgtccttccagcagtcgagcaccgc 421 caagtcggccacctggacgtattccactgaactgaagaaactctactgccaaattgcaaa 481 gacatgccccatccagatcaaggtgatgaccccacctcctcagggagctgttatccgcgc 541 catgcctgtctacaaaaaagctgagcacgtcacggaggtggtgaagcggtgccccaacca 601 tgagctgagccgtgaattcaacgagggacagattgcccctcctagtcatttgattcgagt 661 agaggggaacagccatgcccagtatgtagaagatcccatcacaggaagacagagtgtgct 721 ggtaccttatgagccaccccaggttggcactgaattcacgacagtcttgtacaatttcat 781 gtgtaacagcagttgtgttggagggatgaaccgccgtccaattttaatcattgttactct 841 ggaaaccagagatgggcaagtcctgggccgacgctgctttgaggcccggatctgtgcttg 901 cccaggaagagacaggaaggcggatgaagatagcatcagaaagcagcaagtttcggacag 961 tacaaagaacggtgatggtacgaagcgcccgtttcgtcagaacacacatggtatccagat 1021 gacatccatcaagaaacgaagatccccagatgatgaactgttatacttaccagtgagggg 1081 ccgtgagacttatgaaatgctgttgaagatcaaagagtccctggaactcatgcagtacct 1141 tcctcagcacacaattgaaacgtacaggcaacagcaacagcagcagcaccagcacttact 1201 tcagaaacagacctcaatacagtctccatcttcatatggtaacagctccccacctctgaa 1261 caaaatgaacagcatgaacaagctgccttctgtgagccagcttatcaaccctcagcagcg 1321 caacgccctcactcctacaaccattcctgatggcatgggagccaacattcccatgatggg 1381 cacccacatgccaatggctggagacatgaatggactcagccccacccaggcactccctcc 1441 cccactctccatgccatccacctcccactgcacacccccacctccgtatcccacagattg 1501 cagcattgtcagtttcttagcgaggttgggctgttcatcatgtctggactatttcacgac 1561 ccaggggctgaccaccatctatcagattgagcattactccatggatgatctggcaagtct 1621 gaaaatccctgagcaatttcgacatgcgatctggaagggcatcctggaccaccggcagct 1681 ccacgaattctcctccccttctcatctcctgcggaccccaagcagtgcctctacagtcag 1741 tgtgggctccagtgagacccggggtgagcgtgttattgatgctgtgcgattcaccctccg 1801 ccagaccatctctttcccaccccgagatgagtggaatgacttcaactttgacatggatgc 1861 tcgccgcaataagcaacagcgcatcaaagaggagggggagtgagcctcaccatgtgagct 1921 cttcctatccctctcctaactgccagccccctaaaagcactcctgcttaatcttcaaagc 1981 cttctccctagctcctccccttcctcttgtctgatttcttaggggaaggagaagtaagag 2041 gctacctcttacctaacatctgacctggcatctaattctgattctggctttaagccttca 2101 aaactatagcttgcagaactgtagctgccatggctaggtagaagtgagcaaaaaagagtt 2161 gggtgtctccttaagctgcagagatttctcattgacttttataaagcatgttcaccctta 2221 tagtctaagactatatatataaatgtataaatatacagtatagatttttgggtggggggc 2281 attgagtattgtttaaaatgtaatttaaatgaaagaaaattgagttgcacttattgacca 2341 ttttttaatttacttgttttggatggcttgtctatactccttcccttaaggggtatcatg 2401 tatggtgataggtatctagagcttaatgctacatgtgagtgacgatgatgtacagattct 2461 ttcagttctttggattctaaatacatgccacatcaaacctttgagtagatccatttccat 2521 tgcttattatgtaggtaagactgtagatatgtattcttttctcagtgttggtatatttta 2581 tattactgacatttcttctagtgatgatggttcacgttggggtgatttaatccagttata 2641 agaagaagttcatgtccaaacgtcctctttagtttttggttgggaatgaggaaaattctt 2701 aaaaggcccatagcagccagttcaaaaacacccgacgtcatgtatttgagcatatcagta 2761 acccccttaaatttaataccagataccttatcttacaatattgattgggaaaacatttgc 2821 tgccattacagaggtattaaaactaaatttcactactagattgactaactcaaatacaca 2881 tttgctactgttgtaagaattctgattgatttgattgggatgaatgccatctatctagtt 2941 ctaacagtgaagttttactgtctattaatattcagggtaaataggaatcattcagaaatg 3001 ttgagtctgtactaaacagtaagatatctcaatgaaccataaattcaactttgtaaaaat 3061 cttttgaagcatagataatattgtttggtaaatgtttcttttgtttggtaaatgtttctt 3121 ttaaagaccctcctattctataaaactctgcatgtagaggcttgtttacctttctctctc 3181 taaggtttacaataggagtggtgatttgaaaaatataaaattatgagattggttttcctg 3241 tggcataaattgcatcactgtatcattttcttttttaaccggtaagagtttcagtttgtt 3301 ggaaagtaactgtgagaacccagtttcccgtccatctcccttagggactacccatagaca 3361 tgaaaggtccccacagagcaagagataagtctttcatggctgctgttgcttaaaccactt 3421 aaacgaagagttcccttgaaactttgggaaaacatgttaatgacaatattccagatcttt 3481 cagaaatataacacatttttttgcatgcatgcaaatgagctctgaaatcttcccatgcat 3541 tctggtcaagggctgtcattgcacataagcttccattttaattttaaagtgcaaaagggc 3601 cagcgtggctctaaaaggtaatgtgtggattgcctctgaaaagtgtgtatatattttgtg 3661 tgaaattgcatactttgtattttgattattttttttttcttcttgggatagtgggatttc 3721 cagaaccacacttgaaacctttttttatcgtttttgtattttcatgaaaataccatttag 3781 taagaataccacatcaaataagaaataatgctacaattttaagaggggagggaagggaaa 3841 gtttttttttattatttttttaaaattttgtatgttaaagagaatgagtccttgatttca 3901 aagttttgttgtacttaaatggtaataagcactgtaaacttctgcaacaagcatgcagct 3961 ttgcaaacccattaaggggaagaatgaaagctgttccttggtcctagtaagaagacaaac 4021 tgcttcccttactttgctgagggtttgaataaacctaggacttccgagctatgtcagtac 4081 tattcaggtaacactagggccttggaaattcctgtactgtgtctcatggatttggcacta 4141 gccaaagcgaggcacccttactggcttacctcctcatggcagcctactctccttgagtgt 4201 atgagtagccagggtaaggggtaaaaggatagtaagcatagaaaccactagaaagtgggc 4261 ttaatggagttcttgtggcctcagctcaatgcagttagctgaagaattgaaaagtttttg 4321 tttggagacgtttataaacagaaatggaaagcagagttttcattaaatccttttaccttt 4381 tttttttcttggtaatcccctaaaataacagtatgtgggatattgaatgttaaagggata 4441 tttttttctattatttttataattgtacaaaattaagcaaatgttaaaagttttatatgc 4501 tttattaatgttttcaaaaggtattatacatgtgatacattttttaagcttcagttgctt 4561 gtcttctggtactttctgttatgggcttttggggagccagaagccaatctacaatctctt 4621 tttgtttgccaggacatgcaataaaatttaaaaaataaataaaaactaattaagaaa SEQIDNO:24Humanp63Isoform4AminoAcidSequence(NP_001108452.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdstkngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsiq 361 spssygnsspplnkmnsmnklpsysqlinpqqrnaltpttipdgmganipmmgthmpmag 421 dmnglsptqalppplsmpstshctppppyptdcsivsflarlgcsscldyfttqglttiy 481 qiehysmddlaslkipeqfrhaiwkgildhrqlhefsspshllrtpssastvsvgssetr 541 gervidavrftlrqtisfpprdewndfnfdmdarrnkqqrikeege SEQIDNO:25Humanp63transcriptvariant5mRNASequence (NM_001114981.2;CDS:143-1528) 1 cagagagagaaagagagagagggacttgagttctgttatcttcttaagtagattcatatt 61 gtaagggtctcggggtgggggggttggcaaaatcctggagccagaagaaaggacagcagc 121 attgatcaatcttacagctaacatgttgtacctggaaaacaatgcccagactcaatttag 181 tgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaacgg 241 ctcctcgtccaccagtccctataacacagaccacgcgcagaacagcgtcacggcgccctc 301 gccctacgcacagcccagctccaccttcgatgctctctctccatcacccgccatcccctc 361 caacaccgactacccaggcccgcacagtttcgacgtgtccttccagcagtcgagcaccgc 421 caagtcggccacctggacgtattccactgaactgaagaaactctactgccaaattgcaaa 481 gacatgccccatccagatcaaggtgatgaccccacctcctcagggagctgttatccgcgc 541 catgcctgtctacaaaaaagctgagcacgtcacggaggtggtgaagcggtgccccaacca 601 tgagctgagccgtgaattcaacgagggacagattgcccctcctagtcatttgattcgagt 661 agaggggaacagccatgcccagtatgtagaagatcccatcacaggaagacagagtgtgct 721 ggtaccttatgagccaccccaggttggcactgaattcacgacagtcttgtacaatttcat 781 gtgtaacagcagttgtgttggagggatgaaccgccgtccaattttaatcattgttactct 841 ggaaaccagagatgggcaagtcctgggccgacgctgctttgaggcccggatctgtgcttg 901 cccaggaagagacaggaaggcggatgaagatagcatcagaaagcagcaagtttcggacag 961 tacaaagaacggtgatggtacgaagcgcccgtttcgtcagaacacacatggtatccagat 1021 gacatccatcaagaaacgaagatccccagatgatgaactgttatacttaccagtgagggg 1081 ccgtgagacttatgaaatgctgttgaagatcaaagagtccctggaactcatgcagtacct 1141 tcctcagcacacaattgaaacgtacaggcaacagcaacagcagcagcaccagcacttact 1201 tcagaaacagacctcaatacagtctccatcttcatatggtaacagctccccacctctgaa 1261 caaaatgaacagcatgaacaagctgccttctgtgagccagcttatcaaccctcagcagcg 1321 caacgccctcactcctacaaccattcctgatggcatgggagccaacattcccatgatggg 1381 cacccacatgccaatggctggagacatgaatggactcagccccacccaggcactccctcc 1441 cccactctccatgccatccacctcccactgcacacccccacctccgtatcccacagattg 1501 cagcattgtcaggatctggcaagtctgaaaatccctgagcaatttcgacatgcgatctgg 1561 aagggcatcctggaccaccggcagctccacgaattctcctccccttctcatctcctgcgg 1621 accccaagcagtgcctctacagtcagtgtgggctccagtgagacccggggtgagcgtgtt 1681 attgatgctgtgcgattcaccctccgccagaccatctctttcccaccccgagatgagtgg 1741 aatgacttcaactttgacatggatgctcgccgcaataagcaacagcgcatcaaagaggag 1801 ggggagtgagcctcaccatgtgagctcttcctatccctctcctaactgccagccccctaa 1861 aagcactcctgcttaatcttcaaagccttctccctagctcctccccttcctcttgtctga 1921 tttcttaggggaaggagaagtaagaggctacctcttacctaacatctgacctggcatcta 1981 attctgattctggctttaagccttcaaaactatagcttgcagaactgtagctgccatggc 2041 taggtagaagtgagcaaaaaagagttgggtgtctccttaagctgcagagatttctcattg 2101 acttttataaagcatgttcacccttatagtctaagactatatatataaatgtataaatat 2161 acagtatagatttttgggtggggggcattgagtattgtttaaaatgtaatttaaatgaaa 2221 gaaaattgagttgcacttattgaccattttttaatttacttgttttggatggcttgtcta 2281 tactccttcccttaaggggtatcatgtatggtgataggtatctagagcttaatgctacat 2341 gtgagtgacgatgatgtacagattctttcagttctttggattctaaatacatgccacatc 2401 aaacctttgagtagatccatttccattgcttattatgtaggtaagactgtagatatgtat 2461 tcttttctcagtgttggtatattttatattactgacatttcttctagtgatgatggttca 2521 cgttggggtgatttaatccagttataagaagaagttcatgtccaaacgtcctctttagtt 2581 tttggttgggaatgaggaaaattcttaaaaggcccatagcagccagttcaaaaacacccg 2641 acgtcatgtatttgagcatatcagtaacccccttaaatttaataccagataccttatctt 2701 acaatattgattgggaaaacatttgctgccattacagaggtattaaaactaaatttcact 2761 actagattgactaactcaaatacacatttgctactgttgtaagaattctgattgatttga 2821 ttgggatgaatgccatctatctagttctaacagtgaagttttactgtctattaatattca 2881 gggtaaataggaatcattcagaaatgttgagtctgtactaaacagtaagatatctcaatg 2941 aaccataaattcaactttgtaaaaatcttttgaagcatagataatattgtttggtaaatg 3001 tttcttttgtttggtaaatgtttcttttaaagaccctcctattctataaaactctgcatg 3061 tagaggcttgtttacctttctctctctaaggtttacaataggagtggtgatttgaaaaat 3121 ataaaattatgagattggttttcctgtggcataaattgcatcactgtatcattttctttt 3181 ttaaccggtaagagtttcagtttgttggaaagtaactgtgagaacccagtttcccgtcca 3241 tctcccttagggactacccatagacatgaaaggtccccacagagcaagagataagtcttt 3301 catggctgctgttgcttaaaccacttaaacgaagagttcccttgaaactttgggaaaaca 3361 tgttaatgacaatattccagatctttcagaaatataacacatttttttgcatgcatgcaa 3421 atgagctctgaaatcttcccatgcattctggtcaagggctgtcattgcacataagcttcc 3481 attttaattttaaagtgcaaaagggccagcgtggctctaaaaggtaatgtgtggattgcc 3541 tctgaaaagtgtgtatatattttgtgtgaaattgcatactttgtattttgattatttttt 3601 ttttcttcttgggatagtgggatttccagaaccacacttgaaacctttttttatcgtttt 3661 tgtattttcatgaaaataccatttagtaagaataccacatcaaataagaaataatgctac 3721 aattttaagaggggagggaagggaaagtttttttttattatttttttaaaattttgtatg 3781 ttaaagagaatgagtccttgatttcaaagttttgttgtacttaaatggtaataagcactg 3841 taaacttctgcaacaagcatgcagctttgcaaacccattaaggggaagaatgaaagctgt 3901 tccttggtcctagtaagaagacaaactgcttcccttactttgctgagggtttgaataaac 3961 ctaggacttccgagctatgtcagtactattcaggtaacactagggccttggaaattcctg 4021 tactgtgtctcatggatttggcactagccaaagcgaggcacccttactggcttacctcct 4081 catggcagcctactctccttgagtgtatgagtagccagggtaaggggtaaaaggatagta 4141 agcatagaaaccactagaaagtgggcttaatggagttcttgtggcctcagctcaatgcag 4201 ttagctgaagaattgaaaagtttttgtttggagacgtttataaacagaaatggaaagcag 4261 agttttcattaaatccttttaccttttttttttcttggtaatcccctaaaataacagtat 4321 gtgggatattgaatgttaaagggatatttttttctattatttttataattgtacaaaatt 4381 aagcaaatgttaaaagttttatatgctttattaatgttttcaaaaggtattatacatgtg 4441 atacattttttaagcttcagttgcttgtcttctggtactttctgttatgggcttttgggg 4501 agccagaagccaatctacaatctctttttgtttgccaggacatgcaataaaatttaaaaa 4561 ataaataaaaactaattaagaaa SEQIDNO:26Humanp63Isoform5AminoAcidSequence(NP_001108453.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdstkngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsiq 361 spssygnsspplnkmnsmnklpsysqlinpqqrnaltpttipdgmganipmmgthmpmag 421 dmnglsptqalppplsmpstshctppppyptdcsivriwqv SEQIDNO:27Humanp63transcriptvariant6mRNASequence (NM_001114982.2;CDS:143-1324) 1 cagagagagaaagagagagagggacttgagttctgttatcttcttaagtagattcatatt 61 gtaagggtctcggggtgggggggttggcaaaatcctggagccagaagaaaggacagcagc 121 attgatcaatcttacagctaacatgttgtacctggaaaacaatgcccagactcaatttag 181 tgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaacgg 241 ctcctcgtccaccagtccctataacacagaccacgcgcagaacagcgtcacggcgccctc 301 gccctacgcacagcccagctccaccttcgatgctctctctccatcacccgccatcccctc 361 caacaccgactacccaggcccgcacagtttcgacgtgtccttccagcagtcgagcaccgc 421 caagtcggccacctggacgtattccactgaactgaagaaactctactgccaaattgcaaa 481 gacatgccccatccagatcaaggtgatgaccccacctcctcagggagctgttatccgcgc 541 catgcctgtctacaaaaaagctgagcacgtcacggaggtggtgaagcggtgccccaacca 601 tgagctgagccgtgaattcaacgagggacagattgcccctcctagtcatttgattcgagt 661 agaggggaacagccatgcccagtatgtagaagatcccatcacaggaagacagagtgtgct 721 ggtaccttatgagccaccccaggttggcactgaattcacgacagtcttgtacaatttcat 781 gtgtaacagcagttgtgttggagggatgaaccgccgtccaattttaatcattgttactct 841 ggaaaccagagatgggcaagtcctgggccgacgctgctttgaggcccggatctgtgcttg 901 cccaggaagagacaggaaggcggatgaagatagcatcagaaagcagcaagtttcggacag 961 tacaaagaacggtgatggtacgaagcgcccgtttcgtcagaacacacatggtatccagat 1021 gacatccatcaagaaacgaagatccccagatgatgaactgttatacttaccagtgagggg 1081 ccgtgagacttatgaaatgctgttgaagatcaaagagtccctggaactcatgcagtacct 1141 tcctcagcacacaattgaaacgtacaggcaacagcaacagcagcagcaccagcacttact 1201 tcagaaacatctcctttcagcctgcttcaggaatgagcttgtggagccccggagagaaac 1261 tccaaaacaatctgacgtcttctttagacattccaagcccccaaaccgatcagtgtaccc 1321 atagagccctatctctatattttaagtgtgtgtgttgtatttccatgtgtatatgtgagt 1381 gtgtgtgtgtgtatgtgtgtgcgtgtgtatctagccctcataaacaggacttgaagacac 1441 tttggctcagagacccaactgctcaaaggcacaaagccactagtgagagaatcttttgaa 1501 gggactcaaacctttacaagaaaggatgttttctgcagattttgtatccttagaccggcc 1561 attggtgggtgaggaaccactgtgtttgtctgtgagctttctgttgtttcctgggaggga 1621 ggggtcaggtggggaaaggggcattaagatgtttattggaacccttttctgtcttcttct 1681 gttgtttttctaaaattcacagggaagcttttgagcaggtctcaaacttaagatgtcttt 1741 ttaagaaaaggagaaaaaagttgttattgtctgtgcataagtaagttgtaggtgactgag 1801 agactcagtcagacccttttaatgctggtcatgtaataatattgcaagtagtaagaaacg 1861 aaggtgtcaagtgtactgctgggcagcgaggtgatcattaccaaaagtaatcaactttgt 1921 gggtggagagttctttgtgagaacttgcattatttgtgtcctcccctcatgtgtaggtag 1981 aacatttcttaatgctgtgtacctgcctctgccactgtatgttggcatctgttatgctaa 2041 agtttttcttgtacatgaaaccctggaagacctactacaaaaaaactgttgtttggcccc 2101 catagcaggtgaactcattttgtgcttttaatagaaagacaaatccaccccagtaatatt 2161 gcccttacgtagttgtttaccattattcaaagctcaaaatagaatttgaagccctctcac 2221 aaaatctgtgattaatttgcttaattagagcttctatccctcaagcctacctaccataaa 2281 accagccatattactgatactgttcagtgcatttagccaggagacttacgttttgagtaa 2341 gtgagatccaagcagacgtgttaaaatcagcactcctggactggaaattaaagattgaaa 2401 gggtagactacttttcttttttttactcaaaagtttagagaatctctgtttctttccatt 2461 ttaaaaacatattttaagataatagcataaagactttaaaaatgttcctcccctccatct 2521 tcccacacccagtcaccagcactgtattttctgtcaccaagacaatgatttcttgttatt 2581 gaggctgttgcttttgtggatgtgtgattttaattttcaataaacttttgcatcttggtt 2641 tatcttgca SEQIDNO:28Humanp63Isoform6Sequence(NP_001108454.1) 1 mlylennaqtqfsepqytnlgllnsmdqqlqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdstkngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkhllsa 361 cfrnelveprretpkqsdvffrhskppnrsvyp SEQIDNO:29Humanp63transcriptvariant7mRNASequence (NM_001329144.2;CDS:128-1660) 1 ctatgtctgatagcatttgaccctattgcttttagcctcccggctttatatctatatata 61 cacaggtatatgtgtatattttatataattgttctccgttcgttgatatcaaagacagtt 121 gaaggaaatgaattttgaaacttcacggtgtgccaccctacagtactgccctgaccctta 181 catccagcgtttcgtagaaaccccagctcatttctcttggaaagaaagttattaccgatc 241 caccatgtcccagagcacacagacaaatgaattcctcagtccagaggttttccagcatat 301 ctgggattttctggaacagcctatatgttcagttcagcccattgacttgaactttgtgga 361 tgaaccatcagaagatggtgcgacaaacaagattgagattagcatggactgtatccgcat 421 gcaggactcggacctgagtgaccccatgtggccacagtacacgaacctggggctcctgaa 481 cagcatggaccagcagattcagaacggctcctcgtccaccagtccctataacacagacca 541 cgcgcagaacagcgtcacggcgccctcgccctacgcacagcccagctccaccttcgatgc 601 tctctctccatcacccgccatcccctccaacaccgactacccaggcccgcacagtttcga 661 cgtgtccttccagcagtcgagcaccgccaagtcggccacctggacgtattccactgaact 721 gaagaaactctactgccaaattgcaaagacatgccccatccagatcaaggtgatgacccc 781 acctcctcagggagctgttatccgcgccatgcctgtctacaaaaaagctgagcacgtcac 841 ggaggtggtgaagcggtgccccaaccatgagctgagccgtgaattcaacgagggacagat 901 tgcccctcctagtcatttgattcgagtagaggggaacagccatgcccagtatgtagaaga 961 tcccatcacaggaagacagagtgtgctggtaccttatgagccaccccaggttggcactga 1021 attcacgacagtcttgtacaatttcatgtgtaacagcagttgtgttggagggatgaaccg 1081 ccgtccaattttaatcattgttactctggaaaccagagatgggcaagtcctgggccgacg 1141 ctgctttgaggcccggatctgtgcttgcccaggaagagacaggaaggcggatgaagatag 1201 catcagaaagcagcaagtttcggacagtacaaagaacggtgatggtacgaagcgcccgtt 1261 tcgtcagaacacacatggtatccagatgacatccatcaagaaacgaagatccccagatga 1321 tgaactgttatacttaccagtgaggggccgtgagacttatgaaatgctgttgaagatcaa 1381 agagtccctggaactcatgcagtaccttcctcagcacacaattgaaacgtacaggcaaca 1441 gcaacagcagcagcaccagcacttacttcagaaacagacctcaatacagtctccatcttc 1501 atatggtaacagctccccacctctgaacaaaatgaacagcatgaacaagctgccttctgt 1561 gagccagcttatcaaccctcagcagcgcaacgccctcactcctacaaccattcctgatgg 1621 catgggagccaacagatctggcaagtctgaaaatccctgagcaatttcgacatgcgatct 1681 ggaagggcatcctggaccaccggcagctccacgaattctcctccccttctcatctcctgc 1741 ggaccccaagcagtgcctctacagtcagtgtgggctccagtgagacccggggtgagcgtg 1801 ttattgatgctgtgcgattcaccctccgccagaccatctctttcccaccccgagatgagt 1861 ggaatgacttcaactttgacatggatgctcgccgcaataagcaacagcgcatcaaagagg 1921 agggggagtgagcctcaccatgtgagctcttcctatccctctcctaactgccagccccct 1981 aaaagcactcctgcttaatcttcaaagccttctccctagctcctccccttcctcttgtct 2041 gatttcttaggggaaggagaagtaagaggctacctcttacctaacatctgacctggcatc 2101 taattctgattctggctttaagccttcaaaactatagcttgcagaactgtagctgccatg 2161 gctaggtagaagtgagcaaaaaagagttgggtgtctccttaagctgcagagatttctcat 2221 tgacttttataaagcatgttcacccttatagtctaagactatatatataaatgtataaat 2281 atacagtatagatttttgggtggggggcattgagtattgtttaaaatgtaatttaaatga 2341 aagaaaattgagttgcacttattgaccattttttaatttacttgttttggatggcttgtc 2401 tatactccttcccttaaggggtatcatgtatggtgataggtatctagagcttaatgctac 2461 atgtgagtgacgatgatgtacagattctttcagttctttggattctaaatacatgccaca 2521 tcaaacctttgagtagatccatttccattgcttattatgtaggtaagactgtagatatgt 2581 attcttttctcagtgttggtatattttatattactgacatttcttctagtgatgatggtt 2641 cacgttggggtgatttaatccagttataagaagaagttcatgtccaaacgtcctctttag 2701 tttttggttgggaatgaggaaaattcttaaaaggcccatagcagccagttcaaaaacacc 2761 cgacgtcatgtatttgagcatatcagtaacccccttaaatttaataccagataccttatc 2821 ttacaatattgattgggaaaacatttgctgccattacagaggtattaaaactaaatttca 2881 ctactagattgactaactcaaatacacatttgctactgttgtaagaattctgattgattt 2941 gattgggatgaatgccatctatctagttctaacagtgaagttttactgtctattaatatt 3001 cagggtaaataggaatcattcagaaatgttgagtctgtactaaacagtaagatatctcaa 3061 tgaaccataaattcaactttgtaaaaatcttttgaagcatagataatattgtttggtaaa 3121 tgtttcttttgtttggtaaatgtttcttttaaagaccctcctattctataaaactctgca 3181 tgtagaggcttgtttacctttctctctctaaggtttacaataggagtggtgatttgaaaa 3241 atataaaattatgagattggttttcctgtggcataaattgcatcactgtatcattttctt 3301 ttttaaccggtaagagtttcagtttgttggaaagtaactgtgagaacccagtttcccgtc 3361 catctcccttagggactacccatagacatgaaaggtccccacagagcaagagataagtct 3421 ttcatggctgctgttgcttaaaccacttaaacgaagagttcccttgaaactttgggaaaa 3481 catgttaatgacaatattccagatctttcagaaatataacacatttttttgcatgcatgc 3541 aaatgagctctgaaatcttcccatgcattctggtcaagggctgtcattgcacataagctt 3601 ccattttaattttaaagtgcaaaagggccagcgtggctctaaaaggtaatgtgtggattg 3661 cctctgaaaagtgtgtatatattttgtgtgaaattgcatactttgtattttgattatttt 3721 ttttttcttcttgggatagtgggatttccagaaccacacttgaaacctttttttatcgtt 3781 tttgtattttcatgaaaataccatttagtaagaataccacatcaaataagaaataatgct 3841 acaattttaagaggggagggaagggaaagtttttttttattatttttttaaaattttgta 3901 tgttaaagagaatgagtccttgatttcaaagttttgttgtacttaaatggtaataagcac 3961 tgtaaacttctgcaacaagcatgcagctttgcaaacccattaaggggaagaatgaaagct 4021 gttccttggtcctagtaagaagacaaactgcttcccttactttgctgagggtttgaataa 4081 acctaggacttccgagctatgtcagtactattcaggtaacactagggccttggaaattcc 4141 tgtactgtgtctcatggatttggcactagccaaagcgaggcacccttactggcttacctc 4201 ctcatggcagcctactctccttgagtgtatgagtagccagggtaaggggtaaaaggatag 4261 taagcatagaaaccactagaaagtgggcttaatggagttcttgtggcctcagctcaatgc 4321 agttagctgaagaattgaaaagtttttgtttggagacgtttataaacagaaatggaaagc 4381 agagttttcattaaatccttttaccttttttttttcttggtaatcccctaaaataacagt 4441 atgtgggatattgaatgttaaagggatatttttttctattatttttataattgtacaaaa 4501 ttaagcaaatgttaaaagttttatatgctttattaatgttttcaaaaggtattatacatg 4561 tgatacattttttaagcttcagttgcttgtcttctggtactttctgttatgggcttttgg 4621 ggagccagaagccaatctacaatctctttttgtttgccaggacatgcaataaaatttaaa 4681 aaataaataaaaactaattaagaaa SEQIDNO:30Humanp63Isoform7AminoAcidSequence(NP_001316073.1) 1 mnfetsrcatlqycpdpyiqrfvetpahfswkesyyrstmsqstqtneflspevfqhiwd 61 fleqpicsvqpidlnfvdepsedgatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdstkngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkqtsiqspssygnssppinkmnsmnklpsvsq 481 linpqqrnaltpttipdgmganrsgksenp SEQIDNO:31Humanp63transcriptvariant8mRNASequence (NM_001329145.2;CDS:143-1393) 1 cagagagagaaagagagagagggacttgagttctgttatcttcttaagtagattcatatt 61 gtaagggtctcggggtgggggggttggcaaaatcctggagccagaagaaaggacagcagc 121 attgatcaatcttacagctaacatgttgtacctggaaaacaatgcccagactcaatttag 181 tgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaacgg 241 ctcctcgtccaccagtccctataacacagaccacgcgcagaacagcgtcacggcgccctc 301 gccctacgcacagcccagctccaccttcgatgctctctctccatcacccgccatcccctc 361 caacaccgactacccaggcccgcacagtttcgacgtgtccttccagcagtcgagcaccgc 421 caagtcggccacctggacgtattccactgaactgaagaaactctactgccaaattgcaaa 481 gacatgccccatccagatcaaggtgatgaccccacctcctcagggagctgttatccgcgc 541 catgcctgtctacaaaaaagctgagcacgtcacggaggtggtgaagcggtgccccaacca 601 tgagctgagccgtgaattcaacgagggacagattgcccctcctagtcatttgattcgagt 661 agaggggaacagccatgcccagtatgtagaagatcccatcacaggaagacagagtgtgct 721 ggtaccttatgagccaccccaggttggcactgaattcacgacagtcttgtacaatttcat 781 gtgtaacagcagttgtgttggagggatgaaccgccgtccaattttaatcattgttactct 841 ggaaaccagagatgggcaagtcctgggccgacgctgctttgaggcccggatctgtgcttg 901 cccaggaagagacaggaaggcggatgaagatagcatcagaaagcagcaagtttcggacag 961 tacaaagaacggtgatggtacgaagcgcccgtttcgtcagaacacacatggtatccagat 1021 gacatccatcaagaaacgaagatccccagatgatgaactgttatacttaccagtgagggg 1081 ccgtgagacttatgaaatgctgttgaagatcaaagagtccctggaactcatgcagtacct 1141 tcctcagcacacaattgaaacgtacaggcaacagcaacagcagcagcaccagcacttact 1201 tcagaaacagacctcaatacagtctccatcttcatatggtaacagctccccacctctgaa 1261 caaaatgaacagcatgaacaagctgccttctgtgagccagcttatcaaccctcagcagcg 1321 caacgccctcactcctacaaccattcctgatggcatgggagccaacagatctggcaagtc 1381 tgaaaatccctgagcaatttcgacatgcgatctggaagggcatcctggaccaccggcagc 1441 tccacgaattctcctccccttctcatctcctgcggaccccaagcagtgcctctacagtca 1501 gtgtgggctccagtgagacccggggtgagcgtgttattgatgctgtgcgattcaccctcc 1561 gccagaccatctctttcccaccccgagatgagtggaatgacttcaactttgacatggatg 1621 ctcgccgcaataagcaacagcgcatcaaagaggagggggagtgagcctcaccatgtgagc 1681 tcttcctatccctctcctaactgccagccccctaaaagcactcctgcttaatcttcaaag 1741 ccttctccctagctcctccccttcctcttgtctgatttcttaggggaaggagaagtaaga 1801 ggctacctcttacctaacatctgacctggcatctaattctgattctggctttaagccttc 1861 aaaactatagcttgcagaactgtagctgccatggctaggtagaagtgagcaaaaaagagt 1921 tgggtgtctccttaagctgcagagatttctcattgacttttataaagcatgttcaccctt 1981 atagtctaagactatatatataaatgtataaatatacagtatagatttttgggtgggggg 2041 cattgagtattgtttaaaatgtaatttaaatgaaagaaaattgagttgcacttattgacc 2101 attttttaatttacttgttttggatggcttgtctatactccttcccttaaggggtatcat 2161 gtatggtgataggtatctagagcttaatgctacatgtgagtgacgatgatgtacagattc 2221 tttcagttctttggattctaaatacatgccacatcaaacctttgagtagatccatttcca 2281 ttgcttattatgtaggtaagactgtagatatgtattcttttctcagtgttggtatatttt 2341 atattactgacatttcttctagtgatgatggttcacgttggggtgatttaatccagttat 2401 aagaagaagttcatgtccaaacgtcctctttagtttttggttgggaatgaggaaaattct 2461 taaaaggcccatagcagccagttcaaaaacacccgacgtcatgtatttgagcatatcagt 2521 aacccccttaaatttaataccagataccttatcttacaatattgattgggaaaacatttg 2581 ctgccattacagaggtattaaaactaaatttcactactagattgactaactcaaatacac 2641 atttgctactgttgtaagaattctgattgatttgattgggatgaatgccatctatctagt 2701 tctaacagtgaagttttactgtctattaatattcagggtaaataggaatcattcagaaat 2761 gttgagtctgtactaaacagtaagatatctcaatgaaccataaattcaactttgtaaaaa 2821 tcttttgaagcatagataatattgtttggtaaatgtttcttttgtttggtaaatgtttct 2881 tttaaagaccctcctattctataaaactctgcatgtagaggcttgtttacctttctctct 2941 ctaaggtttacaataggagtggtgatttgaaaaatataaaattatgagattggttttcct 3001 gtggcataaattgcatcactgtatcattttcttttttaaccggtaagagtttcagtttgt 3061 tggaaagtaactgtgagaacccagtttcccgtccatctcccttagggactacccatagac 3121 atgaaaggtccccacagagcaagagataagtctttcatggctgctgttgcttaaaccact 3181 taaacgaagagttcccttgaaactttgggaaaacatgttaatgacaatattccagatctt 3241 tcagaaatataacacatttttttgcatgcatgcaaatgagctctgaaatcttcccatgca 3301 ttctggtcaagggctgtcattgcacataagcttccattttaattttaaagtgcaaaaggg 3361 ccagcgtggctctaaaaggtaatgtgtggattgcctctgaaaagtgtgtatatattttgt 3421 gtgaaattgcatactttgtattttgattattttttttttcttcttgggatagtgggattt 3481 ccagaaccacacttgaaacctttttttatcgtttttgtattttcatgaaaataccattta 3541 gtaagaataccacatcaaataagaaataatgctacaattttaagaggggagggaagggaa 3601 agtttttttttattatttttttaaaattttgtatgttaaagagaatgagtccttgatttc 3661 aaagttttgttgtacttaaatggtaataagcactgtaaacttctgcaacaagcatgcagc 3721 tttgcaaacccattaaggggaagaatgaaagctgttccttggtcctagtaagaagacaaa 3781 ctgcttcccttactttgctgagggtttgaataaacctaggacttccgagctatgtcagta 3841 ctattcaggtaacactagggccttggaaattcctgtactgtgtctcatggatttggcact 3901 agccaaagcgaggcacccttactggcttacctcctcatggcagcctactctccttgagtg 3961 tatgagtagccagggtaaggggtaaaaggatagtaagcatagaaaccactagaaagtggg 4021 cttaatggagttcttgtggcctcagctcaatgcagttagctgaagaattgaaaagttttt 4081 gtttggagacgtttataaacagaaatggaaagcagagttttcattaaatccttttacctt 4141 ttttttttcttggtaatcccctaaaataacagtatgtgggatattgaatgttaaagggat 4201 atttttttctattatttttataattgtacaaaattaagcaaatgttaaaagttttatatg 4261 ctttattaatgttttcaaaaggtattatacatgtgatacattttttaagcttcagttgct 4321 tgtcttctggtactttctgttatgggcttttggggagccagaagccaatctacaatctct 4381 ttttgtttgccaggacatgcaataaaatttaaaaaataaataaaaactaattaagaaa SEQIDNO:32Humanp63Isoform8AminoAcidSequence(NP_001316074.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdstkngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsiq 361 spssygnssppinkmnsmnklpsvsqlinpqqrnaltpttipdgmganrsgksenp SEQIDNO:33Humanp63transcriptvariant9mRNASequence NM_001329146.2;CDS:143-1648) 1 cagagagagaaagagagagagggacttgagttctgttatcttcttaagtagattcatatt 61 gtaagggtctcggggtgggggggttggcaaaatcctggagccagaagaaaggacagcagc 121 attgatcaatcttacagctaacatgttgtacctggaaaacaatgcccagactcaatttag 181 tgagtattccactgaactgaagaaactctactgccaaattgcaaagacatgccccatcca 241 gatcaaggtgatgaccccacctcctcagggagctgttatccgcgccatgcctgtctacaa 301 aaaagctgagcacgtcacggaggtggtgaagcggtgccccaaccatgagctgagccgtga 361 attcaacgagggacagattgcccctcctagtcatttgattcgagtagaggggaacagcca 421 tgcccagtatgtagaagatcccatcacaggaagacagagtgtgctggtaccttatgagcc 481 accccaggttggcactgaattcacgacagtcttgtacaatttcatgtgtaacagcagttg 541 tgttggagggatgaaccgccgtccaattttaatcattgttactctggaaaccagagatgg 601 gcaagtcctgggccgacgctgctttgaggcccggatctgtgcttgcccaggaagagacag 661 gaaggcggatgaagatagcatcagaaagcagcaagtttcggacagtacaaagaacggtga 721 tggtacgaagcgcccgtttcgtcagaacacacatggtatccagatgacatccatcaagaa 781 acgaagatccccagatgatgaactgttatacttaccagtgaggggccgtgagacttatga 841 aatgctgttgaagatcaaagagtccctggaactcatgcagtaccttcctcagcacacaat 901 tgaaacgtacaggcaacagcaacagcagcagcaccagcacttacttcagaaacagacctc 961 aatacagtctccatcttcatatggtaacagctccccacctctgaacaaaatgaacagcat 1021 gaacaagctgccttctgtgagccagcttatcaaccctcagcagcgcaacgccctcactcc 1081 tacaaccattcctgatggcatgggagccaacattcccatgatgggcacccacatgccaat 1141 ggctggagacatgaatggactcagccccacccaggcactccctcccccactctccatgcc 1201 atccacctcccactgcacacccccacctccgtatcccacagattgcagcattgtcagttt 1261 cttagcgaggttgggctgttcatcatgtctggactatttcacgacccaggggctgaccac 1321 catctatcagattgagcattactccatggatgatctggcaagtctgaaaatccctgagca 1381 atttcgacatgcgatctggaagggcatcctggaccaccggcagctccacgaattctcctc 1441 cccttctcatctcctgcggaccccaagcagtgcctctacagtcagtgtgggctccagtga 1501 gacccggggtgagcgtgttattgatgctgtgcgattcaccctccgccagaccatctcttt 1561 cccaccccgagatgagtggaatgacttcaactttgacatggatgctcgccgcaataagca 1621 acagcgcatcaaagaggagggggagtgagcctcaccatgtgagctcttcctatccctctc 1681 ctaactgccagccccctaaaagcactcctgcttaatcttcaaagccttctccctagctcc 1741 tccccttcctcttgtctgatttcttaggggaaggagaagtaagaggctacctcttaccta 1801 acatctgacctggcatctaattctgattctggctttaagccttcaaaactatagcttgca 1861 gaactgtagctgccatggctaggtagaagtgagcaaaaaagagttgggtgtctccttaag 1921 ctgcagagatttctcattgacttttataaagcatgttcacccttatagtctaagactata 1981 tatataaatgtataaatatacagtatagatttttgggtggggggcattgagtattgttta 2041 aaatgtaatttaaatgaaagaaaattgagttgcacttattgaccattttttaatttactt 2101 gttttggatggcttgtctatactccttcccttaaggggtatcatgtatggtgataggtat 2161 ctagagcttaatgctacatgtgagtgacgatgatgtacagattctttcagttctttggat 2221 tctaaatacatgccacatcaaacctttgagtagatccatttccattgcttattatgtagg 2281 taagactgtagatatgtattcttttctcagtgttggtatattttatattactgacatttc 2341 ttctagtgatgatggttcacgttggggtgatttaatccagttataagaagaagttcatgt 2401 ccaaacgtcctctttagtttttggttgggaatgaggaaaattcttaaaaggcccatagca 2461 gccagttcaaaaacacccgacgtcatgtatttgagcatatcagtaacccccttaaattta 2521 ataccagataccttatcttacaatattgattgggaaaacatttgctgccattacagaggt 2581 attaaaactaaatttcactactagattgactaactcaaatacacatttgctactgttgta 2641 agaattctgattgatttgattgggatgaatgccatctatctagttctaacagtgaagttt 2701 tactgtctattaatattcagggtaaataggaatcattcagaaatgttgagtctgtactaa 2761 acagtaagatatctcaatgaaccataaattcaactttgtaaaaatcttttgaagcataga 2821 taatattgtttggtaaatgtttcttttgtttggtaaatgtttcttttaaagaccctccta 2881 ttctataaaactctgcatgtagaggcttgtttacctttctctctctaaggtttacaatag 2941 gagtggtgatttgaaaaatataaaattatgagattggttttcctgtggcataaattgcat 3001 cactgtatcattttcttttttaaccggtaagagtttcagtttgttggaaagtaactgtga 3061 gaacccagtttcccgtccatctcccttagggactacccatagacatgaaaggtccccaca 3121 gagcaagagataagtctttcatggctgctgttgcttaaaccacttaaacgaagagttccc 3181 ttgaaactttgggaaaacatgttaatgacaatattccagatctttcagaaatataacaca 3241 tttttttgcatgcatgcaaatgagctctgaaatcttcccatgcattctggtcaagggctg 3301 tcattgcacataagcttccattttaattttaaagtgcaaaagggccagcgtggctctaaa 3361 aggtaatgtgtggattgcctctgaaaagtgtgtatatattttgtgtgaaattgcatactt 3421 tgtattttgattattttttttttcttcttgggatagtgggatttccagaaccacacttga 3481 aacctttttttatcgtttttgtattttcatgaaaataccatttagtaagaataccacatc 3541 aaataagaaataatgctacaattttaagaggggagggaagggaaagtttttttttattat 3601 ttttttaaaattttgtatgttaaagagaatgagtccttgatttcaaagttttgttgtact 3661 taaatggtaataagcactgtaaacttctgcaacaagcatgcagctttgcaaacccattaa 3721 ggggaagaatgaaagctgttccttggtcctagtaagaagacaaactgcttcccttacttt 3781 gctgagggtttgaataaacctaggacttccgagctatgtcagtactattcaggtaacact 3841 agggccttggaaattcctgtactgtgtctcatggatttggcactagccaaagcgaggcac 3901 ccttactggcttacctcctcatggcagcctactctccttgagtgtatgagtagccagggt 3961 aaggggtaaaaggatagtaagcatagaaaccactagaaagtgggcttaatggagttcttg 4021 tggcctcagctcaatgcagttagctgaagaattgaaaagtttttgtttggagacgtttat 4081 aaacagaaatggaaagcagagttttcattaaatccttttaccttttttttttcttggtaa 4141 tcccctaaaataacagtatgtgggatattgaatgttaaagggatatttttttctattatt 4201 tttataattgtacaaaattaagcaaatgttaaaagttttatatgctttattaatgttttc 4261 aaaaggtattatacatgtgatacattttttaagcttcagttgcttgtcttctggtacttt 4321 ctgttatgggcttttggggagccagaagccaatctacaatctctttttgtttgccaggac 4381 atgcaataaaatttaaaaaataaataaaaactaattaagaaa SEQIDNO:34Humanp63Isoform9AminoAcidSequence(NP_001316075.1) 1 mlylennaqtqfseystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvte 61 vvkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgtef 121 ttvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsi 181 rkqqvsdstkngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkike 241 slelmqylpqhtietyrqqqqqqhqhllqkqtsiqspssygnsspplnkmnsmnklpsvs 301 qlinpqqrnaltpttipdgmganipmmgthmpmagdmnglsptqalppplsmpstshctp 361 pppyptdcsivsflarlgcsscldyfttqglttiyqiehysmddlaslkipeqfrhaiwk 421 gildhrqlhefsspshllrtpssastvsvgssetrgervidavrftlrqtisfpprdewn 481 dfnfdmdarrnkqqrikeege SEQIDNO:35Humanp63transcriptvariant10mRNASequence NM_001329148.2;CDS:128-2158) 1 ctatgtctgatagcatttgaccctattgcttttagcctcccggctttatatctatatata 61 cacaggtatatgtgtatattttatataattgttctccgttcgttgatatcaaagacagtt 121 gaaggaaatgaattttgaaacttcacggtgtgccaccctacagtactgccctgaccctta 181 catccagcgtttcgtagaaaccccagctcatttctcttggaaagaaagttattaccgatc 241 caccatgtcccagagcacacagacaaatgaattcctcagtccagaggttttccagcatat 301 ctgggattttctggaacagcctatatgttcagttcagcccattgacttgaactttgtgga 361 tgaaccatcagaagatggtgcgacaaacaagattgagattagcatggactgtatccgcat 421 gcaggactcggacctgagtgaccccatgtggccacagtacacgaacctggggctcctgaa 481 cagcatggaccagcagattcagaacggctcctcgtccaccagtccctataacacagacca 541 cgcgcagaacagcgtcacggcgccctcgccctacgcacagcccagctccaccttcgatgc 601 tctctctccatcacccgccatcccctccaacaccgactacccaggcccgcacagtttcga 661 cgtgtccttccagcagtcgagcaccgccaagtcggccacctggacgtattccactgaact 721 gaagaaactctactgccaaattgcaaagacatgccccatccagatcaaggtgatgacccc 781 acctcctcagggagctgttatccgcgccatgcctgtctacaaaaaagctgagcacgtcac 841 ggaggtggtgaagcggtgccccaaccatgagctgagccgtgaattcaacgagggacagat 901 tgcccctcctagtcatttgattcgagtagaggggaacagccatgcccagtatgtagaaga 961 tcccatcacaggaagacagagtgtgctggtaccttatgagccaccccaggttggcactga 1021 attcacgacagtcttgtacaatttcatgtgtaacagcagttgtgttggagggatgaaccg 1081 ccgtccaattttaatcattgttactctggaaaccagagatgggcaagtcctgggccgacg 1141 ctgctttgaggcccggatctgtgcttgcccaggaagagacaggaaggcggatgaagatag 1201 catcagaaagcagcaagtttcggacagtacaaagaacggtgatgcgtttcgtcagaacac 1261 acatggtatccagatgacatccatcaagaaacgaagatccccagatgatgaactgttata 1321 cttaccagtgaggggccgtgagacttatgaaatgctgttgaagatcaaagagtccctgga 1381 actcatgcagtaccttcctcagcacacaattgaaacgtacaggcaacagcaacagcagca 1441 gcaccagcacttacttcagaaacagacctcaatacagtctccatcttcatatggtaacag 1501 ctccccacctctgaacaaaatgaacagcatgaacaagctgccttctgtgagccagcttat 1561 caaccctcagcagcgcaacgccctcactcctacaaccattcctgatggcatgggagccaa 1621 cattcccatgatgggcacccacatgccaatggctggagacatgaatggactcagccccac 1681 ccaggcactccctcccccactctccatgccatccacctcccactgcacacccccacctcc 1741 gtatcccacagattgcagcattgtcagtttcttagcgaggttgggctgttcatcatgtct 1801 ggactatttcacgacccaggggctgaccaccatctatcagattgagcattactccatgga 1861 tgatctggcaagtctgaaaatccctgagcaatttcgacatgcgatctggaagggcatcct 1921 ggaccaccggcagctccacgaattctcctccccttctcatctcctgcggaccccaagcag 1981 tgcctctacagtcagtgtgggctccagtgagacccggggtgagcgtgttattgatgctgt 2041 gcgattcaccctccgccagaccatctctttcccaccccgagatgagtggaatgacttcaa 2101 ctttgacatggatgctcgccgcaataagcaacagcgcatcaaagaggagggggagtgagc 2161 ctcaccatgtgagctcttcctatccctctcctaactgccagccccctaaaagcactcctg 2221 cttaatcttcaaagccttctccctagctcctccccttcctcttgtctgatttcttagggg 2281 aaggagaagtaagaggctacctcttacctaacatctgacctggcatctaattctgattct 2341 ggctttaagccttcaaaactatagcttgcagaactgtagctgccatggctaggtagaagt 2401 gagcaaaaaagagttgggtgtctccttaagctgcagagatttctcattgacttttataaa 2461 gcatgttcacccttatagtctaagactatatatataaatgtataaatatacagtatagat 2521 ttttgggtggggggcattgagtattgtttaaaatgtaatttaaatgaaagaaaattgagt 2581 tgcacttattgaccattttttaatttacttgttttggatggcttgtctatactccttccc 2641 ttaaggggtatcatgtatggtgataggtatctagagcttaatgctacatgtgagtgacga 2701 tgatgtacagattctttcagttctttggattctaaatacatgccacatcaaacctttgag 2761 tagatccatttccattgcttattatgtaggtaagactgtagatatgtattcttttctcag 2821 tgttggtatattttatattactgacatttcttctagtgatgatggttcacgttggggtga 2881 tttaatccagttataagaagaagttcatgtccaaacgtcctctttagtttttggttggga 2941 atgaggaaaattcttaaaaggcccatagcagccagttcaaaaacacccgacgtcatgtat 3001 ttgagcatatcagtaacccccttaaatttaataccagataccttatcttacaatattgat 3061 tgggaaaacatttgctgccattacagaggtattaaaactaaatttcactactagattgac 3121 taactcaaatacacatttgctactgttgtaagaattctgattgatttgattgggatgaat 3181 gccatctatctagttctaacagtgaagttttactgtctattaatattcagggtaaatagg 3241 aatcattcagaaatgttgagtctgtactaaacagtaagatatctcaatgaaccataaatt 3301 caactttgtaaaaatcttttgaagcatagataatattgtttggtaaatgtttcttttgtt 3361 tggtaaatgtttcttttaaagaccctcctattctataaaactctgcatgtagaggcttgt 3421 ttacctttctctctctaaggtttacaataggagtggtgatttgaaaaatataaaattatg 3481 agattggttttcctgtggcataaattgcatcactgtatcattttcttttttaaccggtaa 3541 gagtttcagtttgttggaaagtaactgtgagaacccagtttcccgtccatctcccttagg 3601 gactacccatagacatgaaaggtccccacagagcaagagataagtctttcatggctgctg 3661 ttgcttaaaccacttaaacgaagagttcccttgaaactttgggaaaacatgttaatgaca 3721 atattccagatctttcagaaatataacacatttttttgcatgcatgcaaatgagctctga 3781 aatcttcccatgcattctggtcaagggctgtcattgcacataagcttccattttaatttt 3841 aaagtgcaaaagggccagcgtggctctaaaaggtaatgtgtggattgcctctgaaaagtg 3901 tgtatatattttgtgtgaaattgcatactttgtattttgattattttttttttcttcttg 3961 ggatagtgggatttccagaaccacacttgaaacctttttttatcgtttttgtattttcat 4021 gaaaataccatttagtaagaataccacatcaaataagaaataatgctacaattttaagag 4081 gggagggaagggaaagtttttttttattatttttttaaaattttgtatgttaaagagaat 4141 gagtccttgatttcaaagttttgttgtacttaaatggtaataagcactgtaaacttctgc 4201 aacaagcatgcagctttgcaaacccattaaggggaagaatgaaagctgttccttggtcct 4261 agtaagaagacaaactgcttcccttactttgctgagggtttgaataaacctaggacttcc 4321 gagctatgtcagtactattcaggtaacactagggccttggaaattcctgtactgtgtctc 4381 atggatttggcactagccaaagcgaggcacccttactggcttacctcctcatggcagcct 4441 actctccttgagtgtatgagtagccagggtaaggggtaaaaggatagtaagcatagaaac 4501 cactagaaagtgggcttaatggagttcttgtggcctcagctcaatgcagttagctgaaga 4561 attgaaaagtttttgtttggagacgtttataaacagaaatggaaagcagagttttcatta 4621 aatccttttaccttttttttttcttggtaatcccctaaaataacagtatgtgggatattg 4681 aatgttaaagggatatttttttctattatttttataattgtacaaaattaagcaaatgtt 4741 aaaagttttatatgctttattaatgttttcaaaaggtattatacatgtgatacatttttt 4801 aagcttcagttgcttgtcttctggtactttctgttatgggcttttggggagccagaagcc 4861 aatctacaatctctttttgtttgccaggacatgcaataaaatttaaaaaataaataaaaa 4921 ctaattaagaaa SEQIDNO:36Humanp63Isoform10AminoAcidSequence(NP_001316077.1) 1 mnfetsrcatlqycpdpyiqrfvetpahfswkesyyrstmsqstqtneflspevfqhiwd 61 fleqpicsvqpidlnfvdepsedgatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdstkngdafrqnthgiqmtsikkrrspddellylpvrgretyemllkikeslelm 421 qylpqhtietyrqqqqqqhqhllqkqtsiqspssygnsspplnkmnsmnklpsvsqlinp 481 qqrnaltpttipdgmganipmmgthmpmagdmnglsptqalppplsmpstshctppppyp 541 tdcsivsflarlgcsscldyfttqglttiyqiehysmddlaslkipeqfrhaiwkgildh 601 rqlhefsspshllrtpssastvsvgssetrgervidavrftlrqtisfpprdewndfnfd 661 mdarrnkqqrikeege SEQIDNO:37Humanp63transcriptvariant11 (NM_001329149.2;CDS:143-1381)mRNASequence 1 cagagagagaaagagagagagggacttgagttctgttatcttcttaagtagattcatatt 61 gtaagggtctcggggtgggggggttggcaaaatcctggagccagaagaaaggacagcagc 121 attgatcaatcttacagctaacatgttgtacctggaaaacaatgcccagactcaatttag 181 tgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaacgg 241 ctcctcgtccaccagtccctataacacagaccacgcgcagaacagcgtcacggcgccctc 301 gccctacgcacagcccagctccaccttcgatgctctctctccatcacccgccatcccctc 361 caacaccgactacccaggcccgcacagtttcgacgtgtccttccagcagtcgagcaccgc 421 caagtcggccacctggacgtattccactgaactgaagaaactctactgccaaattgcaaa 481 gacatgccccatccagatcaaggtgatgaccccacctcctcagggagctgttatccgcgc 541 catgcctgtctacaaaaaagctgagcacgtcacggaggtggtgaagcggtgccccaacca 601 tgagctgagccgtgaattcaacgagggacagattgcccctcctagtcatttgattcgagt 661 agaggggaacagccatgcccagtatgtagaagatcccatcacaggaagacagagtgtgct 721 ggtaccttatgagccaccccaggttggcactgaattcacgacagtcttgtacaatttcat 781 gtgtaacagcagttgtgttggagggatgaaccgccgtccaattttaatcattgttactct 841 ggaaaccagagatgggcaagtcctgggccgacgctgctttgaggcccggatctgtgcttg 901 cccaggaagagacaggaaggcggatgaagatagcatcagaaagcagcaagtttcggacag 961 tacaaagaacggtgatgcgtttcgtcagaacacacatggtatccagatgacatccatcaa 1021 gaaacgaagatccccagatgatgaactgttatacttaccagtgaggggccgtgagactta 1081 tgaaatgctgttgaagatcaaagagtccctggaactcatgcagtaccttcctcagcacac 1141 aattgaaacgtacaggcaacagcaacagcagcagcaccagcacttacttcagaaacagac 1201 ctcaatacagtctccatcttcatatggtaacagctccccacctctgaacaaaatgaacag 1261 catgaacaagctgccttctgtgagccagcttatcaaccctcagcagcgcaacgccctcac 1321 tcctacaaccattcctgatggcatgggagccaacagatctggcaagtctgaaaatccctg 1381 agcaatttcgacatgcgatctggaagggcatcctggaccaccggcagctccacgaattct 1441 cctccccttctcatctcctgcggaccccaagcagtgcctctacagtcagtgtgggctcca 1501 gtgagacccggggtgagcgtgttattgatgctgtgcgattcaccctccgccagaccatct 1561 ctttcccaccccgagatgagtggaatgacttcaactttgacatggatgctcgccgcaata 1621 agcaacagcgcatcaaagaggagggggagtgagcctcaccatgtgagctcttcctatccc 1681 tctcctaactgccagccccctaaaagcactcctgcttaatcttcaaagccttctccctag 1741 ctcctccccttcctcttgtctgatttcttaggggaaggagaagtaagaggctacctctta 1801 cctaacatctgacctggcatctaattctgattctggctttaagccttcaaaactatagct 1861 tgcagaactgtagctgccatggctaggtagaagtgagcaaaaaagagttgggtgtctcct 1921 taagctgcagagatttctcattgacttttataaagcatgttcacccttatagtctaagac 1981 tatatatataaatgtataaatatacagtatagatttttgggtggggggcattgagtattg 2041 tttaaaatgtaatttaaatgaaagaaaattgagttgcacttattgaccattttttaattt 2101 acttgttttggatggcttgtctatactccttcccttaaggggtatcatgtatggtgatag 2161 gtatctagagcttaatgctacatgtgagtgacgatgatgtacagattctttcagttcttt 2221 ggattctaaatacatgccacatcaaacctttgagtagatccatttccattgcttattatg 2281 taggtaagactgtagatatgtattcttttctcagtgttggtatattttatattactgaca 2341 tttcttctagtgatgatggttcacgttggggtgatttaatccagttataagaagaagttc 2401 atgtccaaacgtcctctttagtttttggttgggaatgaggaaaattcttaaaaggcccat 2461 agcagccagttcaaaaacacccgacgtcatgtatttgagcatatcagtaacccccttaaa 2521 tttaataccagataccttatcttacaatattgattgggaaaacatttgctgccattacag 2581 aggtattaaaactaaatttcactactagattgactaactcaaatacacatttgctactgt 2641 tgtaagaattctgattgatttgattgggatgaatgccatctatctagttctaacagtgaa 2701 gttttactgtctattaatattcagggtaaataggaatcattcagaaatgttgagtctgta 2761 ctaaacagtaagatatctcaatgaaccataaattcaactttgtaaaaatcttttgaagca 2821 tagataatattgtttggtaaatgtttcttttgtttggtaaatgtttcttttaaagaccct 2881 cctattctataaaactctgcatgtagaggcttgtttacctttctctctctaaggtttaca 2941 ataggagtggtgatttgaaaaatataaaattatgagattggttttcctgtggcataaatt 3001 gcatcactgtatcattttcttttttaaccggtaagagtttcagtttgttggaaagtaact 3061 gtgagaacccagtttcccgtccatctcccttagggactacccatagacatgaaaggtccc 3121 cacagagcaagagataagtctttcatggctgctgttgcttaaaccacttaaacgaagagt 3181 tcccttgaaactttgggaaaacatgttaatgacaatattccagatctttcagaaatataa 3241 cacatttttttgcatgcatgcaaatgagctctgaaatcttcccatgcattctggtcaagg 3301 gctgtcattgcacataagcttccattttaattttaaagtgcaaaagggccagcgtggctc 3361 taaaaggtaatgtgtggattgcctctgaaaagtgtgtatatattttgtgtgaaattgcat 3421 actttgtattttgattattttttttttcttcttgggatagtgggatttccagaaccacac 3481 ttgaaacctttttttatcgtttttgtattttcatgaaaataccatttagtaagaatacca 3541 catcaaataagaaataatgctacaattttaagaggggagggaagggaaagttttttttta 3601 ttatttttttaaaattttgtatgttaaagagaatgagtccttgatttcaaagttttgttg 3661 tacttaaatggtaataagcactgtaaacttctgcaacaagcatgcagctttgcaaaccca 3721 ttaaggggaagaatgaaagctgttccttggtcctagtaagaagacaaactgcttccctta 3781 ctttgctgagggtttgaataaacctaggacttccgagctatgtcagtactattcaggtaa 3841 cactagggccttggaaattcctgtactgtgtctcatggatttggcactagccaaagcgag 3901 gcacccttactggcttacctcctcatggcagcctactctccttgagtgtatgagtagcca 3961 gggtaaggggtaaaaggatagtaagcatagaaaccactagaaagtgggcttaatggagtt 4021 cttgtggcctcagctcaatgcagttagctgaagaattgaaaagtttttgtttggagacgt 4081 ttataaacagaaatggaaagcagagttttcattaaatccttttaccttttttttttcttg 4141 gtaatcccctaaaataacagtatgtgggatattgaatgttaaagggatatttttttctat 4201 tatttttataattgtacaaaattaagcaaatgttaaaagttttatatgctttattaatgt 4261 tttcaaaaggtattatacatgtgatacattttttaagcttcagttgcttgtcttctggta 4321 ctttctgttatgggcttttggggagccagaagccaatctacaatctctttttgtttgcca 4381 ggacatgcaataaaatttaaaaaataaataaaaactaattaagaaa SEQIDNO:38Humanp63Isoform11AminoAcidSequence(NP_001316078.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdstkngdafrqnthgiqmtsikkrrspdd 301 ellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsiqspss 361 ygnsspplnkmnsmnklpsvsqlinpqqrnaltpttipdgmganrsgksenp SEQIDNO:39Humanp63transcriptvariant12mRNASequence (NM_001329150.2;CDS:143-1126) 1 cagagagagaaagagagagagggacttgagttctgttatcttcttaagtagattcatatt 61 gtaagggtctcggggtgggggggttggcaaaatcctggagccagaagaaaggacagcagc 121 attgatcaatcttacagctaacatgttgtacctggaaaacaatgcccagactcaatttag 181 tgagtattccactgaactgaagaaactctactgccaaattgcaaagacatgccccatcca 241 gatcaaggtgatgaccccacctcctcagggagctgttatccgcgccatgcctgtctacaa 301 aaaagctgagcacgtcacggaggtggtgaagcggtgccccaaccatgagctgagccgtga 361 attcaacgagggacagattgcccctcctagtcatttgattcgagtagaggggaacagcca 421 tgcccagtatgtagaagatcccatcacaggaagacagagtgtgctggtaccttatgagcc 481 accccaggttggcactgaattcacgacagtcttgtacaatttcatgtgtaacagcagttg 541 tgttggagggatgaaccgccgtccaattttaatcattgttactctggaaaccagagatgg 601 gcaagtcctgggccgacgctgctttgaggcccggatctgtgcttgcccaggaagagacag 661 gaaggcggatgaagatagcatcagaaagcagcaagtttcggacagtacaaagaacggtga 721 tgcgtttcgtcagaacacacatggtatccagatgacatccatcaagaaacgaagatcccc 781 agatgatgaactgttatacttaccagtgaggggccgtgagacttatgaaatgctgttgaa 841 gatcaaagagtccctggaactcatgcagtaccttcctcagcacacaattgaaacgtacag 901 gcaacagcaacagcagcagcaccagcacttacttcagaaacagacctcaatacagtctcc 961 atcttcatatggtaacagctccccacctctgaacaaaatgaacagcatgaacaagctgcc 1021 ttctgtgagccagcttatcaaccctcagcagcgcaacgccctcactcctacaaccattcc 1081 tgatggcatgggagccaacagatctggcaagtctgaaaatccctgagcaatttcgacatg 1141 cgatctggaagggcatcctggaccaccggcagctccacgaattctcctccccttctcatc 1201 tcctgcggaccccaagcagtgcctctacagtcagtgtgggctccagtgagacccggggtg 1261 agcgtgttattgatgctgtgcgattcaccctccgccagaccatctctttcccaccccgag 1321 atgagtggaatgacttcaactttgacatggatgctcgccgcaataagcaacagcgcatca 1381 aagaggagggggagtgagcctcaccatgtgagctcttcctatccctctcctaactgccag 1441 ccccctaaaagcactcctgcttaatcttcaaagccttctccctagctcctccccttcctc 1501 ttgtctgatttcttaggggaaggagaagtaagaggctacctcttacctaacatctgacct 1561 ggcatctaattctgattctggctttaagccttcaaaactatagcttgcagaactgtagct 1621 gccatggctaggtagaagtgagcaaaaaagagttgggtgtctccttaagctgcagagatt 1681 tctcattgacttttataaagcatgttcacccttatagtctaagactatatatataaatgt 1741 ataaatatacagtatagatttttgggtggggggcattgagtattgtttaaaatgtaattt 1801 aaatgaaagaaaattgagttgcacttattgaccattttttaatttacttgttttggatgg 1861 cttgtctatactccttcccttaaggggtatcatgtatggtgataggtatctagagcttaa 1921 tgctacatgtgagtgacgatgatgtacagattctttcagttctttggattctaaatacat 1981 gccacatcaaacctttgagtagatccatttccattgcttattatgtaggtaagactgtag 2041 atatgtattcttttctcagtgttggtatattttatattactgacatttcttctagtgatg 2101 atggttcacgttggggtgatttaatccagttataagaagaagttcatgtccaaacgtcct 2161 ctttagtttttggttgggaatgaggaaaattcttaaaaggcccatagcagccagttcaaa 2221 aacacccgacgtcatgtatttgagcatatcagtaacccccttaaatttaataccagatac 2281 cttatcttacaatattgattgggaaaacatttgctgccattacagaggtattaaaactaa 2341 atttcactactagattgactaactcaaatacacatttgctactgttgtaagaattctgat 2401 tgatttgattgggatgaatgccatctatctagttctaacagtgaagttttactgtctatt 2461 aatattcagggtaaataggaatcattcagaaatgttgagtctgtactaaacagtaagata 2521 tctcaatgaaccataaattcaactttgtaaaaatcttttgaagcatagataatattgttt 2581 ggtaaatgtttcttttgtttggtaaatgtttcttttaaagaccctcctattctataaaac 2641 tctgcatgtagaggcttgtttacctttctctctctaaggtttacaataggagtggtgatt 2701 tgaaaaatataaaattatgagattggttttcctgtggcataaattgcatcactgtatcat 2761 tttcttttttaaccggtaagagtttcagtttgttggaaagtaactgtgagaacccagttt 2821 cccgtccatctcccttagggactacccatagacatgaaaggtccccacagagcaagagat 2881 aagtctttcatggctgctgttgcttaaaccacttaaacgaagagttcccttgaaactttg 2941 ggaaaacatgttaatgacaatattccagatctttcagaaatataacacatttttttgcat 3001 gcatgcaaatgagctctgaaatcttcccatgcattctggtcaagggctgtcattgcacat 3061 aagcttccattttaattttaaagtgcaaaagggccagcgtggctctaaaaggtaatgtgt 3121 ggattgcctctgaaaagtgtgtatatattttgtgtgaaattgcatactttgtattttgat 3181 tattttttttttcttcttgggatagtgggatttccagaaccacacttgaaaccttttttt 3241 atcgtttttgtattttcatgaaaataccatttagtaagaataccacatcaaataagaaat 3301 aatgctacaattttaagaggggagggaagggaaagtttttttttattatttttttaaaat 3361 tttgtatgttaaagagaatgagtccttgatttcaaagttttgttgtacttaaatggtaat 3421 aagcactgtaaacttctgcaacaagcatgcagctttgcaaacccattaaggggaagaatg 3481 aaagctgttccttggtcctagtaagaagacaaactgcttcccttactttgctgagggttt 3541 gaataaacctaggacttccgagctatgtcagtactattcaggtaacactagggccttgga 3601 aattcctgtactgtgtctcatggatttggcactagccaaagcgaggcacccttactggct 3661 tacctcctcatggcagcctactctccttgagtgtatgagtagccagggtaaggggtaaaa 3721 ggatagtaagcatagaaaccactagaaagtgggcttaatggagttcttgtggcctcagct 3781 caatgcagttagctgaagaattgaaaagtttttgtttggagacgtttataaacagaaatg 3841 gaaagcagagttttcattaaatccttttaccttttttttttcttggtaatcccctaaaat 3901 aacagtatgtgggatattgaatgttaaagggatatttttttctattatttttataattgt 3961 acaaaattaagcaaatgttaaaagttttatatgctttattaatgttttcaaaaggtatta 4021 tacatgtgatacattttttaagcttcagttgcttgtcttctggtactttctgttatgggc 4081 ttttggggagccagaagccaatctacaatctctttttgtttgccaggacatgcaataaaa 4141 tttaaaaaataaataaaaactaattaagaaa SEQIDNO:40Humanp63Isoform12AminoAcidSequence(NP_001316079.1) 1 mlylennaqtqfseystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvte 61 vvkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgtef 121 ttvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsi 181 rkqqvsdstkngdafrqnthgiqmtsikkrrspddellylpvrgretyemllkikeslel 241 mqylpqhtietyrqqqqqqhqhllqkqtsiqspssygnsspplnkmnsmnklpsvsqlin 301 pqqrnaltpttipdgmganrsgksenp SEQIDNO:41Humanp63transcriptvariant13mRNASequence (NM_001329964.1;CDS:438-2474) 1 ggcaacccgctggggtcaccttccacactgtggaagctttgttcttttgctctttgcagt 61 aaatcttgctactgctcactctttgggtgcacactgcttttatgagctgtaacactcacc 121 gtgaaggtctgcagcttcactcctgaagccagcgagaccaggagtccactgggaggaacg 181 aacaactccagacgcaccgccttaagaacttcaacactcactgcgaaggtctgcagcttc 241 actcctgagccagcgagaccacgaacccaccgtaaggaagaaactccgaacacatccgaa 301 catcagaaggaacaaactccagacgcgccaccttaagagctgtaacactcaccgccaggg 361 tccgcggcttcattcttgaagtcagagagaccaagaacccaccaattccggacaccctat 421 cagagattttgaaaactatgaagtgctgggaacagagagactggacagccttcacaaagg 481 tggggaaaccttgtttcgtagaaaccccagctcatttctcttggaaagaaagttattacc 541 gatccaccatgtcccagagcacacagacaaatgaattcctcagtccagaggttttccagc 601 atatctgggattttctggaacagcctatatgttcagttcagcccattgacttgaactttg 661 tggatgaaccatcagaagatggtgcgacaaacaagattgagattagcatggactgtatcc 721 gcatgcaggactcggacctgagtgaccccatgtggccacagtacacgaacctggggctcc 781 tgaacagcatggaccagcagattcagaacggctcctcgtccaccagtccctataacacag 841 accacgcgcagaacagcgtcacggcgccctcgccctacgcacagcccagctccaccttcg 901 atgctctctctccatcacccgccatcccctccaacaccgactacccaggcccgcacagtt 961 tcgacgtgtccttccagcagtcgagcaccgccaagtcggccacctggacgtattccactg 1021 aactgaagaaactctactgccaaattgcaaagacatgccccatccagatcaaggtgatga 1081 ccccacctcctcagggagctgttatccgcgccatgcctgtctacaaaaaagctgagcacg 1141 tcacggaggtggtgaagcggtgccccaaccatgagctgagccgtgaattcaacgagggac 1201 agattgcccctcctagtcatttgattcgagtagaggggaacagccatgcccagtatgtag 1261 aagatcccatcacaggaagacagagtgtgctggtaccttatgagccaccccaggttggca 1321 ctgaattcacgacagtcttgtacaatttcatgtgtaacagcagttgtgttggagggatga 1381 accgccgtccaattttaatcattgttactctggaaaccagagatgggcaagtcctgggcc 1441 gacgctgctttgaggcccggatctgtgcttgcccaggaagagacaggaaggcggatgaag 1501 atagcatcagaaagcagcaagtttcggacagtacaaagaacggtgatggtacgaagcgcc 1561 cgtttcgtcagaacacacatggtatccagatgacatccatcaagaaacgaagatccccag 1621 atgatgaactgttatacttaccagtgaggggccgtgagacttatgaaatgctgttgaaga 1681 tcaaagagtccctggaactcatgcagtaccttcctcagcacacaattgaaacgtacaggc 1741 aacagcaacagcagcagcaccagcacttacttcagaaacagacctcaatacagtctccat 1801 cttcatatggtaacagctccccacctctgaacaaaatgaacagcatgaacaagctgcctt 1861 ctgtgagccagcttatcaaccctcagcagcgcaacgccctcactcctacaaccattcctg 1921 atggcatgggagccaacattcccatgatgggcacccacatgccaatggctggagacatga 1981 atggactcagccccacccaggcactccctcccccactctccatgccatccacctcccact 2041 gcacacccccacctccgtatcccacagattgcagcattgtcagtttcttagcgaggttgg 2101 gctgttcatcatgtctggactatttcacgacccaggggctgaccaccatctatcagattg 2161 agcattactccatggatgatctggcaagtctgaaaatccctgagcaatttcgacatgcga 2221 tctggaagggcatcctggaccaccggcagctccacgaattctcctccccttctcatctcc 2281 tgcggaccccaagcagtgcctctacagtcagtgtgggctccagtgagacccggggtgagc 2341 gtgttattgatgctgtgcgattcaccctccgccagaccatctctttcccaccccgagatg 2401 agtggaatgacttcaactttgacatggatgctcgccgcaataagcaacagcgcatcaaag 2461 aggagggggagtgagcctcaccatgtgagctcttcctatccctctcctaactgccagccc 2521 cctaaaagcactcctgcttaatcttcaaagccttctccctagctcctccccttcctcttg 2581 tctgatttcttaggggaaggagaagtaagaggctacctcttacctaacatctgacctggc 2641 atctaattctgattctggctttaagccttcaaaactatagcttgcagaactgtagctgcc 2701 atggctaggtagaagtgagcaaaaaagagttgggtgtctccttaagctgcagagatttct 2761 cattgacttttataaagcatgttcacccttatagtctaagactatatatataaatgtata 2821 aatatacagtatagatttttgggtggggggcattgagtattgtttaaaatgtaatttaaa 2881 tgaaagaaaattgagttgcacttattgaccattttttaatttacttgttttggatggctt 2941 gtctatactccttcccttaaggggtatcatgtatggtgataggtatctagagcttaatgc 3001 tacatgtgagtgacgatgatgtacagattctttcagttctttggattctaaatacatgcc 3061 acatcaaacctttgagtagatccatttccattgcttattatgtaggtaagactgtagata 3121 tgtattcttttctcagtgttggtatattttatattactgacatttcttctagtgatgatg 3181 gttcacgttggggtgatttaatccagttataagaagaagttcatgtccaaacgtcctctt 3241 tagtttttggttgggaatgaggaaaattcttaaaaggcccatagcagccagttcaaaaac 3301 acccgacgtcatgtatttgagcatatcagtaacccccttaaatttaataccagatacctt 3361 atcttacaatattgattgggaaaacatttgctgccattacagaggtattaaaactaaatt 3421 tcactactagattgactaactcaaatacacatttgctactgttgtaagaattctgattga 3481 tttgattgggatgaatgccatctatctagttctaacagtgaagttttactgtctattaat 3541 attcagggtaaataggaatcattcagaaatgttgagtctgtactaaacagtaagatatct 3601 caatgaaccataaattcaactttgtaaaaatcttttgaagcatagataatattgtttggt 3661 aaatgtttcttttgtttggtaaatgtttcttttaaagaccctcctattctataaaactct 3721 gcatgtagaggcttgtttacctttctctctctaaggtttacaataggagtggtgatttga 3781 aaaatataaaattatgagattggttttcctgtggcataaattgcatcactgtatcatttt 3841 cttttttaaccggtaagagtttcagtttgttggaaagtaactgtgagaacccagtttccc 3901 gtccatctcccttagggactacccatagacatgaaaggtccccacagagcaagagataag 3961 tctttcatggctgctgttgcttaaaccacttaaacgaagagttcccttgaaactttggga 4021 aaacatgttaatgacaatattccagatctttcagaaatataacacatttttttgcatgca 4081 tgcaaatgagctctgaaatcttcccatgcattctggtcaagggctgtcattgcacataag 4141 cttccattttaattttaaagtgcaaaagggccagcgtggctctaaaaggtaatgtgtgga 4201 ttgcctctgaaaagtgtgtatatattttgtgtgaaattgcatactttgtattttgattat 4261 tttttttttcttcttgggatagtgggatttccagaaccacacttgaaacctttttttatc 4321 gtttttgtattttcatgaaaataccatttagtaagaataccacatcaaataagaaataat 4381 gctacaattttaagaggggagggaagggaaagtttttttttattatttttttaaaatttt 4441 gtatgttaaagagaatgagtccttgatttcaaagttttgttgtacttaaatggtaataag 4501 cactgtaaacttctgcaacaagcatgcagctttgcaaacccattaaggggaagaatgaaa 4561 gctgttccttggtcctagtaagaagacaaactgcttcccttactttgctgagggtttgaa 4621 taaacctaggacttccgagctatgtcagtactattcaggtaacactagggccttggaaat 4681 tcctgtactgtgtctcatggatttggcactagccaaagcgaggcacccttactggcttac 4741 ctcctcatggcagcctactctccttgagtgtatgagtagccagggtaaggggtaaaagga 4801 tagtaagcatagaaaccactagaaagtgggcttaatggagttcttgtggcctcagctcaa 4861 tgcagttagctgaagaattgaaaagtttttgtttggagacgtttataaacagaaatggaa 4921 agcagagttttcattaaatccttttaccttttttttttcttggtaatcccctaaaataac 4981 agtatgtgggatattgaatgttaaagggatatttttttctattatttttataattgtaca 5041 aaattaagcaaatgttaaaagttttatatgctttattaatgttttcaaaaggtattatac 5101 atgtgatacattttttaagcttcagttgcttgtcttctggtactttctgttatgggcttt 5161 tggggagccagaagccaatctacaatctctttttgtttgccaggacatgcaataaaattt 5221 aaaaaataaataaaaactaattaagaaattgaaaaaaaaaaaaaaaaaa SEQIDNO:42Humanp63Isoform13AminoAcidSequence(NP_001316893.1) 1 mkcweqrdwtaftkvgkpcfvetpahfswkesyyrstmsqstqtneflspevfqhiwdfl 61 eqpicsvqpidlnfvdepsedgatnkieismdcirmqdsdlsdpmwpqytnlgllnsmdq 121 qiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvsfq 181 qsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtevvk 241 rcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgtefttv 301 lynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsirkq 361 qvsdstkngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikesle 421 lmqylpqhtietyrqqqqqqhqhllqkqtsiqspssygnsspplnkmnsmnklpsvsqli 481 npqqrnaltpttipdgmganipmmgthmpmagdmnglsptqalppplsmpstshctpppp 541 yptdcsivsflarlgcsscldyfttqglttiyqiehysmddlaslkipeqfrhaiwkgil 601 dhrqlhefsspshllrtpssastvsvgssetrgervidavrftlrqtisfpprdewndfn 661 fdmdarrnkqqrikeege SEQIDNO:43Mousep63transcriptvariant1mRNASequence(NM_001127259.1; CDS:526-2568) 1 aaaacattgtagccacagcagaactgacaggagctctcaaatcaagtcagaatacagata 61 caaggagatgttattcagttggagcaagggggacatttattagctcagtgacaagtcctg 121 gcttctgtgattaaactctgatgccattcataccagcacccaatcccaagcaagatcaga 181 agttcagagatgcctacaaattgccaacaagtgtggccactctacgtcaagggctctaaa 241 actgtggcagagaggaagaacagctttacagggggtgcccagctggtaagaattgacggt 301 ttatgatgctctggttacttgaagactctcattggctgaaaggaagaaacgccccgcctc 361 tttgcaaatctgagtaaaggggggaagtgtctaaacttctatgtctgatggcatttgacc 421 ctattgctttcagcctcctggctacatacctagatattctcaggtgtatatgtatatttt 481 atagaattgcttcccatctgttggtatcaaagagagttgaaggaaatgaattttgaaact 541 tcacggtgtgccaccctacagtactgccccgacccttacatccagcgtttcatagaaacc 601 ccagctcatttctcgtggaaagaaagttattacagatctgccatgtcgcagagcacccag 661 acaagcgagttcctcagcccagaggtcttccagcatatctgggattttctggaacagcct 721 atatgctcagtacagcccatcgagttgaactttgtggatgaaccttccgaaaatggtgca 781 acaaacaagattgagattagcatggattgtatccgcatgcaagactcagacctcagtgac 841 cccatgtggccacagtacacgaacctggggctcctgaacagcatggaccagcagattcag 901 aacggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcg 961 ccctcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccatt 1021 ccctccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagc 1081 actgccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagatt 1141 gcgaagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatc 1201 cgtgccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccct 1261 aaccatgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgatt 1321 cgagtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagc 1381 gtgctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaat 1441 ttcatgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgtt 1501 actctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgt 1561 gcttgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcg 1621 gacagcgcaaagaacggcgatggtacgaagcgccctttccgtcagaatacacacggaatc 1681 cagatgacttccatcaagaaacggagatccccagatgatgagctgctgtacctaccagtg 1741 agaggtcgtgagacgtacgagatgttgctgaagatcaaagagtcactggagctcatgcag 1801 tacctccctcagcacacgatcgaaacgtacaggcagcagcagcagcagcagcaccagcac 1861 ctacttcagaaacagacctcgatgcagtctcagtcttcatatggcaacagttccccacct 1921 ctgaacaaaatgaacagcatgaacaagctgccttccgtgagccagcttatcaacccacag 1981 cagcgcaatgccctcactcccaccaccatgcctgagggcatgggagccaacattcctatg 2041 atgggcactcacatgccaatggctggagacatgaatggactcagccctacccaagctctc 2101 cctcctccactctccatgccctccacctcccactgcaccccaccaccgccctaccccaca 2161 gactgcagcattgtcagtttcttagcaaggttgggctgctcatcatgcctggactatttc 2221 acgacccaggggctgaccaccatctatcagattgagcattactccatggatgatttggca 2281 agtctgaagatccctgaacagttccgacatgccatctggaagggcatcctggaccacagg 2341 cagctgcacgacttctcctcacctcctcatctcctgaggaccccaagtggtgcctctacc 2401 gtcagtgtgggctccagtgagacccgtggtgaacgtgtgatcgatgccgtgcgctttacc 2461 ctccgccagaccatctcttttccaccccgtgacgagtggaatgatttcaactttgacatg 2521 gattctcgtcgcaacaagcagcagcgtatcaaagaggaaggagaatgagcgcccattgcg 2581 gggttcttcctgtcttcttccacctcccagcccctacagggcacgcctgcttgatcctca 2641 gagccttctcgttagctcttctccttctccttctcagtctggtttctaaagggacggaga 2701 attaggaggctgcctgttacctaaagtctgacctgtcacctgattctgattctggcttta 2761 agccttcaatactcttgcttgcaagatgcattgacattgctagatagaagttagcaaaga 2821 agcagtaggtctctttaagcagtggagatctctcattgacttttataaagcattttcagc 2881 cttatagtctaagactatatatataaatatataaatatccgatatatattttgggtgtgg 2941 ggggtattgagtattgtttaaatgtaatttaatggaaattgagttgcacttatcatcctt 3001 ctttggaatttgcttgtttcggatggctgagctgtactcctttctcaggggtatcatgta 3061 tggtgacagatatctagagttgaatggtctatgtgagtaacaatgacgtataggacctct 3121 cctcatcctttggatggttattgtttagcacatcaaacctgtggatgcatccagtgtgtt 3181 taccattgcttcctatgaggtaaaactgtatatatgtacacagttttctctgtcagtata 3241 ttttatgttactggtgtccattccagttaggctggttcactctgtggctattacaagcca 3301 cattttaggtttgctttgtcacacactataagacagggcattgtctcttgcttttgtttg 3361 agaatgaggaatgcagttgtgttgtggtttgttttgttttattttgttttgttttctgga 3421 aactcttaaatggttcaagtcagccattccaaatatctgatgaaatttagcccaatatag 3481 cagtagctctttgaaatttaaggcccaacaccctagtatttattagaaaaataaacattt 3541 gctgttgttagaatagtcttaaaaataaatttctctgctagattgactaagtaaaataga 3601 cattctctgctgttgtgagaatttgggccaattagaatgaatgaaattcgtctagttttc 3661 atggggagttgtaatgtctattagaaagattcaggaaaaataagaatgattcagaaatac 3721 tgaatttccatgaaaaggaaaacagaaagcgattcatcccaccaaactctgaattgaagt 3781 tccttttgaagggtggagtgatgcttgggaagtggaccttttaaagactttcctatctat 3841 gagacactgcatgcacaggcaagtttctctctccccaagggctaaaataagaataatggc 3901 ttggaaaatacaaacttcgtagtgtagttttcacatagcatgagctgaaccactgttatc 3961 ttcctcttgatcatcaaagcttcattgttttagaaagcagaggtgaagacccagttttcc 4021 gcctgacactttccaagctagtgtagaccaagacctgtctacaaacccacgacaaacctt 4081 ttcacctgtttaatccatatccagaaagacttgtttcataccttgggaaagcatgcaaca 4141 gtattccccttagatattttggaaacattttgagacaagtatattttttttcctgcctaa 4201 accaagtgttgtttgtatgctaatgagctctacaatcttcccacacattttgttaaatga 4261 ctttcattgcacatgagctcccattttttattttaaagtgcaaatgggctaataggcctt 4321 tgacgtgtaatgtatgagttttgccagaaaatcatatcttgtgtatatgcgtgtgtgtga 4381 aattgcttactatgctggttttgtttgttatggctttctctttgggatagttgggttttc 4441 cagaaccacagatgaaactttttttgttgctatttttatatttttgcagaaacaccgttt 4501 agtgagaattcaatgtcaaatatgacatgataccttaattgtaagaagaaggtgggaagg 4561 gaaagttggtttattaatttttttaaattttgtatgcaaaagcaaatgagtccttaattt 4621 caacattttgttgtgtttaaataatgataagcatcattaacttctgtaacaaactcacag 4681 ctttacaaattcaatgggtggagaagaaagctgtgtcttagccatgttaggaagacaaat 4741 ggcttcctgtgtgttgtaagtatttgggctgtttcagcagtgttggtgtggcacagggga 4801 ctctgtggcatttcagcactatttaggtggcactagggactctgaaattcctgtactgta 4861 tctgatgattttggcattagccataggtaggcacagtttgtctcctcacaccagtgttta 4921 gtgtgtgaatagccagagctgtggggaagaacacagagaacagacatctgctggatgcct 4981 ctcagtggagaatgggattccttcacttggtggtgaagcagataggatagaaagcaggat 5041 tctctttgttaatccagttagcttttgttttcttgatatcccccctgaatacgttgagta 5101 tgagagatatgtgggttttttttatttttataattgtacaaaattaagcaaatatcaaat 5161 gttttatatactttattaatgttttttttcaaaaggtactttcttatagacatgatactt 5221 ttttacagcttcagttgcttgtcttctggtatttttgtgttatgggctatggtgagccag 5281 aggcaaatctataagccatttttgtttgccaggacatgcaataaaatttaaaaataaatg 5341 aaaatacactgaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa SEQIDNO:44Mousep63IsoformAAminoAcidSequence(NP_001120731.1) 1 mnfetsrcatlqycpdpyiqrfietpahfswkesyyrsamsqstqtseflspevfqhiwd 61 fleqpicsvqpielnfvdepsengatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdsakngdgtkrpfrqnthgiqmtsikkrrspddel1ylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkqtsmqsqssygnsspplnkmnsmnklpsvsq 481 linpqqrnaltpttmpegmganipmmgthmpmagdmnglsptqalppplsmpstshctpp 541 ppyptdcsivsflarlgcsscldyfttqglttiyqiehysmddlaslkipeqfrhaiwkg 601 ildhrqlhdfsspphllrtpsgastvsvgssetrgervidavrftlrqtisfpprdewnd 661 fnfdmdsrrnkqqrikeege SEQIDNO:45Mousep63transcriptvariant2mRNASequence(NM_001127260.1; CDS:526-2193) 1 aaaacattgtagccacagcagaactgacaggagctctcaaatcaagtcagaatacagata 61 caaggagatgttattcagttggagcaagggggacatttattagctcagtgacaagtcctg 121 gcttctgtgattaaactctgatgccattcataccagcacccaatcccaagcaagatcaga 181 agttcagagatgcctacaaattgccaacaagtgtggccactctacgtcaagggctctaaa 241 actgtggcagagaggaagaacagctttacagggggtgcccagctggtaagaattgacggt 301 ttatgatgctctggttacttgaagactctcattggctgaaaggaagaaacgccccgcctc 361 tttgcaaatctgagtaaaggggggaagtgtctaaacttctatgtctgatggcatttgacc 421 ctattgctttcagcctcctggctacatacctagatattctcaggtgtatatgtatatttt 481 atagaattgcttcccatctgttggtatcaaagagagttgaaggaaatgaattttgaaact 541 tcacggtgtgccaccctacagtactgccccgacccttacatccagcgtttcatagaaacc 601 ccagctcatttctcgtggaaagaaagttattacagatctgccatgtcgcagagcacccag 661 acaagcgagttcctcagcccagaggtcttccagcatatctgggattttctggaacagcct 721 atatgctcagtacagcccatcgagttgaactttgtggatgaaccttccgaaaatggtgca 781 acaaacaagattgagattagcatggattgtatccgcatgcaagactcagacctcagtgac 841 cccatgtggccacagtacacgaacctggggctcctgaacagcatggaccagcagattcag 901 aacggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcg 961 ccctcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccatt 1021 ccctccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagc 1081 actgccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagatt 1141 gcgaagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatc 1201 cgtgccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccct 1261 aaccatgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgatt 1321 cgagtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagc 1381 gtgctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaat 1441 ttcatgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgtt 1501 actctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgt 1561 gcttgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcg 1621 gacagcgcaaagaacggcgatggtacgaagcgccctttccgtcagaatacacacggaatc 1681 cagatgacttccatcaagaaacggagatccccagatgatgagctgctgtacctaccagtg 1741 agaggtcgtgagacgtacgagatgttgctgaagatcaaagagtcactggagctcatgcag 1801 tacctccctcagcacacgatcgaaacgtacaggcagcagcagcagcagcagcaccagcac 1861 ctacttcagaaacagacctcgatgcagtctcagtcttcatatggcaacagttccccacct 1921 ctgaacaaaatgaacagcatgaacaagctgccttccgtgagccagcttatcaacccacag 1981 cagcgcaatgccctcactcccaccaccatgcctgagggcatgggagccaacattcctatg 2041 atgggcactcacatgccaatggctggagacatgaatggactcagccctacccaagctctc 2101 cctcctccactctccatgccctccacctcccactgcaccccaccaccgccctaccccaca 2161 gactgcagcattgtcaggatttggcaagtctgaagatccctgaacagttccgacatgcca 2221 tctggaagggcatcctggaccacaggcagctgcacgacttctcctcacctcctcatctcc 2281 tgaggaccccaagtggtgcctctaccgtcagtgtgggctccagtgagacccgtggtgaac 2341 gtgtgatcgatgccgtgcgctttaccctccgccagaccatctcttttccaccccgtgacg 2401 agtggaatgatttcaactttgacatggattctcgtcgcaacaagcagcagcgtatcaaag 2461 aggaaggagaatgagcgcccattgcggggttcttcctgtcttcttccacctcccagcccc 2521 tacagggcacgcctgcttgatcctcagagccttctcgttagctcttctccttctccttct 2581 cagtctggtttctaaagggacggagaattaggaggctgcctgttacctaaagtctgacct 2641 gtcacctgattctgattctggctttaagccttcaatactcttgcttgcaagatgcattga 2701 cattgctagatagaagttagcaaagaagcagtaggtctctttaagcagtggagatctctc 2761 attgacttttataaagcattttcagccttatagtctaagactatatatataaatatataa 2821 atatccgatatatattttgggtgtggggggtattgagtattgtttaaatgtaatttaatg 2881 gaaattgagttgcacttatcatccttctttggaatttgcttgtttcggatggctgagctg 2941 tactcctttctcaggggtatcatgtatggtgacagatatctagagttgaatggtctatgt 3001 gagtaacaatgacgtataggacctctcctcatcctttggatggttattgtttagcacatc 3061 aaacctgtggatgcatccagtgtgtttaccattgcttcctatgaggtaaaactgtatata 3121 tgtacacagttttctctgtcagtatattttatgttactggtgtccattccagttaggctg 3181 gttcactctgtggctattacaagccacattttaggtttgctttgtcacacactataagac 3241 agggcattgtctcttgcttttgtttgagaatgaggaatgcagttgtgttgtggtttgttt 3301 tgttttattttgttttgttttctggaaactcttaaatggttcaagtcagccattccaaat 3361 atctgatgaaatttagcccaatatagcagtagctctttgaaatttaaggcccaacaccct 3421 agtatttattagaaaaataaacatttgctgttgttagaatagtcttaaaaataaatttct 3481 ctgctagattgactaagtaaaatagacattctctgctgttgtgagaatttgggccaatta 3541 gaatgaatgaaattcgtctagttttcatggggagttgtaatgtctattagaaagattcag 3601 gaaaaataagaatgattcagaaatactgaatttccatgaaaaggaaaacagaaagcgatt 3661 catcccaccaaactctgaattgaagttccttttgaagggtggagtgatgcttgggaagtg 3721 gaccttttaaagactttcctatctatgagacactgcatgcacaggcaagtttctctctcc 3781 ccaagggctaaaataagaataatggcttggaaaatacaaacttcgtagtgtagttttcac 3841 atagcatgagctgaaccactgttatcttcctcttgatcatcaaagcttcattgttttaga 3901 aagcagaggtgaagacccagttttccgcctgacactttccaagctagtgtagaccaagac 3961 ctgtctacaaacccacgacaaaccttttcacctgtttaatccatatccagaaagacttgt 4021 ttcataccttgggaaagcatgcaacagtattccccttagatattttggaaacattttgag 4081 acaagtatattttttttcctgcctaaaccaagtgttgtttgtatgctaatgagctctaca 4141 atcttcccacacattttgttaaatgactttcattgcacatgagctcccattttttatttt 4201 aaagtgcaaatgggctaataggcctttgacgtgtaatgtatgagttttgccagaaaatca 4261 tatcttgtgtatatgcgtgtgtgtgaaattgcttactatgctggttttgtttgttatggc 4321 tttctctttgggatagttgggttttccagaaccacagatgaaactttttttgttgctatt 4381 tttatatttttgcagaaacaccgtttagtgagaattcaatgtcaaatatgacatgatacc 4441 ttaattgtaagaagaaggtgggaagggaaagttggtttattaatttttttaaattttgta 4501 tgcaaaagcaaatgagtccttaatttcaacattttgttgtgtttaaataatgataagcat 4561 cattaacttctgtaacaaactcacagctttacaaattcaatgggtggagaagaaagctgt 4621 gtcttagccatgttaggaagacaaatggcttcctgtgtgttgtaagtatttgggctgttt 4681 cagcagtgttggtgtggcacaggggactctgtggcatttcagcactatttaggtggcact 4741 agggactctgaaattcctgtactgtatctgatgattttggcattagccataggtaggcac 4801 agtttgtctcctcacaccagtgtttagtgtgtgaatagccagagctgtggggaagaacac 4861 agagaacagacatctgctggatgcctctcagtggagaatgggattccttcacttggtggt 4921 gaagcagataggatagaaagcaggattctctttgttaatccagttagcttttgttttctt 4981 gatatcccccctgaatacgttgagtatgagagatatgtgggttttttttatttttataat 5041 tgtacaaaattaagcaaatatcaaatgttttatatactttattaatgttttttttcaaaa 5101 ggtactttcttatagacatgatacttttttacagcttcagttgcttgtcttctggtattt 5161 ttgtgttatgggctatggtgagccagaggcaaatctataagccatttttgtttgccagga 5221 catgcaataaaatttaaaaataaatgaaaatacactgaaaaaaaaaaaaaaaaaaaaaaa 5281 aaaaaaaa SEQIDNO:46Mousep63IsoformBAminoAcidSequence(NP_001120732.1) 1 mnfetsrcatlqycpdpyiqrfietpahfswkesyyrsamsqstqtseflspevfqhiwd 61 fleqpicsvqpielnfvdepsengatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdsakngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkqtsmqsqssygnsspplnkmnsmnklpsvsq 481 linpqqrnaltpttmpegmganipmmgthmpmagdmnglsptqalppplsmpstshctpp 541 ppyptdcsivriwqv SEQIDNO:47Mousep63transcriptvariant3mRNASequence(NM_001127261.1; CDS:526-1977) 1 aaaacattgtagccacagcagaactgacaggagctctcaaatcaagtcagaatacagata 61 caaggagatgttattcagttggagcaagggggacatttattagctcagtgacaagtcctg 121 gcttctgtgattaaactctgatgccattcataccagcacccaatcccaagcaagatcaga 181 agttcagagatgcctacaaattgccaacaagtgtggccactctacgtcaagggctctaaa 241 actgtggcagagaggaagaacagctttacagggggtgcccagctggtaagaattgacggt 301 ttatgatgctctggttacttgaagactctcattggctgaaaggaagaaacgccccgcctc 361 tttgcaaatctgagtaaaggggggaagtgtctaaacttctatgtctgatggcatttgacc 421 ctattgctttcagcctcctggctacatacctagatattctcaggtgtatatgtatatttt 481 atagaattgcttcccatctgttggtatcaaagagagttgaaggaaatgaattttgaaact 541 tcacggtgtgccaccctacagtactgccccgacccttacatccagcgtttcatagaaacc 601 ccagctcatttctcgtggaaagaaagttattacagatctgccatgtcgcagagcacccag 661 acaagcgagttcctcagcccagaggtcttccagcatatctgggattttctggaacagcct 721 atatgctcagtacagcccatcgagttgaactttgtggatgaaccttccgaaaatggtgca 781 acaaacaagattgagattagcatggattgtatccgcatgcaagactcagacctcagtgac 841 cccatgtggccacagtacacgaacctggggctcctgaacagcatggaccagcagattcag 901 aacggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcg 961 ccctcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccatt 1021 ccctccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagc 1081 actgccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagatt 1141 gcgaagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatc 1201 cgtgccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccct 1261 aaccatgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgatt 1321 cgagtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagc 1381 gtgctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaat 1441 ttcatgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgtt 1501 actctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgt 1561 gcttgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcg 1621 gacagcgcaaagaacggcgatgctttccgtcagaatacacacggaatccagatgacttcc 1681 atcaagaaacggagatccccagatgatgagctgctgtacctaccagtgagaggtcgtgag 1741 acgtacgagatgttgctgaagatcaaagagtcactggagctcatgcagtacctccctcag 1801 cacacgatcgaaacgtacaggcagcagcagcagcagcagcaccagcacctacttcagaaa 1861 catctcctttcagcctgcttcaggaatgagcttgtggagccccggggagaagctccgaca 1921 cagtctgacgtcttctttagacattccaaccccccaaaccactccgtgtacccataggtc 1981 cccagctatgtgtttgagttcatgtgcttgttgtgtttctgtgtgcgtttgtgtatatgc 2041 acatgcgtgttagtgtttccagccctcacaaacaggacttgaagacattttggctcagag 2101 acccagctgctcaaaggcacacatccactagtgagagaatctttgaagggactcaaaatt 2161 ttacaaagcagagatgctttctgcacattttgtatctttagatcctgccttggttggacg 2221 ggagccgcgactgtgcttgtctgtgagctttctattgttttcccaggagggagggggaat 2281 ccattgggaaagaggcattgcaaagtttattggaaaccttttctgttacctcctgttgtg 2341 tttctaaaactcataataaagcttttgagcaggtctcaaa SEQIDNO:48Mousep63IsoformCAminoAcidSequence(NP_001120733.1) 1 mnfetsrcatlqycpdpyiqrfietpahfswkesyyrsamsqstqtseflspevfqhiwd 61 fleqpicsvqpielnfvdepsengatnkieismdcirmqdsdlsdpmwpqytnlgllnsm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdsakngdafrqnthgiqmtsikkrrspddellylpvrgretyemllkikeslelm 421 qylpqhtietyrqqqqqqhqhllqkhllsacfrnelveprgeaptqsdvffrhsnppnhs 481 vyp SEQIDNO:49Mousep63transcriptvariant6mRNASequence(NM_001127262.1; CDS:145-1530) 1 agagagagagagagagagaggcacctgaattctgttatcttcttagaagattcgcagcgc 61 aaggctctcagagggggtgggggggctggcaaaaccctggaagcagaaaagaggagagca 121 gccttgaccagtctcactgctaacatgttgtacctggaaaacaatgcccagactcaattt 181 agtgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaac 241 ggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcgccc 301 tcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccattccc 361 tccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagcact 421 gccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagattgcg 481 aagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatccgt 541 gccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccctaac 601 catgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgattcga 661 gtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagcgtg 721 ctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaatttc 781 atgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgttact 841 ctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgtgct 901 tgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcggac 961 agcgcaaagaacggcgatggtacgaagcgccctttccgtcagaatacacacggaatccag 1021 atgacttccatcaagaaacggagatccccagatgatgagctgctgtacctaccagtgaga 1081 ggtcgtgagacgtacgagatgttgctgaagatcaaagagtcactggagctcatgcagtac 1141 ctccctcagcacacgatcgaaacgtacaggcagcagcagcagcagcagcaccagcaccta 1201 cttcagaaacagacctcgatgcagtctcagtcttcatatggcaacagttccccacctctg 1261 aacaaaatgaacagcatgaacaagctgccttccgtgagccagcttatcaacccacagcag 1321 cgcaatgccctcactcccaccaccatgcctgagggcatgggagccaacattcctatgatg 1381 ggcactcacatgccaatggctggagacatgaatggactcagccctacccaagctctccct 1441 cctccactctccatgccctccacctcccactgcaccccaccaccgccctaccccacagac 1501 tgcagcattgtcaggatttggcaagtctgaagatccctgaacagttccgacatgccatct 1561 ggaagggcatcctggaccacaggcagctgcacgacttctcctcacctcctcatctcctga 1621 ggaccccaagtggtgcctctaccgtcagtgtgggctccagtgagacccgtggtgaacgtg 1681 tgatcgatgccgtgcgctttaccctccgccagaccatctcttttccaccccgtgacgagt 1741 ggaatgatttcaactttgacatggattctcgtcgcaacaagcagcagcgtatcaaagagg 1801 aaggagaatgagcgcccattgcggggttcttcctgtcttcttccacctcccagcccctac 1861 agggcacgcctgcttgatcctcagagccttctcgttagctcttctccttctccttctcag 1921 tctggtttctaaagggacggagaattaggaggctgcctgttacctaaagtctgacctgtc 1981 acctgattctgattctggctttaagccttcaatactcttgcttgcaagatgcattgacat 2041 tgctagatagaagttagcaaagaagcagtaggtctctttaagcagtggagatctctcatt 2101 gacttttataaagcattttcagccttatagtctaagactatatatataaatatataaata 2161 tccgatatatattttgggtgtggggggtattgagtattgtttaaatgtaatttaatggaa 2221 attgagttgcacttatcatccttctttggaatttgcttgtttcggatggctgagctgtac 2281 tcctttctcaggggtatcatgtatggtgacagatatctagagttgaatggtctatgtgag 2341 taacaatgacgtataggacctctcctcatcctttggatggttattgtttagcacatcaaa 2401 cctgtggatgcatccagtgtgtttaccattgcttcctatgaggtaaaactgtatatatgt 2461 acacagttttctctgtcagtatattttatgttactggtgtccattccagttaggctggtt 2521 cactctgtggctattacaagccacattttaggtttgctttgtcacacactataagacagg 2581 gcattgtctcttgcttttgtttgagaatgaggaatgcagttgtgttgtggtttgttttgt 2641 tttattttgttttgttttctggaaactcttaaatggttcaagtcagccattccaaatatc 2701 tgatgaaatttagcccaatatagcagtagctctttgaaatttaaggcccaacaccctagt 2761 atttattagaaaaataaacatttgctgttgttagaatagtcttaaaaataaatttctctg 2821 ctagattgactaagtaaaatagacattctctgctgttgtgagaatttgggccaattagaa 2881 tgaatgaaattcgtctagttttcatggggagttgtaatgtctattagaaagattcaggaa 2941 aaataagaatgattcagaaatactgaatttccatgaaaaggaaaacagaaagcgattcat 3001 cccaccaaactctgaattgaagttccttttgaagggtggagtgatgcttgggaagtggac 3061 cttttaaagactttcctatctatgagacactgcatgcacaggcaagtttctctctcccca 3121 agggctaaaataagaataatggcttggaaaatacaaacttcgtagtgtagttttcacata 3181 gcatgagctgaaccactgttatcttcctcttgatcatcaaagcttcattgttttagaaag 3241 cagaggtgaagacccagttttccgcctgacactttccaagctagtgtagaccaagacctg 3301 tctacaaacccacgacaaaccttttcacctgtttaatccatatccagaaagacttgtttc 3361 ataccttgggaaagcatgcaacagtattccccttagatattttggaaacattttgagaca 3421 agtatattttttttcctgcctaaaccaagtgttgtttgtatgctaatgagctctacaatc 3481 ttcccacacattttgttaaatgactttcattgcacatgagctcccattttttattttaaa 3541 gtgcaaatgggctaataggcctttgacgtgtaatgtatgagttttgccagaaaatcatat 3601 cttgtgtatatgcgtgtgtgtgaaattgcttactatgctggttttgtttgttatggcttt 3661 ctctttgggatagttgggttttccagaaccacagatgaaactttttttgttgctattttt 3721 atatttttgcagaaacaccgtttagtgagaattcaatgtcaaatatgacatgatacctta 3781 attgtaagaagaaggtgggaagggaaagttggtttattaatttttttaaattttgtatgc 3841 aaaagcaaatgagtccttaatttcaacattttgttgtgtttaaataatgataagcatcat 3901 taacttctgtaacaaactcacagctttacaaattcaatgggtggagaagaaagctgtgtc 3961 ttagccatgttaggaagacaaatggcttcctgtgtgttgtaagtatttgggctgtttcag 4021 cagtgttggtgtggcacaggggactctgtggcatttcagcactatttaggtggcactagg 4081 gactctgaaattcctgtactgtatctgatgattttggcattagccataggtaggcacagt 4141 ttgtctcctcacaccagtgtttagtgtgtgaatagccagagctgtggggaagaacacaga 4201 gaacagacatctgctggatgcctctcagtggagaatgggattccttcacttggtggtgaa 4261 gcagataggatagaaagcaggattctctttgttaatccagttagcttttgttttcttgat 4321 atcccccctgaatacgttgagtatgagagatatgtgggttttttttatttttataattgt 4381 acaaaattaagcaaatatcaaatgttttatatactttattaatgttttttttcaaaaggt 4441 actttcttatagacatgatacttttttacagcttcagttgcttgtcttctggtatttttg 4501 tgttatgggctatggtgagccagaggcaaatctataagccatttttgtttgccaggacat 4561 gcaataaaatttaaaaataaatgaaaatacactgaaaaaaaaaaaaaaaaaaaaaaaaaa 4621 aaaaa SEQIDNO:50Mousep63IsoformFAminoAcidSequence(NP_001120734.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsmq 361 sqssygnsspplnkmnsmnklpsysqlinpqqrnaltpttmpegmganipmmgthmpmag 421 dmnglsptqalppplsmpstshctppppyptdcsivriwqv SEQIDNO:51Mousep63transcriptvariant7mRNASequence(NM_001127263.1; CDS:145-1326) 1 agagagagagagagagagaggcacctgaattctgttatcttcttagaagattcgcagcgc 61 aaggctctcagagggggtgggggggctggcaaaaccctggaagcagaaaagaggagagca 121 gccttgaccagtctcactgctaacatgttgtacctggaaaacaatgcccagactcaattt 181 agtgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaac 241 ggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcgccc 301 tcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccattccc 361 tccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagcact 421 gccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagattgcg 481 aagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatccgt 541 gccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccctaac 601 catgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgattcga 661 gtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagcgtg 721 ctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaatttc 781 atgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgttact 841 ctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgtgct 901 tgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcggac 961 agcgcaaagaacggcgatggtacgaagcgccctttccgtcagaatacacacggaatccag 1021 atgacttccatcaagaaacggagatccccagatgatgagctgctgtacctaccagtgaga 1081 ggtcgtgagacgtacgagatgttgctgaagatcaaagagtcactggagctcatgcagtac 1141 ctccctcagcacacgatcgaaacgtacaggcagcagcagcagcagcagcaccagcaccta 1201 cttcagaaacatctcctttcagcctgcttcaggaatgagcttgtggagccccggggagaa 1261 gctccgacacagtctgacgtcttctttagacattccaaccccccaaaccactccgtgtac 1321 ccataggtccccagctatgtgtttgagttcatgtgcttgttgtgtttctgtgtgcgtttg 1381 tgtatatgcacatgcgtgttagtgtttccagccctcacaaacaggacttgaagacatttt 1441 ggctcagagacccagctgctcaaaggcacacatccactagtgagagaatctttgaaggga 1501 ctcaaaattttacaaagcagagatgctttctgcacattttgtatctttagatcctgcctt 1561 ggttggacgggagccgcgactgtgcttgtctgtgagctttctattgttttcccaggaggg 1621 agggggaatccattgggaaagaggcattgcaaagtttattggaaaccttttctgttacct 1681 cctgttgtgtttctaaaactcataataaagcttttgagcaggtctcaaa SEQIDNO:52Mousep63IsoformGAminoAcidSequence(NP_001120735.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkhllsa 361 cfrnelveprgeaptqsdvffrhsnppnhsvyp SEQIDNO:53Mousep63transcriptvariant5mRNASequence(NM_001127264.1; CDS:145-1893) 1 agagagagagagagagagaggcacctgaattctgttatcttcttagaagattcgcagcgc 61 aaggctctcagagggggtgggggggctggcaaaaccctggaagcagaaaagaggagagca 121 gccttgaccagtctcactgctaacatgttgtacctggaaaacaatgcccagactcaattt 181 agtgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaac 241 ggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcgccc 301 tcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccattccc 361 tccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagcact 421 gccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagattgcg 481 aagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatccgt 541 gccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccctaac 601 catgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgattcga 661 gtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagcgtg 721 ctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaatttc 781 atgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgttact 841 ctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgtgct 901 tgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcggac 961 agcgcaaagaacggcgatgctttccgtcagaatacacacggaatccagatgacttccatc 1021 aagaaacggagatccccagatgatgagctgctgtacctaccagtgagaggtcgtgagacg 1081 tacgagatgttgctgaagatcaaagagtcactggagctcatgcagtacctccctcagcac 1141 acgatcgaaacgtacaggcagcagcagcagcagcagcaccagcacctacttcagaaacag 1201 acctcgatgcagtctcagtcttcatatggcaacagttccccacctctgaacaaaatgaac 1261 agcatgaacaagctgccttccgtgagccagcttatcaacccacagcagcgcaatgccctc 1321 actcccaccaccatgcctgagggcatgggagccaacattcctatgatgggcactcacatg 1381 ccaatggctggagacatgaatggactcagccctacccaagctctccctcctccactctcc 1441 atgccctccacctcccactgcaccccaccaccgccctaccccacagactgcagcattgtc 1501 agtttcttagcaaggttgggctgctcatcatgcctggactatttcacgacccaggggctg 1561 accaccatctatcagattgagcattactccatggatgatttggcaagtctgaagatccct 1621 gaacagttccgacatgccatctggaagggcatcctggaccacaggcagctgcacgacttc 1681 tcctcacctcctcatctcctgaggaccccaagtggtgcctctaccgtcagtgtgggctcc 1741 agtgagacccgtggtgaacgtgtgatcgatgccgtgcgctttaccctccgccagaccatc 1801 tcttttccaccccgtgacgagtggaatgatttcaactttgacatggattctcgtcgcaac 1861 aagcagcagcgtatcaaagaggaaggagaatgagcgcccattgcggggttcttcctgtct 1921 tcttccacctcccagcccctacagggcacgcctgcttgatcctcagagccttctcgttag 1981 ctcttctccttctccttctcagtctggtttctaaagggacggagaattaggaggctgcct 2041 gttacctaaagtctgacctgtcacctgattctgattctggctttaagccttcaatactct 2101 tgcttgcaagatgcattgacattgctagatagaagttagcaaagaagcagtaggtctctt 2161 taagcagtggagatctctcattgacttttataaagcattttcagccttatagtctaagac 2221 tatatatataaatatataaatatccgatatatattttgggtgtggggggtattgagtatt 2281 gtttaaatgtaatttaatggaaattgagttgcacttatcatccttctttggaatttgctt 2341 gtttcggatggctgagctgtactcctttctcaggggtatcatgtatggtgacagatatct 2401 agagttgaatggtctatgtgagtaacaatgacgtataggacctctcctcatcctttggat 2461 ggttattgtttagcacatcaaacctgtggatgcatccagtgtgtttaccattgcttccta 2521 tgaggtaaaactgtatatatgtacacagttttctctgtcagtatattttatgttactggt 2581 gtccattccagttaggctggttcactctgtggctattacaagccacattttaggtttgct 2641 ttgtcacacactataagacagggcattgtctcttgcttttgtttgagaatgaggaatgca 2701 gttgtgttgtggtttgttttgttttattttgttttgttttctggaaactcttaaatggtt 2761 caagtcagccattccaaatatctgatgaaatttagcccaatatagcagtagctctttgaa 2821 atttaaggcccaacaccctagtatttattagaaaaataaacatttgctgttgttagaata 2881 gtcttaaaaataaatttctctgctagattgactaagtaaaatagacattctctgctgttg 2941 tgagaatttgggccaattagaatgaatgaaattcgtctagttttcatggggagttgtaat 3001 gtctattagaaagattcaggaaaaataagaatgattcagaaatactgaatttccatgaaa 3061 aggaaaacagaaagcgattcatcccaccaaactctgaattgaagttccttttgaagggtg 3121 gagtgatgcttgggaagtggaccttttaaagactttcctatctatgagacactgcatgca 3181 caggcaagtttctctctccccaagggctaaaataagaataatggcttggaaaatacaaac 3241 ttcgtagtgtagttttcacatagcatgagctgaaccactgttatcttcctcttgatcatc 3301 aaagcttcattgttttagaaagcagaggtgaagacccagttttccgcctgacactttcca 3361 agctagtgtagaccaagacctgtctacaaacccacgacaaaccttttcacctgtttaatc 3421 catatccagaaagacttgtttcataccttgggaaagcatgcaacagtattccccttagat 3481 attttggaaacattttgagacaagtatattttttttcctgcctaaaccaagtgttgtttg 3541 tatgctaatgagctctacaatcttcccacacattttgttaaatgactttcattgcacatg 3601 agctcccattttttattttaaagtgcaaatgggctaataggcctttgacgtgtaatgtat 3661 gagttttgccagaaaatcatatcttgtgtatatgcgtgtgtgtgaaattgcttactatgc 3721 tggttttgtttgttatggctttctctttgggatagttgggttttccagaaccacagatga 3781 aactttttttgttgctatttttatatttttgcagaaacaccgtttagtgagaattcaatg 3841 tcaaatatgacatgataccttaattgtaagaagaaggtgggaagggaaagttggtttatt 3901 aatttttttaaattttgtatgcaaaagcaaatgagtccttaatttcaacattttgttgtg 3961 tttaaataatgataagcatcattaacttctgtaacaaactcacagctttacaaattcaat 4021 gggtggagaagaaagctgtgtcttagccatgttaggaagacaaatggcttcctgtgtgtt 4081 gtaagtatttgggctgtttcagcagtgttggtgtggcacaggggactctgtggcatttca 4141 gcactatttaggtggcactagggactctgaaattcctgtactgtatctgatgattttggc 4201 attagccataggtaggcacagtttgtctcctcacaccagtgtttagtgtgtgaatagcca 4261 gagctgtggggaagaacacagagaacagacatctgctggatgcctctcagtggagaatgg 4321 gattccttcacttggtggtgaagcagataggatagaaagcaggattctctttgttaatcc 4381 agttagcttttgttttcttgatatcccccctgaatacgttgagtatgagagatatgtggg 4441 ttttttttatttttataattgtacaaaattaagcaaatatcaaatgttttatatacttta 4501 ttaatgttttttttcaaaaggtactttcttatagacatgatacttttttacagcttcagt 4561 tgcttgtcttctggtatttttgtgttatgggctatggtgagccagaggcaaatctataag 4621 ccatttttgtttgccaggacatgcaataaaatttaaaaataaatgaaaatacactgaaaa 4681 aaaaaaaaaaaaaaaaaaaaaaaaaaa SEQIDNO:54Mousep63IsoformESequence(NP_001120736.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdafrqnthgiqmtsikkrrspdd 301 ellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsmqsqss 361 ygnsspplnkmnsmnklpsvsqlinpqqrnaltpttmpegmganipmmgthmpmagdmng 421 lsptqalppplsmpstshctppppyptdcsivsflarlgcsscldyfttqglttiyqieh 481 ysmddlaslkipeqfrhaiwkgildhrqlhdfsspphllrtpsgastvsvgssetrgerv 541 idavrftlrqtisfpprdewndfnfdmdsrrnkqqrikeege SEQIDNO:55Mousep63transcriptvariant8mRNASequence(NM_001127265.1; CDS:145-1314) 1 agagagagagagagagagaggcacctgaattctgttatcttcttagaagattcgcagcgc 61 aaggctctcagagggggtgggggggctggcaaaaccctggaagcagaaaagaggagagca 121 gccttgaccagtctcactgctaacatgttgtacctggaaaacaatgcccagactcaattt 181 agtgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaac 241 ggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcgccc 301 tcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccattccc 361 tccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagcact 421 gccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagattgcg 481 aagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatccgt 541 gccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccctaac 601 catgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgattcga 661 gtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagcgtg 721 ctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaatttc 781 atgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgttact 841 ctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgtgct 901 tgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcggac 961 agcgcaaagaacggcgatgctttccgtcagaatacacacggaatccagatgacttccatc 1021 aagaaacggagatccccagatgatgagctgctgtacctaccagtgagaggtcgtgagacg 1081 tacgagatgttgctgaagatcaaagagtcactggagctcatgcagtacctccctcagcac 1141 acgatcgaaacgtacaggcagcagcagcagcagcagcaccagcacctacttcagaaacat 1201 ctcctttcagcctgcttcaggaatgagcttgtggagccccggggagaagctccgacacag 1261 tctgacgtcttctttagacattccaaccccccaaaccactccgtgtacccataggtcccc 1321 agctatgtgtttgagttcatgtgcttgttgtgtttctgtgtgcgtttgtgtatatgcaca 1381 tgcgtgttagtgtttccagccctcacaaacaggacttgaagacattttggctcagagacc 1441 cagctgctcaaaggcacacatccactagtgagagaatctttgaagggactcaaaatttta 1501 caaagcagagatgctttctgcacattttgtatctttagatcctgccttggttggacggga 1561 gccgcgactgtgcttgtctgtgagctttctattgttttcccaggagggagggggaatcca 1621 ttgggaaagaggcattgcaaagtttattggaaaccttttctgttacctcctgttgtgttt 1681 ctaaaactcataataaagcttttgagcaggtctcaaa SEQIDNO:56Mousep63IsoformHAminoAcidSequence(NP_001120737.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdafrqnthgiqmtsikkrrspdd 301 ellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkhllsacfrn 361 elveprgeaptqsdvffrhsnppnhsvyp SEQIDNO:57Mousep63transcriptvariant4mRNASequence(NM_011641.2; CDS:145-1905) 1 agagagagagagagagagaggcacctgaattctgttatcttcttagaagattcgcagcgc 61 aaggctctcagagggggtgggggggctggcaaaaccctggaagcagaaaagaggagagca 121 gccttgaccagtctcactgctaacatgttgtacctggaaaacaatgcccagactcaattt 181 agtgagccacagtacacgaacctggggctcctgaacagcatggaccagcagattcagaac 241 ggctcctcgtccaccagcccctacaacacagaccacgcacagaatagcgtgacggcgccc 301 tcgccctatgcacagcccagctccacctttgatgccctctctccatcccctgccattccc 361 tccaacacagattacccgggcccacacagcttcgatgtgtccttccagcagtcaagcact 421 gccaagtcagccacctggacgtattccaccgaactgaagaagctgtactgccagattgcg 481 aagacatgccccatccagatcaaggtgatgaccccacccccacagggcgctgttatccgt 541 gccatgcctgtctacaagaaagctgagcatgtcaccgaggttgtgaaacgatgccctaac 601 catgagctgagccgtgagttcaatgagggacagattgcccctcccagtcatctgattcga 661 gtagaagggaacagccatgcccagtatgtagaagatcctatcacgggaaggcagagcgtg 721 ctggtcccttatgagccaccacaggttggcactgaattcacaacagtcctgtacaatttc 781 atgtgtaacagcagctgcgtcggaggaatgaacagacgtccaattttaatcatcgttact 841 ctggaaaccagagatgggcaagtcctgggccgacggtgctttgaggcccggatctgtgct 901 tgcccaggaagagaccggaaggcagatgaagacagcatcagaaagcagcaagtatcggac 961 agcgcaaagaacggcgatggtacgaagcgccctttccgtcagaatacacacggaatccag 1021 atgacttccatcaagaaacggagatccccagatgatgagctgctgtacctaccagtgaga 1081 ggtcgtgagacgtacgagatgttgctgaagatcaaagagtcactggagctcatgcagtac 1141 ctccctcagcacacgatcgaaacgtacaggcagcagcagcagcagcagcaccagcaccta 1201 cttcagaaacagacctcgatgcagtctcagtcttcatatggcaacagttccccacctctg 1261 aacaaaatgaacagcatgaacaagctgccttccgtgagccagcttatcaacccacagcag 1321 cgcaatgccctcactcccaccaccatgcctgagggcatgggagccaacattcctatgatg 1381 ggcactcacatgccaatggctggagacatgaatggactcagccctacccaagctctccct 1441 cctccactctccatgccctccacctcccactgcaccccaccaccgccctaccccacagac 1501 tgcagcattgtcagtttcttagcaaggttgggctgctcatcatgcctggactatttcacg 1561 acccaggggctgaccaccatctatcagattgagcattactccatggatgatttggcaagt 1621 ctgaagatccctgaacagttccgacatgccatctggaagggcatcctggaccacaggcag 1681 ctgcacgacttctcctcacctcctcatctcctgaggaccccaagtggtgcctctaccgtc 1741 agtgtgggctccagtgagacccgtggtgaacgtgtgatcgatgccgtgcgctttaccctc 1801 cgccagaccatctcttttccaccccgtgacgagtggaatgatttcaactttgacatggat 1861 tctcgtcgcaacaagcagcagcgtatcaaagaggaaggagaatgagcgcccattgcgggg 1921 ttcttcctgtcttcttccacctcccagcccctacagggcacgcctgcttgatcctcagag 1981 ccttctcgttagctcttctccttctccttctcagtctggtttctaaagggacggagaatt 2041 aggaggctgcctgttacctaaagtctgacctgtcacctgattctgattctggctttaagc 2101 cttcaatactcttgcttgcaagatgcattgacattgctagatagaagttagcaaagaagc 2161 agtaggtctctttaagcagtggagatctctcattgacttttataaagcattttcagcctt 2221 atagtctaagactatatatataaatatataaatatccgatatatattttgggtgtggggg 2281 gtattgagtattgtttaaatgtaatttaatggaaattgagttgcacttatcatccttctt 2341 tggaatttgcttgtttcggatggctgagctgtactcctttctcaggggtatcatgtatgg 2401 tgacagatatctagagttgaatggtctatgtgagtaacaatgacgtataggacctctcct 2461 catcctttggatggttattgtttagcacatcaaacctgtggatgcatccagtgtgtttac 2521 cattgcttcctatgaggtaaaactgtatatatgtacacagttttctctgtcagtatattt 2581 tatgttactggtgtccattccagttaggctggttcactctgtggctattacaagccacat 2641 tttaggtttgctttgtcacacactataagacagggcattgtctcttgcttttgtttgaga 2701 atgaggaatgcagttgtgttgtggtttgttttgttttattttgttttgttttctggaaac 2761 tcttaaatggttcaagtcagccattccaaatatctgatgaaatttagcccaatatagcag 2821 tagctctttgaaatttaaggcccaacaccctagtatttattagaaaaataaacatttgct 2881 gttgttagaatagtcttaaaaataaatttctctgctagattgactaagtaaaatagacat 2941 tctctgctgttgtgagaatttgggccaattagaatgaatgaaattcgtctagttttcatg 3001 gggagttgtaatgtctattagaaagattcaggaaaaataagaatgattcagaaatactga 3061 atttccatgaaaaggaaaacagaaagcgattcatcccaccaaactctgaattgaagttcc 3121 ttttgaagggtggagtgatgcttgggaagtggaccttttaaagactttcctatctatgag 3181 acactgcatgcacaggcaagtttctctctccccaagggctaaaataagaataatggcttg 3241 gaaaatacaaacttcgtagtgtagttttcacatagcatgagctgaaccactgttatcttc 3301 ctcttgatcatcaaagcttcattgttttagaaagcagaggtgaagacccagttttccgcc 3361 tgacactttccaagctagtgtagaccaagacctgtctacaaacccacgacaaaccttttc 3421 acctgtttaatccatatccagaaagacttgtttcataccttgggaaagcatgcaacagta 3481 ttccccttagatattttggaaacattttgagacaagtatattttttttcctgcctaaacc 3541 aagtgttgtttgtatgctaatgagctctacaatcttcccacacattttgttaaatgactt 3601 tcattgcacatgagctcccattttttattttaaagtgcaaatgggctaataggcctttga 3661 cgtgtaatgtatgagttttgccagaaaatcatatcttgtgtatatgcgtgtgtgtgaaat 3721 tgcttactatgctggttttgtttgttatggctttctctttgggatagttgggttttccag 3781 aaccacagatgaaactttttttgttgctatttttatatttttgcagaaacaccgtttagt 3841 gagaattcaatgtcaaatatgacatgataccttaattgtaagaagaaggtgggaagggaa 3901 agttggtttattaatttttttaaattttgtatgcaaaagcaaatgagtccttaatttcaa 3961 cattttgttgtgtttaaataatgataagcatcattaacttctgtaacaaactcacagctt 4021 tacaaattcaatgggtggagaagaaagctgtgtcttagccatgttaggaagacaaatggc 4081 ttcctgtgtgttgtaagtatttgggctgtttcagcagtgttggtgtggcacaggggactc 4141 tgtggcatttcagcactatttaggtggcactagggactctgaaattcctgtactgtatct 4201 gatgattttggcattagccataggtaggcacagtttgtctcctcacaccagtgtttagtg 4261 tgtgaatagccagagctgtggggaagaacacagagaacagacatctgctggatgcctctc 4321 agtggagaatgggattccttcacttggtggtgaagcagataggatagaaagcaggattct 4381 ctttgttaatccagttagcttttgttttcttgatatcccccctgaatacgttgagtatga 4441 gagatatgtgggttttttttatttttataattgtacaaaattaagcaaatatcaaatgtt 4501 ttatatactttattaatgttttttttcaaaaggtactttcttatagacatgatacttttt 4561 tacagcttcagttgcttgtcttctggtatttttgtgttatgggctatggtgagccagagg 4621 caaatctataagccatttttgtttgccaggacatgcaataaaatttaaaaataaatgaaa 4681 atacactgaaaaaaaaaaaaaaaaaaaaaa SEQIDNO:58Mousep63IsoformDAminoAcidSequence(NP_035771.1) 1 mlylennaqtqfsepqytnlgllnsmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsmq 361 sqssygnsspplnkmnsmnklpsysqlinpqqrnaltpttmpegmganipmmgthmpmag 421 dmnglsptqalppplsmpstshctppppyptdcsivsflarlgcsscldyfttqglttiy 481 qiehysmddlaslkipeqfrhaiwkgildhrqlhdfsspphllrtpsgastvsvgssetr 541 gervidavrftlrqtisfpprdewndfnfdmdsrrnkqqrikeege SEQIDNO:59Ratp63transcriptvariant1Sequence(NM_019221.3;CDS:148- 2190) 1 ggggggaagtgtctaaacttctatgtctgatggcatttgaccctattgctttcagcctcc 61 tggctatatacctagatattctcaggtgtatatgtatattttatagaattgttccccatc 121 tgttggtatcaaagagagttgaaggaaatgaattttgaaacttcacggtgtgctacccta 181 cagtactgccctgacccttacatccagcgtttcatagaaaccccatctcatttctcctgg 241 aaagaaagttattaccggtccgccatgtcgcagagcacccagacaagtgagttcctcagc 301 ccagaggtgttccagcatatctgggattttctggaacagcctatatgctcagtacagccc 361 atcgacttgaactttgtggacgaaccatcagaaaatggtgcaacaaacaagattgagatt 421 agcatggattgtatccgcatgcaagactcagacctcagtgaccccatgtggccacagtac 481 acgaacctggggctcctgaacggcatggaccagcagattcagaacggctcctcatctacc 541 agcccctataacacagaccatgcacagaacagcgtgacggcaccctcgccctatgcacag 601 cccagctcaaccttcgatgccctttctccatcccctgccattccctccaacacagattac 661 ccaggcccacacagcttcgatgtgtccttccagcagtcaagcaccgccaagtcagctacc 721 tggacgtattccaccgaactgaagaaactctactgccagattgcaaagacctgccccatc 781 cagatcaaggtgatgaccccacccccacagggcgccgtcattcgtgccatgcctgtctac 841 aagaaagccgagcatgtcaccgaggttgtgaaacgatgtcctaaccacgagctgagccgc 901 gagttcaatgagggacagattgcccctcccagtcatctgattcgagtagaagggaacagc 961 catgcccagtatgtagaagatcctatcacaggaaggcagagcgtgctggtcccttatgag 1021 ccaccacaggttggcactgaattcacaacagtcctgtacaatttcatgtgcaacagcagc 1081 tgtgtcggaggaatgaaccgccgtccaattttaatcatcgttactctggaaaccagagat 1141 gggcaagtcctgggccgacgttgctttgaggcccggatctgcgcttgcccaggaagagac 1201 cggaaggccgatgaagacagcatcagaaagcagcaagtatcagacagcgcaaagaacggc 1261 gatggtacgaagcgccctttccgtcagaatacccacggaatccagatgacttccatcaag 1321 aaacggagatccccagatgatgagctgctgtacctaccagtgagaggccgtgagacttat 1381 gaaatgctgctcaagatcaaggagtcgctcgagctcatgcagtatctccctcagcacacg 1441 atcgagacgtacaggcagcagcagcagcagcagcaccaacacctacttcagaaacagacc 1501 tcgatgcagtctcagtcttcatacggtaacagctcaccacctctgaacaaaatgaacagc 1561 atgaacaagctgccgtctgtgagccagcttatcaacccacagcagcgcaacgccctgact 1621 cccaccaccatgcctgagggcatgggagccaacattcctatgatgggcactcacatgcca 1681 atggctggagacatgaatggactcagccccacccaagctcttcctcctccactctccatg 1741 ccctccacctcccactgcacccccccacctccgtacccaacagactgcagcattgtcagt 1801 ttcttagcaaggttgggctgttcatcatgtctggactatttcacgacccaggggctgacc 1861 accatctatcagattgagcattactccatggatgatttggcaagtctgaagatccctgag 1921 cagttccgacatgccatctggaaggggatcctggaccacaggcagctgcatgacttctcc 1981 tcacctccgcatctcctgagaacccccagtggtgcctctacagtcagtgtgggctccagt 2041 gagacccgtggagaacgtgtgattgatgccgtgcgctttactctccgccagaccatctct 2101 ttcccaccccgtgatgagtggaacgatttcaactttgacatggattcccgtcgcaacaag 2161 cagcagcgcatcaaagaggaaggagaatgaacgtccgtcgccgggttcttcctgttttct 2221 tcctcctcccagctcccacagggcacgcctgcttgatcctcaaagccttctcgctagctc 2281 tcctcctcctccttctcagtctggtttctaaagggacggagaattaagaggctacctgtt 2341 acctaaagtctgacctgtcacctgattctgatcctggctttaagccttcaatactcttgc 2401 ttgcaagatgcgttgacattgctagatagacgttagcagagaagcagtgggtctctctaa 2461 gcactggagatcgctcattgacttttataaagcattttcagccttatagtctaagactat 2521 atatataaatatataaatatacaatatatatttcgggtgggggtattgagtattgtttaa 2581 atgtaatttaatggaaatcgagttgcacttatcaaccttctttggaatttgcttgttttg 2641 gttggctgatctgtacccctttctcaggggtatcatgtatggtgacagatatttagagtt 2701 gaatggtctatgtgagtaacagtgatatataggtcctctcctttctttggatgattgccg 2761 tttagcacatcaaacctgtggatgcgtccagtctgtttaccattgctccttatgaggtaa 2821 aactgcatatactgtcagtctattttatgttactggtgtccattccagttaggctggttc 2881 actctgtggccattccaagcaaaattttatgtttgctttgtcacacactagaagacaggg 2941 catcatctcttgcttttgtttgagaatgaggagtacttttttttttttctggaaaatctt 3001 aaatggtccaaatcagccattccaaatggctgatgaaatgtagccaatatagcagttagc 3061 tctctaaaatttaagacccaacaccctcgtatttattagtaaaacaaaaatgaaacattt 3121 gctgtcattagagtagccttaaaattaaatttcaataccagattgactgagtaaactatg 3181 cattcaatgttgttgtgagaattggggctaattagtcaggatgattggaatttgtgtagt 3241 tttttatggtgagttgcaatatctatttaggaaggttcaggaataataagaatgactcag 3301 aaatactcaatctccgtgacaacagaaagcaatctcaccaaactctgaatttaaacccct 3361 tttgaaacatggagtgaggcttgggaaatgtaccttttaaagactttcctatctataaga 3421 cactgcatgcaggggcaagtttaatctctcatcaaggtggaaaataagaatagtagctcg 3481 gaaactacaaacttgctagtgtagctttcacatggcatgagctcaactattgttattttc 3541 ctctttatcatcaaagctccattgctgtagaaagcagaggtgaagacccagttttccacc 3601 tgacactttccgggcaaggcatagaccaagaactgtctacaaaaccagggcaaagctctt 3661 cagtgaagctgtttaattcacatggagaaacacttgtttcccactttgggaaagcatgca 3721 acagtgttccccctagatgttttggaaacattttgagtcaaatatatttttcccagacta 3781 aaccaggctaatgagctctacaatcctcctgcacattttggtaaagggctgtcattgcac 3841 aggagctcccatttttatcttaaagtgcaaatgggctaatacgcctacgaaatgtaatgt 3901 atgggttttgccagaaaatagtatattgtgtacacgtgtctgtgtgtgagtgtgagagtg 3961 tgtgtgtgtgtgtgtgtgtgtgtgtgtgtgaaattgcatactatgctggttttgtttgtt 4021 actctttctcttggggatagttgggttttccagaaccacagacgaaacttttttttgttg 4081 ctgtttttatatttttgcagaaacaccatttagtgagaattcaatgtcaaattagacatg 4141 acaccttaattgtaagaaggggggagagggaaagttggttttttttaattttttaaaatt 4201 ttgtatactaaagagaatgagtccttaatttcaacattctgttgcatttaaataatgata 4261 agcatcattaacttctgtaacaacttcccagcttggcaaattcaatgcatggagaacaaa 4321 gctgggccttagccatgttagggagaaaaatggcttcttgggggttgtgagcatttgggt 4381 tgctttagcaccgttgaggtggcacaggggactcctgaggcatttcagcactacttacgt 4441 agcactagggactcggaaattcctgtactgtagctaatgattttggcgttcaccattagc 4501 agtagataggccgtttctctcctcacaccagtgttaagcgtgtgagtagccagagctgtg 4561 gggaagagcatggagaacagacgtctgctggatgcctctcaccggagaatgagattcctt 4621 cgcgtggtggtgaagtaggataggaagcaggagtctccttgttagtccagttagctattg 4681 ttttcttgatattcccccccaaaacattgactatgagagatatgtggggcttttttattt 4741 ttataattgtacaaaattaaacaaatatgaaatgttttatatactttattaatgtttttt 4801 ttcaaaaggtactttcttatagacatgatcctttttttacaggttcagttgcttgtccct 4861 tggtatttttgtgttatgggctatggtgagcctgaggcaaatctataagccatttttgtt 4921 tgccaggacatgcaataaaatttaaaaataaatgaaaatacactgaaaaaaaaaaaaaaa 4981 aaaaaaaaaaa SEQIDNO:60Ratp63IsoformAAminoAcidSequence(NP_062094.1) 1 mnfetsrcatlqycpdpyiqrfietpshfswkesyyrsamsqstqtseflspevfqhiwd 61 fleqpicsvqpidlnfvdepsengatnkieismdcirmqdsdlsdpmwpqytnlgllngm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdsakngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkqtsmqsqssygnsspplnkmnsmnklpsvsq 481 linpqqrnaltpttmpegmganipmmgthmpmagdmnglsptqalppplsmpstshctpp 541 ppyptdcsivsflarlgcsscldyfttqglttiyqiehysmddlaslkipeqfrhaiwkg 601 ildhrqlhdfsspphllrtpsgastvsvgssetrgervidavrftlrqtisfpprdewnd 661 fnfdmdsrrnkqqrikeege SEQIDNO:61Ratp63transcriptvariant2Sequence(NM_0011273391;(CDS:148- 1815) 1 ggggggaagtgtctaaacttctatgtctgatggcatttgaccctattgctttcagcctcc 61 tggctatatacctagatattctcaggtgtatatgtatattttatagaattgttccccatc 121 tgttggtatcaaagagagttgaaggaaatgaattttgaaacttcacggtgtgctacccta 181 cagtactgccctgacccttacatccagcgtttcatagaaaccccatctcatttctcctgg 241 aaagaaagttattaccggtccgccatgtcgcagagcacccagacaagtgagttcctcagc 301 ccagaggtgttccagcatatctgggattttctggaacagcctatatgctcagtacagccc 361 atcgacttgaactttgtggacgaaccatcagaaaatggtgcaacaaacaagattgagatt 421 agcatggattgtatccgcatgcaagactcagacctcagtgaccccatgtggccacagtac 481 acgaacctggggctcctgaacggcatggaccagcagattcagaacggctcctcatctacc 541 agcccctataacacagaccatgcacagaacagcgtgacggcaccctcgccctatgcacag 601 cccagctcaaccttcgatgccctttctccatcccctgccattccctccaacacagattac 661 ccaggcccacacagcttcgatgtgtccttccagcagtcaagcaccgccaagtcagctacc 721 tggacgtattccaccgaactgaagaaactctactgccagattgcaaagacctgccccatc 781 cagatcaaggtgatgaccccacccccacagggcgccgtcattcgtgccatgcctgtctac 841 aagaaagccgagcatgtcaccgaggttgtgaaacgatgtcctaaccacgagctgagccgc 901 gagttcaatgagggacagattgcccctcccagtcatctgattcgagtagaagggaacagc 961 catgcccagtatgtagaagatcctatcacaggaaggcagagcgtgctggtcccttatgag 1021 ccaccacaggttggcactgaattcacaacagtcctgtacaatttcatgtgcaacagcagc 1081 tgtgtcggaggaatgaaccgccgtccaattttaatcatcgttactctggaaaccagagat 1141 gggcaagtcctgggccgacgttgctttgaggcccggatctgcgcttgcccaggaagagac 1201 cggaaggccgatgaagacagcatcagaaagcagcaagtatcagacagcgcaaagaacggc 1261 gatggtacgaagcgccctttccgtcagaatacccacggaatccagatgacttccatcaag 1321 aaacggagatccccagatgatgagctgctgtacctaccagtgagaggccgtgagacttat 1381 gaaatgctgctcaagatcaaggagtcgctcgagctcatgcagtatctccctcagcacacg 1441 atcgagacgtacaggcagcagcagcagcagcagcaccaacacctacttcagaaacagacc 1501 tcgatgcagtctcagtcttcatacggtaacagctcaccacctctgaacaaaatgaacagc 1561 atgaacaagctgccgtctgtgagccagcttatcaacccacagcagcgcaacgccctgact 1621 cccaccaccatgcctgagggcatgggagccaacattcctatgatgggcactcacatgcca 1681 atggctggagacatgaatggactcagccccacccaagctcttcctcctccactctccatg 1741 ccctccacctcccactgcacccccccacctccgtacccaacagactgcagcattgtcagg 1801 atttggcaagtctgaagatccctgagcagttccgacatgccatctggaaggggatcctgg 1861 accacaggcagctgcatgacttctcctcacctccgcatctcctgagaacccccagtggtg 1921 cctctacagtcagtgtgggctccagtgagacccgtggagaacgtgtgattgatgccgtgc 1981 gctttactctccgccagaccatctctttcccaccccgtgatgagtggaacgatttcaact 2041 ttgacatggattcccgtcgcaacaagcagcagcgcatcaaagaggaaggagaatgaacgt 2101 ccgtcgccgggttcttcctgttttcttcctcctcccagctcccacagggcacgcctgctt 2161 gatcctcaaagccttctcgctagctctcctcctcctccttctcagtctggtttctaaagg 2221 gacggagaattaagaggctacctgttacctaaagtctgacctgtcacctgattctgatcc 2281 tggctttaagccttcaatactcttgcttgcaagatgcgttgacattgctagatagacgtt 2341 agcagagaagcagtgggtctctctaagcactggagatcgctcattgacttttataaagca 2401 ttttcagccttatagtctaagactatatatataaatatataaatatacaatatatatttc 2461 gggtgggggtattgagtattgtttaaatgtaatttaatggaaatcgagttgcacttatca 2521 accttctttggaatttgcttgttttggttggctgatctgtacccctttctcaggggtatc 2581 atgtatggtgacagatatttagagttgaatggtctatgtgagtaacagtgatatataggt 2641 cctctcctttctttggatgattgccgtttagcacatcaaacctgtggatgcgtccagtct 2701 gtttaccattgctccttatgaggtaaaactgcatatactgtcagtctattttatgttact 2761 ggtgtccattccagttaggctggttcactctgtggccattccaagcaaaattttatgttt 2821 gctttgtcacacactagaagacagggcatcatctcttgcttttgtttgagaatgaggagt 2881 acttttttttttttctggaaaatcttaaatggtccaaatcagccattccaaatggctgat 2941 gaaatgtagccaatatagcagttagctctctaaaatttaagacccaacaccctcgtattt 3001 attagtaaaacaaaaatgaaacatttgctgtcattagagtagccttaaaattaaatttca 3061 ataccagattgactgagtaaactatgcattcaatgttgttgtgagaattggggctaatta 3121 gtcaggatgattggaatttgtgtagttttttatggtgagttgcaatatctatttaggaag 3181 gttcaggaataataagaatgactcagaaatactcaatctccgtgacaacagaaagcaatc 3241 tcaccaaactctgaatttaaaccccttttgaaacatggagtgaggcttgggaaatgtacc 3301 ttttaaagactttcctatctataagacactgcatgcaggggcaagtttaatctctcatca 3361 aggtggaaaataagaatagtagctcggaaactacaaacttgctagtgtagctttcacatg 3421 gcatgagctcaactattgttattttcctctttatcatcaaagctccattgctgtagaaag 3481 cagaggtgaagacccagttttccacctgacactttccgggcaaggcatagaccaagaact 3541 gtctacaaaaccagggcaaagctcttcagtgaagctgtttaattcacatggagaaacact 3601 tgtttcccactttgggaaagcatgcaacagtgttccccctagatgttttggaaacatttt 3661 gagtcaaatatatttttcccagactaaaccaggctaatgagctctacaatcctcctgcac 3721 attttggtaaagggctgtcattgcacaggagctcccatttttatcttaaagtgcaaatgg 3781 gctaatacgcctacgaaatgtaatgtatgggttttgccagaaaatagtatattgtgtaca 3841 cgtgtctgtgtgtgagtgtgagagtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgaaat 3901 tgcatactatgctggttttgtttgttactctttctcttggggatagttgggttttccaga 3961 accacagacgaaacttttttttgttgctgtttttatatttttgcagaaacaccatttagt 4021 gagaattcaatgtcaaattagacatgacaccttaattgtaagaaggggggagagggaaag 4081 ttggttttttttaattttttaaaattttgtatactaaagagaatgagtccttaatttcaa 4141 cattctgttgcatttaaataatgataagcatcattaacttctgtaacaacttcccagctt 4201 ggcaaattcaatgcatggagaacaaagctgggccttagccatgttagggagaaaaatggc 4261 ttcttgggggttgtgagcatttgggttgctttagcaccgttgaggtggcacaggggactc 4321 ctgaggcatttcagcactacttacgtagcactagggactcggaaattcctgtactgtagc 4381 taatgattttggcgttcaccattagcagtagataggccgtttctctcctcacaccagtgt 4441 taagcgtgtgagtagccagagctgtggggaagagcatggagaacagacgtctgctggatg 4501 cctctcaccggagaatgagattccttcgcgtggtggtgaagtaggataggaagcaggagt 4561 ctccttgttagtccagttagctattgttttcttgatattcccccccaaaacattgactat 4621 gagagatatgtggggcttttttatttttataattgtacaaaattaaacaaatatgaaatg 4681 ttttatatactttattaatgttttttttcaaaaggtactttcttatagacatgatccttt 4741 ttttacaggttcagttgcttgtcccttggtatttttgtgttatgggctatggtgagcctg 4801 aggcaaatctataagccatttttgtttgccaggacatgcaataaaatttaaaaataaatg 4861 aaaatacactgaaaaaaaaaaaaaaaaaaaaaaaaaa SEQIDNO:62Ratp63IsoformBAminoAcidSequence(NP_001120811.1) 1 mnfetsrcatlqycpdpyiqrfietpshfswkesyyrsamsqstqtseflspevfqhiwd 61 fleqpicsvqpidlnfvdepsengatnkieismdcirmqdsdlsdpmwpqytnlgllngm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdsakngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkqtsmqsqssygnsspplnkmnsmnklpsysq 481 linpqqrnaltpttmpegmganipmmgthmpmagdmnglsptqalppplsmpstshctpp 541 ppyptdcsivriwqv SEQIDNO:63Ratp63transcriptvariant3Sequence(NM_001127341.1;CDS:148 1611) 1 ggggggaagtgtctaaacttctatgtctgatggcatttgaccctattgctttcagcctcc 61 tggctatatacctagatattctcaggtgtatatgtatattttatagaattgttccccatc 121 tgttggtatcaaagagagttgaaggaaatgaattttgaaacttcacggtgtgctacccta 181 cagtactgccctgacccttacatccagcgtttcatagaaaccccatctcatttctcctgg 241 aaagaaagttattaccggtccgccatgtcgcagagcacccagacaagtgagttcctcagc 301 ccagaggtgttccagcatatctgggattttctggaacagcctatatgctcagtacagccc 361 atcgacttgaactttgtggacgaaccatcagaaaatggtgcaacaaacaagattgagatt 421 agcatggattgtatccgcatgcaagactcagacctcagtgaccccatgtggccacagtac 481 acgaacctggggctcctgaacggcatggaccagcagattcagaacggctcctcatctacc 541 agcccctataacacagaccatgcacagaacagcgtgacggcaccctcgccctatgcacag 601 cccagctcaaccttcgatgccctttctccatcccctgccattccctccaacacagattac 661 ccaggcccacacagcttcgatgtgtccttccagcagtcaagcaccgccaagtcagctacc 721 tggacgtattccaccgaactgaagaaactctactgccagattgcaaagacctgccccatc 781 cagatcaaggtgatgaccccacccccacagggcgccgtcattcgtgccatgcctgtctac 841 aagaaagccgagcatgtcaccgaggttgtgaaacgatgtcctaaccacgagctgagccgc 901 gagttcaatgagggacagattgcccctcccagtcatctgattcgagtagaagggaacagc 961 catgcccagtatgtagaagatcctatcacaggaaggcagagcgtgctggtcccttatgag 1021 ccaccacaggttggcactgaattcacaacagtcctgtacaatttcatgtgcaacagcagc 1081 tgtgtcggaggaatgaaccgccgtccaattttaatcatcgttactctggaaaccagagat 1141 gggcaagtcctgggccgacgttgctttgaggcccggatctgcgcttgcccaggaagagac 1201 cggaaggccgatgaagacagcatcagaaagcagcaagtatcagacagcgcaaagaacggc 1261 gatggtacgaagcgccctttccgtcagaatacccacggaatccagatgacttccatcaag 1321 aaacggagatccccagatgatgagctgctgtacctaccagtgagaggccgtgagacttat 1381 gaaatgctgctcaagatcaaggagtcgctcgagctcatgcagtatctccctcagcacacg 1441 atcgagacgtacaggcagcagcagcagcagcagcaccaacacctacttcagaaacatctc 1501 ctttcagcctgcttcaggaatgagcttgtggagtcccggagagaagctccgacacagtct 1561 gacgtcttctttagacattccaaccccccaaaccactcagtgtacccatag SEQIDNO:64Ratp63IsoformCAminoAcidSequence(NP_001120813.1) 1 mnfetsrcatlqycpdpyiqrfietpshfswkesyyrsamsqstqtseflspevfqhiwd 61 fleqpicsvqpidlnfvdepsengatnkieismdcirmqdsdlsdpmwpqytnlgllngm 121 dqqiqngssstspyntdhaqnsvtapspyaqpsstfdalspspaipsntdypgphsfdvs 181 fqqsstaksatwtystelkklycqiaktcpiqikvmtpppqgavirampvykkaehvtev 241 vkrcpnhelsrefnegqiappshlirvegnshaqyvedpitgrqsvlvpyeppqvgteft 301 tvlynfmcnsscvggmnrrpiliivtletrdgqvlgrrcfearicacpgrdrkadedsir 361 kqqvsdsakngdgtkrpfrqnthgiqmtsikkrrspddellylpvrgretyemllkikes 421 lelmqylpqhtietyrqqqqqqhqhllqkhllsacfrnelvesrreaptqsdvffrhsnp 481 pnhsvyp SEQIDNO:65Ratp63transcriptvariant4Sequence(NM_001127342.1;CDS:1- 1761) 1 atgttgtacctggaaagcaatgcccagactcaatttagtgagccacagtacacgaacctg 61 gggctcctgaacggcatggaccagcagattcagaacggctcctcatctaccagcccctat 121 aacacagaccatgcacagaacagcgtgacggcaccctcgccctatgcacagcccagctca 181 accttcgatgccctttctccatcccctgccattccctccaacacagattacccaggccca 241 cacagcttcgatgtgtccttccagcagtcaagcaccgccaagtcagctacctggacgtat 301 tccaccgaactgaagaaactctactgccagattgcaaagacctgccccatccagatcaag 361 gtgatgaccccacccccacagggcgccgtcattcgtgccatgcctgtctacaagaaagcc 421 gagcatgtcaccgaggttgtgaaacgatgtcctaaccacgagctgagccgcgagttcaat 481 gagggacagattgcccctcccagtcatctgattcgagtagaagggaacagccatgcccag 541 tatgtagaagatcctatcacaggaaggcagagcgtgctggtcccttatgagccaccacag 601 gttggcactgaattcacaacagtcctgtacaatttcatgtgcaacagcagctgtgtcgga 661 ggaatgaaccgccgtccaattttaatcatcgttactctggaaaccagagatgggcaagtc 721 ctgggccgacgttgctttgaggcccggatctgcgcttgcccaggaagagaccggaaggcc 781 gatgaagacagcatcagaaagcagcaagtatcagacagcgcaaagaacggcgatggtacg 841 aagcgccctttccgtcagaatacccacggaatccagatgacttccatcaagaaacggaga 901 tccccagatgatgagctgctgtacctaccagtgagaggccgtgagacttatgaaatgctg 961 ctcaagatcaaggagtcgctcgagctcatgcagtatctccctcagcacacgatcgagacg 1021 tacaggcagcagcagcagcagcagcaccaacacctacttcagaaacagacctcgatgcag 1081 tctcagtcttcatacggtaacagctcaccacctctgaacaaaatgaacagcatgaacaag 1141 ctgccgtctgtgagccagcttatcaacccacagcagcgcaacgccctgactcccaccacc 1201 atgcctgagggcatgggagccaacattcctatgatgggcactcacatgccaatggctgga 1261 gacatgaatggactcagccccacccaagctcttcctcctccactctccatgccctccacc 1321 tcccactgcacccccccacctccgtacccaacagactgcagcattgtcagtttcttagca 1381 aggttgggctgttcatcatgtctggactatttcacgacccaggggctgaccaccatctat 1441 cagattgagcattactccatggatgatttggcaagtctgaagatccctgagcagttccga 1501 catgccatctggaaggggatcctggaccacaggcagctgcatgacttctcctcacctccg 1561 catctcctgagaacccccagtggtgcctctacagtcagtgtgggctccagtgagacccgt 1621 ggagaacgtgtgattgatgccgtgcgctttactctccgccagaccatctctttcccaccc 1681 cgtgatgagtggaacgatttcaactttgacatggattcccgtcgcaacaagcagcagcgc 1741 atcaaagaggaaggagaatgaacgtccgtcgccgggttcttcctgttttcttcctcctcc 1801 cagctcccacagggcacgcctgcttgatcctcaaagccttctcgctagctctcctcctcc 1861 tccttctcagtctggtttctaaagggacggagaattaagaggctacctgttacctaaagt 1921 ctgacctgtcacctgattctgatcctggctttaagccttcaatactcttgcttgcaagat 1981 gcgttgacattgctagatagacgttagcagagaagcagtgggtctctctaagcactggag 2041 atcgctcattgacttttataaagcattttcagccttatagtctaagactatatatataaa 2101 tatataaatatacaatatatatttcgggtgggggtattgagtattgtttaaatgtaattt 2161 aatggaaatcgagttgcacttatcaaccttctttggaatttgcttgttttggttggctga 2221 tctgtacccctttctcaggggtatcatgtatggtgacagatatttagagttgaatggtct 2281 atgtgagtaacagtgatatataggtcctctcctttctttggatgattgccgtttagcaca 2341 tcaaacctgtggatgcgtccagtctgtttaccattgctccttatgaggtaaaactgcata 2401 tactgtcagtctattttatgttactggtgtccattccagttaggctggttcactctgtgg 2461 ccattccaagcaaaattttatgtttgctttgtcacacactagaagacagggcatcatctc 2521 ttgcttttgtttgagaatgaggagtacttttttttttttctggaaaatcttaaatggtcc 2581 aaatcagccattccaaatggctgatgaaatgtagccaatatagcagttagctctctaaaa 2641 tttaagacccaacaccctcgtatttattagtaaaacaaaaatgaaacatttgctgtcatt 2701 agagtagccttaaaattaaatttcaataccagattgactgagtaaactatgcattcaatg 2761 ttgttgtgagaattggggctaattagtcaggatgattggaatttgtgtagttttttatgg 2821 tgagttgcaatatctatttaggaaggttcaggaataataagaatgactcagaaatactca 2881 atctccgtgacaacagaaagcaatctcaccaaactctgaatttaaaccccttttgaaaca 2941 tggagtgaggcttgggaaatgtaccttttaaagactttcctatctataagacactgcatg 3001 caggggcaagtttaatctctcatcaaggtggaaaataagaatagtagctcggaaactaca 3061 aacttgctagtgtagctttcacatggcatgagctcaactattgttattttcctctttatc 3121 atcaaagctccattgctgtagaaagcagaggtgaagacccagttttccacctgacacttt 3181 ccgggcaaggcatagaccaagaactgtctacaaaaccagggcaaagctcttcagtgaagc 3241 tgtttaattcacatggagaaacacttgtttcccactttgggaaagcatgcaacagtgttc 3301 cccctagatgttttggaaacattttgagtcaaatatatttttcccagactaaaccaggct 3361 aatgagctctacaatcctcctgcacattttggtaaagggctgtcattgcacaggagctcc 3421 catttttatcttaaagtgcaaatgggctaatacgcctacgaaatgtaatgtatgggtttt 3481 gccagaaaatagtatattgtgtacacgtgtctgtgtgtgagtgtgagagtgtgtgtgtgt 3541 gtgtgtgtgtgtgtgtgtgtgaaattgcatactatgctggttttgtttgttactctttct 3601 cttggggatagttgggttttccagaaccacagacgaaacttttttttgttgctgttttta 3661 tatttttgcagaaacaccatttagtgagaattcaatgtcaaattagacatgacaccttaa 3721 ttgtaagaaggggggagagggaaagttggttttttttaattttttaaaattttgtatact 3781 aaagagaatgagtccttaatttcaacattctgttgcatttaaataatgataagcatcatt 3841 aacttctgtaacaacttcccagcttggcaaattcaatgcatggagaacaaagctgggcct 3901 tagccatgttagggagaaaaatggcttcttgggggttgtgagcatttgggttgctttagc 3961 accgttgaggtggcacaggggactcctgaggcatttcagcactacttacgtagcactagg 4021 gactcggaaattcctgtactgtagctaatgattttggcgttcaccattagcagtagatag 4081 gccgtttctctcctcacaccagtgttaagcgtgtgagtagccagagctgtggggaagagc 4141 atggagaacagacgtctgctggatgcctctcaccggagaatgagattccttcgcgtggtg 4201 gtgaagtaggataggaagcaggagtctccttgttagtccagttagctattgttttcttga 4261 tattcccccccaaaacattgactatgagagatatgtggggcttttttatttttataattg 4321 tacaaaattaaacaaatatgaaatgttttatatactttattaatgttttttttcaaaagg 4381 tactttcttatagacatgatcctttttttacaggttcagttgcttgtcccttggtatttt 4441 tgtgttatgggctatggtgagcctgaggcaaatctataagccatttttgtttgccaggac 4501 atgcaataaaatttaaaaataaatgaaaatacactgaaaaaaaaaaaaaaaaaaaaaaaa 4561 aa SEQIDNO:66Ratp63IsoformDAminoAcidSequence(NP_001120814.1) 1 mlylesnaqtqfsepqytnlgllngmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsmq 361 sqssygnsspplnkmnsmnklpsysqlinpqqrnaltpttmpegmganipmmgthmpmag 421 dmnglsptqalppplsmpstshctppppyptdcsivsflarlgcsscldyfttqglttiy 481 qiehysmddlaslkipeqfrhaiwkgildhrqlhdfsspphllrtpsgastvsvgssetr 541 gervidavrftlrqtisfpprdewndfnfdmdsrrnkqqrikeege SEQIDNO:67Ratp63transcriptvariant5Sequence(NM_001127343.1;CDS:1- 1386) 1 atgttgtacctggaaagcaatgcccagactcaatttagtgagccacagtacacgaacctg 61 gggctcctgaacggcatggaccagcagattcagaacggctcctcatctaccagcccctat 121 aacacagaccatgcacagaacagcgtgacggcaccctcgccctatgcacagcccagctca 181 accttcgatgccctttctccatcccctgccattccctccaacacagattacccaggccca 241 cacagcttcgatgtgtccttccagcagtcaagcaccgccaagtcagctacctggacgtat 301 tccaccgaactgaagaaactctactgccagattgcaaagacctgccccatccagatcaag 361 gtgatgaccccacccccacagggcgccgtcattcgtgccatgcctgtctacaagaaagcc 421 gagcatgtcaccgaggttgtgaaacgatgtcctaaccacgagctgagccgcgagttcaat 481 gagggacagattgcccctcccagtcatctgattcgagtagaagggaacagccatgcccag 541 tatgtagaagatcctatcacaggaaggcagagcgtgctggtcccttatgagccaccacag 601 gttggcactgaattcacaacagtcctgtacaatttcatgtgcaacagcagctgtgtcgga 661 ggaatgaaccgccgtccaattttaatcatcgttactctggaaaccagagatgggcaagtc 721 ctgggccgacgttgctttgaggcccggatctgcgcttgcccaggaagagaccggaaggcc 781 gatgaagacagcatcagaaagcagcaagtatcagacagcgcaaagaacggcgatggtacg 841 aagcgccctttccgtcagaatacccacggaatccagatgacttccatcaagaaacggaga 901 tccccagatgatgagctgctgtacctaccagtgagaggccgtgagacttatgaaatgctg 961 ctcaagatcaaggagtcgctcgagctcatgcagtatctccctcagcacacgatcgagacg 1021 tacaggcagcagcagcagcagcagcaccaacacctacttcagaaacagacctcgatgcag 1081 tctcagtcttcatacggtaacagctcaccacctctgaacaaaatgaacagcatgaacaag 1141 ctgccgtctgtgagccagcttatcaacccacagcagcgcaacgccctgactcccaccacc 1201 atgcctgagggcatgggagccaacattcctatgatgggcactcacatgccaatggctgga 1261 gacatgaatggactcagccccacccaagctcttcctcctccactctccatgccctccacc 1321 tcccactgcacccccccacctccgtacccaacagactgcagcattgtcaggatttggcaa 1381 gtctgaagatccctgagcagttccgacatgccatctggaaggggatcctggaccacaggc 1441 agctgcatgacttctcctcacctccgcatctcctgagaacccccagtggtgcctctacag 1501 tcagtgtgggctccagtgagacccgtggagaacgtgtgattgatgccgtgcgctttactc 1561 tccgccagaccatctctttcccaccccgtgatgagtggaacgatttcaactttgacatgg 1621 attcccgtcgcaacaagcagcagcgcatcaaagaggaaggagaatgaacgtccgtcgccg 1681 ggttcttcctgttttcttcctcctcccagctcccacagggcacgcctgcttgatcctcaa 1741 agccttctcgctagctctcctcctcctccttctcagtctggtttctaaagggacggagaa 1801 ttaagaggctacctgttacctaaagtctgacctgtcacctgattctgatcctggctttaa 1861 gccttcaatactcttgcttgcaagatgcgttgacattgctagatagacgttagcagagaa 1921 gcagtgggtctctctaagcactggagatcgctcattgacttttataaagcattttcagcc 1981 ttatagtctaagactatatatataaatatataaatatacaatatatatttcgggtggggg 2041 tattgagtattgtttaaatgtaatttaatggaaatcgagttgcacttatcaaccttcttt 2101 ggaatttgcttgttttggttggctgatctgtacccctttctcaggggtatcatgtatggt 2161 gacagatatttagagttgaatggtctatgtgagtaacagtgatatataggtcctctcctt 2221 tctttggatgattgccgtttagcacatcaaacctgtggatgcgtccagtctgtttaccat 2281 tgctccttatgaggtaaaactgcatatactgtcagtctattttatgttactggtgtccat 2341 tccagttaggctggttcactctgtggccattccaagcaaaattttatgtttgctttgtca 2401 cacactagaagacagggcatcatctcttgcttttgtttgagaatgaggagtacttttttt 2461 tttttctggaaaatcttaaatggtccaaatcagccattccaaatggctgatgaaatgtag 2521 ccaatatagcagttagctctctaaaatttaagacccaacaccctcgtatttattagtaaa 2581 acaaaaatgaaacatttgctgtcattagagtagccttaaaattaaatttcaataccagat 2641 tgactgagtaaactatgcattcaatgttgttgtgagaattggggctaattagtcaggatg 2701 attggaatttgtgtagttttttatggtgagttgcaatatctatttaggaaggttcaggaa 2761 taataagaatgactcagaaatactcaatctccgtgacaacagaaagcaatctcaccaaac 2821 tctgaatttaaaccccttttgaaacatggagtgaggcttgggaaatgtaccttttaaaga 2881 ctttcctatctataagacactgcatgcaggggcaagtttaatctctcatcaaggtggaaa 2941 ataagaatagtagctcggaaactacaaacttgctagtgtagctttcacatggcatgagct 3001 caactattgttattttcctctttatcatcaaagctccattgctgtagaaagcagaggtga 3061 agacccagttttccacctgacactttccgggcaaggcatagaccaagaactgtctacaaa 3121 accagggcaaagctcttcagtgaagctgtttaattcacatggagaaacacttgtttccca 3181 ctttgggaaagcatgcaacagtgttccccctagatgttttggaaacattttgagtcaaat 3241 atatttttcccagactaaaccaggctaatgagctctacaatcctcctgcacattttggta 3301 aagggctgtcattgcacaggagctcccatttttatcttaaagtgcaaatgggctaatacg 3361 cctacgaaatgtaatgtatgggttttgccagaaaatagtatattgtgtacacgtgtctgt 3421 gtgtgagtgtgagagtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgaaattgcatacta 3481 tgctggttttgtttgttactctttctcttggggatagttgggttttccagaaccacagac 3541 gaaacttttttttgttgctgtttttatatttttgcagaaacaccatttagtgagaattca 3601 atgtcaaattagacatgacaccttaattgtaagaaggggggagagggaaagttggttttt 3661 tttaattttttaaaattttgtatactaaagagaatgagtccttaatttcaacattctgtt 3721 gcatttaaataatgataagcatcattaacttctgtaacaacttcccagcttggcaaattc 3781 aatgcatggagaacaaagctgggccttagccatgttagggagaaaaatggcttcttgggg 3841 gttgtgagcatttgggttgctttagcaccgttgaggtggcacaggggactcctgaggcat 3901 ttcagcactacttacgtagcactagggactcggaaattcctgtactgtagctaatgattt 3961 tggcgttcaccattagcagtagataggccgtttctctcctcacaccagtgttaagcgtgt 4021 gagtagccagagctgtggggaagagcatggagaacagacgtctgctggatgcctctcacc 4081 ggagaatgagattccttcgcgtggtggtgaagtaggataggaagcaggagtctccttgtt 4141 agtccagttagctattgttttcttgatattcccccccaaaacattgactatgagagatat 4201 gtggggcttttttatttttataattgtacaaaattaaacaaatatgaaatgttttatata 4261 ctttattaatgttttttttcaaaaggtactttcttatagacatgatcctttttttacagg 4321 ttcagttgcttgtcccttggtatttttgtgttatgggctatggtgagcctgaggcaaatc 4381 tataagccatttttgtttgccaggacatgcaataaaatttaaaaataaatgaaaatacac 4441 tgaaaaaaaaaaaaaaaaaaaaaaaaaa SEQIDNO:68Ratp63Isoform5AminoAcidSequence(NP_001120815.1) 1 mlylesnaqtqfsepqytnlgllngmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkqtsmq 361 sqssygnsspplnkmnsmnklpsysqlinpqqrnaltpttmpegmganipmmgthmpmag 421 dmnglsptqalppplsmpstshctppppyptdcsivriwqv SEQIDNO:69Ratp63transcriptvariant6Sequence(NM_001127344.1;CDS:1- 1182) 1 atgttgtacctggaaagcaatgcccagactcaatttagtgagccacagtacacgaacctg 61 gggctcctgaacggcatggaccagcagattcagaacggctcctcatctaccagcccctat 121 aacacagaccatgcacagaacagcgtgacggcaccctcgccctatgcacagcccagctca 181 accttcgatgccctttctccatcccctgccattccctccaacacagattacccaggccca 241 cacagcttcgatgtgtccttccagcagtcaagcaccgccaagtcagctacctggacgtat 301 tccaccgaactgaagaaactctactgccagattgcaaagacctgccccatccagatcaag 361 gtgatgaccccacccccacagggcgccgtcattcgtgccatgcctgtctacaagaaagcc 421 gagcatgtcaccgaggttgtgaaacgatgtcctaaccacgagctgagccgcgagttcaat 481 gagggacagattgcccctcccagtcatctgattcgagtagaagggaacagccatgcccag 541 tatgtagaagatcctatcacaggaaggcagagcgtgctggtcccttatgagccaccacag 601 gttggcactgaattcacaacagtcctgtacaatttcatgtgcaacagcagctgtgtcgga 661 ggaatgaaccgccgtccaattttaatcatcgttactctggaaaccagagatgggcaagtc 721 ctgggccgacgttgctttgaggcccggatctgcgcttgcccaggaagagaccggaaggcc 781 gatgaagacagcatcagaaagcagcaagtatcagacagcgcaaagaacggcgatggtacg 841 aagcgccctttccgtcagaatacccacggaatccagatgacttccatcaagaaacggaga 901 tccccagatgatgagctgctgtacctaccagtgagaggccgtgagacttatgaaatgctg 961 ctcaagatcaaggagtcgctcgagctcatgcagtatctccctcagcacacgatcgagacg 1021 tacaggcagcagcagcagcagcagcaccaacacctacttcagaaacatctcctttcagcc 1081 tgcttcaggaatgagcttgtggagtcccggagagaagctccgacacagtctgacgtcttc 1141 tttagacattccaaccccccaaaccactcagtgtacccatag SEQIDNO:70Ratp63Isoform6AminoAcidSequence(NP_001120816.1) 1 mlylesnaqtqfsepqytnlgllngmdqqiqngssstspyntdhaqnsvtapspyaqpss 61 tfdalspspaipsntdypgphsfdvsfqqsstaksatwtystelkklycqiaktcpiqik 121 vmtpppqgavirampvykkaehvtevvkrcpnhelsrefnegqiappshlirvegnshaq 181 yvedpitgrqsvlvpyeppqvgtefttvlynfmcnsscvggmnrrpiliivtletrdgqv 241 lgrrcfearicacpgrdrkadedsirkqqvsdsakngdgtkrpfrqnthgiqmtsikkrr 301 spddellylpvrgretyemllkikeslelmqylpqhtietyrqqqqqqhqhllqkhilsa 361 cfrnelvesrreaptqsdvffrhsnppnhsvyp SEQIDNO:71HumanTP53IsoformaAminoAcidSequence(NP_000537.3; NP_001119584.1) 1 meepqsdpsvepplsqetfsdlwkllpennvlsplpsqamddlmlspddieqwftedpgp 61 deaprmpeaappvapapaaptpaapapapswplsssvpsqktyqgsygfrlgflhsgtak 121 svtctyspalnkmfcqlaktcpvqlwvdstpppgtrvramaiykqsqhmtevvrrcphhe 181 rcsdsdglappqhlirvegnlrveylddrntfrhsvvvpyeppevgsdcttihynymcns 241 scmggmnrrpiltiitledssgnllgrnsfevrvcacpgrdrrteeenlrkkgephhelp 301 pgstkralpnntssspqpkkkpldgeyftlqirgrerfemfrelnealelkdaqagkepg 361 gsrahsshlkskkgqstsrhkklmfktegpdsd SEQIDNO:72HumanTP53transcriptvariant1cDNAsequence(NM_000546.5; CDS:203-1384) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggcagcca 181 gactgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccc 241 tctgagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtc 301 ccccttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatg 361 gttcactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgt 421 ggcccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccct 481 gtcatcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggctt 541 cttgcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagat 601 gttttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcc 661 cggcacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgt 721 gaggcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagca 781 tcttatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcg 841 acatagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatcca 901 ctacaactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcac 961 catcatcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcg 1021 tgtttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagg 1081 ggagcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccag 1141 ctcctctccccagccaaagaagaaaccactggatggagaatatttcacccttcagatccg 1201 tgggcgtgagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgc 1261 ccaggctgggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaa 1321 gggtcagtctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcaga 1381 ctgacattctccacttcttgttccccactgacagcctcccacccccatctctccctcccc 1441 tgccattttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcac 1501 ccaggacttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgt 1561 tttgttgtggggaggaggatggggagtaggacataccagcttagattttaaggtttttac 1621 tgtgagggatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatc 1681 agccacattctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactg 1741 ttgaattttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctc 1801 acagagtgcattgtgagggttaatgaaataatgtacatctggccttgaaaccacctttta 1861 ttacatggggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcg 1921 gtgggttggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctct 1981 gctggcccagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaa 2041 tctcaccccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccac 2101 caagacttgttttatgctcagggtcaatttcttttttcttttttttttttttttttcttt 2161 ttctttgagactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggc 2221 ttactgcagcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgg 2281 gaccacaggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtc 2341 tcacagtgttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagc 2401 ctcccagagtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatc 2461 ttttacattctgcaagcacatctgcattttcaccccacccttcccctccttctccctttt 2521 tatatcccatttttatatcgatctcttattttacaataaaactttgctgccacctgtgtg 2581 tctgaggggtg SEQIDNO:73HumanTP53transcriptvariant2cDNAsequence (NM_001126112.2;CDS:200-1381) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggccagac 181 tgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccctct 241 gagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtcccc 301 cttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatggtt 361 cactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgtggc 421 ccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccctgtc 481 atcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggcttctt 541 gcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagatgtt 601 ttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcccgg 661 cacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgtgag 721 gcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagcatct 781 tatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcgaca 841 tagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatccacta 901 caactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcaccat 961 catcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcgtgt 1021 ttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagggga 1081 gcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccagctc 1141 ctctccccagccaaagaagaaaccactggatggagaatatttcacccttcagatccgtgg 1201 gcgtgagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgccca 1261 ggctgggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaaggg 1321 tcagtctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcagactg 1381 acattctccacttcttgttccccactgacagcctcccacccccatctctccctcccctgc 1441 cattttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcaccca 1501 ggacttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgtttt 1561 gttgtggggaggaggatggggagtaggacataccagcttagattttaaggtttttactgt 1621 gagggatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatcagc 1681 cacattctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactgttg 1741 aattttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctcaca 1801 gagtgcattgtgagggttaatgaaataatgtacatctggccttgaaaccaccttttatta 1861 catggggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcggtg 1921 ggttggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctctgct 1981 ggcccagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaatct 2041 caccccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccaccaa 2101 gacttgttttatgctcagggtcaatttcttttttcttttttttttttttttttctttttc 2161 tttgagactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggctta 2221 ctgcagcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgggac 2281 cacaggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtctca 2341 cagtgttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagcctc 2401 ccagagtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatcttt 2461 tacattctgcaagcacatctgcattttcaccccacccttcccctccttctccctttttat 2521 atcccatttttatatcgatctcttattttacaataaaactttgctgccacctgtgtgtct 2581 gaggggtg SEQIDNO:74HumanTP53isoformbAminoAcidSequence(NP_001119586.1) 1 meepqsdpsvepplsqetfsdlwkllpennvlsplpsqamddlmlspddieqwftedpgp 61 deaprmpeaappvapapaaptpaapapapswplsssvpsqktyqgsygfrlgflhsgtak 121 svtctyspalnkmfcqlaktcpvqlwvdstpppgtrvramaiykqsqhmtevvrrcphhe 181 rcsdsdglappqhlirvegnlrveylddrntfrhsvvvpyeppevgsdcttihynymcns 241 scmggmnrrpiltiitledssgnllgrnsfevrvcacpgrdrrteeenlrkkgephhelp 301 pgstkralpnntssspqpkkkpldgeyftlqdqtsfqkenc SEQIDNO:75HumanTP53transcriptvariant3cDNAsequence (NM_001126114.2;CDS:203-1228) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggcagcca 181 gactgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccc 241 tctgagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtc 301 ccccttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatg 361 gttcactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgt 421 ggcccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccct 481 gtcatcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggctt 541 cttgcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagat 601 gttttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcc 661 cggcacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgt 721 gaggcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagca 781 tcttatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcg 841 acatagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatcca 901 ctacaactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcac 961 catcatcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcg 1021 tgtttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagg 1081 ggagcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccag 1141 ctcctctccccagccaaagaagaaaccactggatggagaatatttcacccttcaggacca 1201 gaccagctttcaaaaagaaaattgttaaagagagcatgaaaatggttctatgactttgcc 1261 tgatacagatgctacttgacttacgatggtgttacttcctgataaactcgtcgtaagttg 1321 aaaatattatccgtgggcgtgagcgcttcgagatgttccgagagctgaatgaggccttgg 1381 aactcaaggatgcccaggctgggaaggagccaggggggagcagggctcactccagccacc 1441 tgaagtccaaaaagggtcagtctacctcccgccataaaaaactcatgttcaagacagaag 1501 ggcctgactcagactgacattctccacttcttgttccccactgacagcctcccaccccca 1561 tctctccctcccctgccattttgggttttgggtctttgaacccttgcttgcaataggtgt 1621 gcgtcagaagcacccaggacttccatttgctttgtcccggggctccactgaacaagttgg 1681 cctgcactggtgttttgttgtggggaggaggatggggagtaggacataccagcttagatt 1741 ttaaggtttttactgtgagggatgtttgggagatgtaagaaatgttcttgcagttaaggg 1801 ttagtttacaatcagccacattctaggtaggggcccacttcaccgtactaaccagggaag 1861 ctgtccctcactgttgaattttctctaacttcaaggcccatatctgtgaaatgctggcat 1921 ttgcacctacctcacagagtgcattgtgagggttaatgaaataatgtacatctggccttg 1981 aaaccaccttttattacatggggtctagaacttgacccccttgagggtgcttgttccctc 2041 tccctgttggtcggtgggttggtagtttctacagttgggcagctggttaggtagagggag 2101 ttgtcaagtctctgctggcccagccaaaccctgtctgacaacctcttggtgaaccttagt 2161 acctaaaaggaaatctcaccccatcccacaccctggaggatttcatctcttgtatatgat 2221 gatctggatccaccaagacttgttttatgctcagggtcaatttcttttttcttttttttt 2281 tttttttttctttttctttgagactgggtctcgctttgttgcccaggctggagtggagtg 2341 gcgtgatcttggcttactgcagcctttgcctccccggctcgagcagtcctgcctcagcct 2401 ccggagtagctgggaccacaggttcatgccaccatggccagccaacttttgcatgttttg 2461 tagagatggggtctcacagtgttgcccaggctggtctcaaactcctgggctcaggcgatc 2521 cacctgtctcagcctcccagagtgctgggattacaattgtgagccaccacgtccagctgg 2581 aagggtcaacatcttttacattctgcaagcacatctgcattttcaccccacccttcccct 2641 ccttctccctttttatatcccatttttatatcgatctcttattttacaataaaactttgc 2701 tgccacctgtgtgtctgaggggtg SEQIDNO:76HumanTP53isoformcAminoAcidSequence(NP_001119585.1) 1 meepqsdpsvepplsqetfsdlwkllpennvlsplpsqamddlmlspddieqwftedpgp 61 deaprmpeaappvapapaaptpaapapapswplsssvpsqktyqgsygfrlgflhsgtak 121 svtctyspalnkmfcqlaktcpvqlwvdstpppgtrvramaiykqsqhmtevvrrcphhe 181 rcsdsdglappqhlirvegnlrveylddrntfrhsvvvpyeppevgsdcttihynymcns 241 scmggmnrrpiltiitledssgnllgrnsfevrvcacpgrdrrteeenlrkkgephhelp 301 pgstkralpnntssspqpkkkpldgeyftlqmlldlrwcyflinss SEQIDNO:77HumanTP53transcriptvariant4cDNAsequence (NM_001126113.2;CDS:203-1243) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggcagcca 181 gactgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccc 241 tctgagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtc 301 ccccttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatg 361 gttcactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgt 421 ggcccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccct 481 gtcatcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggctt 541 cttgcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagat 601 gttttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcc 661 cggcacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgt 721 gaggcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagca 781 tcttatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcg 841 acatagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatcca 901 ctacaactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcac 961 catcatcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcg 1021 tgtttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagg 1081 ggagcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccag 1141 ctcctctccccagccaaagaagaaaccactggatggagaatatttcacccttcagatgct 1201 acttgacttacgatggtgttacttcctgataaactcgtcgtaagttgaaaatattatccg 1261 tgggcgtgagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgc 1321 ccaggctgggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaa 1381 gggtcagtctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcaga 1441 ctgacattctccacttcttgttccccactgacagcctcccacccccatctctccctcccc 1501 tgccattttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcac 1561 ccaggacttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgt 1621 tttgttgtggggaggaggatggggagtaggacataccagcttagattttaaggtttttac 1681 tgtgagggatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatc 1741 agccacattctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactg 1801 ttgaattttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctc 1861 acagagtgcattgtgagggttaatgaaataatgtacatctggccttgaaaccacctttta 1921 ttacatggggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcg 1981 gtgggttggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctct 2041 gctggcccagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaa 2101 tctcaccccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccac 2161 caagacttgttttatgctcagggtcaatttcttttttcttttttttttttttttttcttt 2221 ttctttgagactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggc 2281 ttactgcagcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgg 2341 gaccacaggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtc 2401 tcacagtgttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagc 2461 ctcccagagtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatc 2521 ttttacattctgcaagcacatctgcattttcaccccacccttcccctccttctccctttt 2581 tatatcccatttttatatcgatctcttattttacaataaaactttgctgccacctgtgtg 2641 tctgaggggtg SEQIDNO:78HumanTP53isoformdAminoAcidSequence(NP_001119587.1) 1 mfcqlaktcpvqlwvdstpppgtrvramaiykqsqhmtevvrrcphhercsdsdglappq 61 hlirvegnlrveylddrntfrhsvvvpyeppevgsdcttihynymcnsscmggmnrrpil 121 tiitledssgnllgrnsfevrvcacpgrdrrteeenlrkkgephhelppgstkralpnnt 181 ssspqpkkkpldgeyftlqirgrerfemfrelnealelkdaqagkepggsrahsshlksk 241 kgqstsrhkklmfktegpdsd SEQIDNO:79HumanTP53transcriptvariant5cDNAsequence (NM_001126115.1CDS:279-1064) 1 tgaggccaggagatggaggctgcagtgagctgtgatcacaccactgtgctccagcctgag 61 tgacagagcaagaccctatctcaaaaaaaaaaaaaaaaaagaaaagctcctgaggtgtag 121 acgccaactctctctagctcgctagtgggttgcaggaggtgcttacgcatgtttgtttct 181 ttgctgccgtcttccagttgctttatctgttcacttgtgccctgactttcaactctgtct 241 ccttcctcttcctacagtactcccctgccctcaacaagatgttttgccaactggccaaga 301 cctgccctgtgcagctgtgggttgattccacacccccgcccggcacccgcgtccgcgcca 361 tggccatctacaagcagtcacagcacatgacggaggttgtgaggcgctgcccccaccatg 421 agcgctgctcagatagcgatggtctggcccctcctcagcatcttatccgagtggaaggaa 481 atttgcgtgtggagtatttggatgacagaaacacttttcgacatagtgtggtggtgccct 541 atgagccgcctgaggttggctctgactgtaccaccatccactacaactacatgtgtaaca 601 gttcctgcatgggcggcatgaaccggaggcccatcctcaccatcatcacactggaagact 661 ccagtggtaatctactgggacggaacagctttgaggtgcgtgtttgtgcctgtcctggga 721 gagaccggcgcacagaggaagagaatctccgcaagaaaggggagcctcaccacgagctgc 781 ccccagggagcactaagcgagcactgcccaacaacaccagctcctctccccagccaaaga 841 agaaaccactggatggagaatatttcacccttcagatccgtgggcgtgagcgcttcgaga 901 tgttccgagagctgaatgaggccttggaactcaaggatgcccaggctgggaaggagccag 961 gggggagcagggctcactccagccacctgaagtccaaaaagggtcagtctacctcccgcc 1021 ataaaaaactcatgttcaagacagaagggcctgactcagactgacattctccacttcttg 1081 ttccccactgacagcctcccacccccatctctccctcccctgccattttgggttttgggt 1141 ctttgaacccttgcttgcaataggtgtgcgtcagaagcacccaggacttccatttgcttt 1201 gtcccggggctccactgaacaagttggcctgcactggtgttttgttgtggggaggaggat 1261 ggggagtaggacataccagcttagattttaaggtttttactgtgagggatgtttgggaga 1321 tgtaagaaatgttcttgcagttaagggttagtttacaatcagccacattctaggtagggg 1381 cccacttcaccgtactaaccagggaagctgtccctcactgttgaattttctctaacttca 1441 aggcccatatctgtgaaatgctggcatttgcacctacctcacagagtgcattgtgagggt 1501 taatgaaataatgtacatctggccttgaaaccaccttttattacatggggtctagaactt 1561 gacccccttgagggtgcttgttccctctccctgttggtcggtgggttggtagtttctaca 1621 gttgggcagctggttaggtagagggagttgtcaagtctctgctggcccagccaaaccctg 1681 tctgacaacctcttggtgaaccttagtacctaaaaggaaatctcaccccatcccacaccc 1741 tggaggatttcatctcttgtatatgatgatctggatccaccaagacttgttttatgctca 1801 gggtcaatttcttttttcttttttttttttttttttctttttctttgagactgggtctcg 1861 ctttgttgcccaggctggagtggagtggcgtgatcttggcttactgcagcctttgcctcc 1921 ccggctcgagcagtcctgcctcagcctccggagtagctgggaccacaggttcatgccacc 1981 atggccagccaacttttgcatgttttgtagagatggggtctcacagtgttgcccaggctg 2041 gtctcaaactcctgggctcaggcgatccacctgtctcagcctcccagagtgctgggatta 2101 caattgtgagccaccacgtccagctggaagggtcaacatcttttacattctgcaagcaca 2161 tctgcattttcaccccacccttcccctccttctccctttttatatcccatttttatatcg 2221 atctcttattttacaataaaactttgctgccacctgtgtgtctgaggggtg SEQIDNO:80HumanTP53isoformeAminoAcidSequence(NP_001119588.1) 1 mfcqlaktcpvqlwvdstpppgtrvramaiykqsqhmtevvrrcphhercsdsdglappq 61 hlirvegnlrveylddrntfrhsvvvpyeppevgsdcttihynymcnsscmggmnrrpil 121 tiitledssgnllgrnsfevrvcacpgrdrrteeenlrkkgephhelppgstkralpnnt 181 ssspqpkkkpldgeyftlqdqtsfqkenc SEQIDNO:81HumanTP53transcriptvariant6cDNAsequence (NM_001126116.1;CDS:279-908) 1 tgaggccaggagatggaggctgcagtgagctgtgatcacaccactgtgctccagcctgag 61 tgacagagcaagaccctatctcaaaaaaaaaaaaaaaaaagaaaagctcctgaggtgtag 121 acgccaactctctctagctcgctagtgggttgcaggaggtgcttacgcatgtttgtttct 181 ttgctgccgtcttccagttgctttatctgttcacttgtgccctgactttcaactctgtct 241 ccttcctcttcctacagtactcccctgccctcaacaagatgttttgccaactggccaaga 301 cctgccctgtgcagctgtgggttgattccacacccccgcccggcacccgcgtccgcgcca 361 tggccatctacaagcagtcacagcacatgacggaggttgtgaggcgctgcccccaccatg 421 agcgctgctcagatagcgatggtctggcccctcctcagcatcttatccgagtggaaggaa 481 atttgcgtgtggagtatttggatgacagaaacacttttcgacatagtgtggtggtgccct 541 atgagccgcctgaggttggctctgactgtaccaccatccactacaactacatgtgtaaca 601 gttcctgcatgggcggcatgaaccggaggcccatcctcaccatcatcacactggaagact 661 ccagtggtaatctactgggacggaacagctttgaggtgcgtgtttgtgcctgtcctggga 721 gagaccggcgcacagaggaagagaatctccgcaagaaaggggagcctcaccacgagctgc 781 ccccagggagcactaagcgagcactgcccaacaacaccagctcctctccccagccaaaga 841 agaaaccactggatggagaatatttcacccttcaggaccagaccagctttcaaaaagaaa 901 attgttaaagagagcatgaaaatggttctatgactttgcctgatacagatgctacttgac 961 ttacgatggtgttacttcctgataaactcgtcgtaagttgaaaatattatccgtgggcgt 1021 gagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgcccaggct 1081 gggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaagggtcag 1141 tctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcagactgacat 1201 tctccacttcttgttccccactgacagcctcccacccccatctctccctcccctgccatt 1261 ttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcacccaggac 1321 ttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgttttgttg 1381 tggggaggaggatggggagtaggacataccagcttagattttaaggtttttactgtgagg 1441 gatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatcagccaca 1501 ttctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactgttgaatt 1561 ttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctcacagagt 1621 gcattgtgagggttaatgaaataatgtacatctggccttgaaaccaccttttattacatg 1681 gggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcggtgggtt 1741 ggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctctgctggcc 1801 cagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaatctcacc 1861 ccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccaccaagact 1921 tgttttatgctcagggtcaatttcttttttcttttttttttttttttttctttttctttg 1981 agactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggcttactgc 2041 agcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgggaccaca 2101 ggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtctcacagt 2161 gttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagcctcccag 2221 agtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatcttttaca 2281 ttctgcaagcacatctgcattttcaccccacccttcccctccttctccctttttatatcc 2341 catttttatatcgatctcttattttacaataaaactttgctgccacctgtgtgtctgagg 2401 ggtg SEQIDNO:82HumanTP53isoformfAminoAcidSequence(NP_001119589.1) 1 mfcqlaktcpvqlwvdstpppgtrvramaiykqsqhmtevvrrcphhercsdsdglappq 61 hlirvegnlrveylddrntfrhsvvvpyeppevgsdcttihynymcnsscmggmnrrpil 121 tiitledssgnllgrnsfevrvcacpgrdrrteeenlrkkgephhelppgstkralpnnt 181 ssspqpkkkpldgeyftlqmlldlrwcyflinss SEQIDNO:83HumanTP53transcriptvariant7cDNAsequence (NM_001126117.1;CDS:279-923) 1 tgaggccaggagatggaggctgcagtgagctgtgatcacaccactgtgctccagcctgag 61 tgacagagcaagaccctatctcaaaaaaaaaaaaaaaaaagaaaagctcctgaggtgtag 121 acgccaactctctctagctcgctagtgggttgcaggaggtgcttacgcatgtttgtttct 181 ttgctgccgtcttccagttgctttatctgttcacttgtgccctgactttcaactctgtct 241 ccttcctcttcctacagtactcccctgccctcaacaagatgttttgccaactggccaaga 301 cctgccctgtgcagctgtgggttgattccacacccccgcccggcacccgcgtccgcgcca 361 tggccatctacaagcagtcacagcacatgacggaggttgtgaggcgctgcccccaccatg 421 agcgctgctcagatagcgatggtctggcccctcctcagcatcttatccgagtggaaggaa 481 atttgcgtgtggagtatttggatgacagaaacacttttcgacatagtgtggtggtgccct 541 atgagccgcctgaggttggctctgactgtaccaccatccactacaactacatgtgtaaca 601 gttcctgcatgggcggcatgaaccggaggcccatcctcaccatcatcacactggaagact 661 ccagtggtaatctactgggacggaacagctttgaggtgcgtgtttgtgcctgtcctggga 721 gagaccggcgcacagaggaagagaatctccgcaagaaaggggagcctcaccacgagctgc 781 ccccagggagcactaagcgagcactgcccaacaacaccagctcctctccccagccaaaga 841 agaaaccactggatggagaatatttcacccttcagatgctacttgacttacgatggtgtt 901 acttcctgataaactcgtcgtaagttgaaaatattatccgtgggcgtgagcgcttcgaga 961 tgttccgagagctgaatgaggccttggaactcaaggatgcccaggctgggaaggagccag 1021 gggggagcagggctcactccagccacctgaagtccaaaaagggtcagtctacctcccgcc 1081 ataaaaaactcatgttcaagacagaagggcctgactcagactgacattctccacttcttg 1141 ttccccactgacagcctcccacccccatctctccctcccctgccattttgggttttgggt 1201 ctttgaacccttgcttgcaataggtgtgcgtcagaagcacccaggacttccatttgcttt 1261 gtcccggggctccactgaacaagttggcctgcactggtgttttgttgtggggaggaggat 1321 ggggagtaggacataccagcttagattttaaggtttttactgtgagggatgtttgggaga 1381 tgtaagaaatgttcttgcagttaagggttagtttacaatcagccacattctaggtagggg 1441 cccacttcaccgtactaaccagggaagctgtccctcactgttgaattttctctaacttca 1501 aggcccatatctgtgaaatgctggcatttgcacctacctcacagagtgcattgtgagggt 1561 taatgaaataatgtacatctggccttgaaaccaccttttattacatggggtctagaactt 1621 gacccccttgagggtgcttgttccctctccctgttggtcggtgggttggtagtttctaca 1681 gttgggcagctggttaggtagagggagttgtcaagtctctgctggcccagccaaaccctg 1741 tctgacaacctcttggtgaaccttagtacctaaaaggaaatctcaccccatcccacaccc 1801 tggaggatttcatctcttgtatatgatgatctggatccaccaagacttgttttatgctca 1861 gggtcaatttcttttttcttttttttttttttttttctttttctttgagactgggtctcg 1921 ctttgttgcccaggctggagtggagtggcgtgatcttggcttactgcagcctttgcctcc 1981 ccggctcgagcagtcctgcctcagcctccggagtagctgggaccacaggttcatgccacc 2041 atggccagccaacttttgcatgttttgtagagatggggtctcacagtgttgcccaggctg 2101 gtctcaaactcctgggctcaggcgatccacctgtctcagcctcccagagtgctgggatta 2161 caattgtgagccaccacgtccagctggaagggtcaacatcttttacattctgcaagcaca 2221 tctgcattttcaccccacccttcccctccttctccctttttatatcccatttttatatcg 2281 atctcttattttacaataaaactttgctgccacctgtgtgtctgaggggtg SEQIDNO:84HumanTP53isoformgAminoAcidSequence(NP_001119590.1, NP_001263689.1,andNP_001263690.1) 1 mddlmlspddieqwftedpgpdeaprmpeaappvapapaaptpaapapapswplsssvps 61 qktyqgsygfrlgflhsgtaksvtctyspalnkmfcqlaktcpvqlwvdstpppgtrvra 121 maiykqsqhmtevvrrcphhercsdsdglappqhlirvegnlrveylddrntfrhsvvvp 181 yeppevgsdcttihynymcnsscmggmnrrpiltiitledssgnllgrnsfevrvcacpg 241 rdrrteeenlrkkgephhelppgstkralpnntssspqpkkkpldgeyftlqirgrerfe 301 mfrelnealelkdaqagkepggsrahsshlkskkgqstsrhkklmfktegpdsd SEQIDNO:85HumanTP53transcriptvariant8cDNAsequence (NM_001126118.1;CDS:437-1501) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggcagcca 181 gactgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccc 241 tctgagtcaggaaacattttcagacctatggaaactgtgagtggatccattggaagggca 301 ggcccaccacccccaccccaaccccagccccctagcagagacctgtgggaagcgaaaatt 361 ccatgggactgactttctgctcttgtctttcagacttcctgaaaacaacgttctgtcccc 421 cttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatggtt 481 cactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgtggc 541 ccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccctgtc 601 atcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggcttctt 661 gcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagatgtt 721 ttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcccgg 781 cacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgtgag 841 gcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagcatct 901 tatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcgaca 961 tagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatccacta 1021 caactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcaccat 1081 catcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcgtgt 1141 ttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagggga 1201 gcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccagctc 1261 ctctccccagccaaagaagaaaccactggatggagaatatttcacccttcagatccgtgg 1321 gcgtgagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgccca 1381 ggctgggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaaggg 1441 tcagtctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcagactg 1501 acattctccacttcttgttccccactgacagcctcccacccccatctctccctcccctgc 1561 cattttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcaccca 1621 ggacttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgtttt 1681 gttgtggggaggaggatggggagtaggacataccagcttagattttaaggtttttactgt 1741 gagggatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatcagc 1801 cacattctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactgttg 1861 aattttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctcaca 1921 gagtgcattgtgagggttaatgaaataatgtacatctggccttgaaaccaccttttatta 1981 catggggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcggtg 2041 ggttggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctctgct 2101 ggcccagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaatct 2161 caccccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccaccaa 2221 gacttgttttatgctcagggtcaatttcttttttcttttttttttttttttttctttttc 2281 tttgagactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggctta 2341 ctgcagcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgggac 2401 cacaggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtctca 2461 cagtgttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagcctc 2521 ccagagtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatcttt 2581 tacattctgcaagcacatctgcattttcaccccacccttcccctccttctccctttttat 2641 atcccatttttatatcgatctcttattttacaataaaactttgctgccacctgtgtgtct 2701 gaggggtg SEQIDNO:86HumanTP53transcriptvariant1cDNASequence (NM_001276760.1;CDS:320-1384) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggcagcca 181 gactgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccc 241 tctgagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtc 301 ccccttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatg 361 gttcactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgt 421 ggcccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccct 481 gtcatcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggctt 541 cttgcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagat 601 gttttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcc 661 cggcacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgt 721 gaggcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagca 781 tcttatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcg 841 acatagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatcca 901 ctacaactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcac 961 catcatcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcg 1021 tgtttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagg 1081 ggagcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccag 1141 ctcctctccccagccaaagaagaaaccactggatggagaatatttcacccttcagatccg 1201 tgggcgtgagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgc 1261 ccaggctgggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaa 1321 gggtcagtctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcaga 1381 ctgacattctccacttcttgttccccactgacagcctcccacccccatctctccctcccc 1441 tgccattttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcac 1501 ccaggacttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgt 1561 tttgttgtggggaggaggatggggagtaggacataccagcttagattttaaggtttttac 1621 tgtgagggatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatc 1681 agccacattctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactg 1741 ttgaattttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctc 1801 acagagtgcattgtgagggttaatgaaataatgtacatctggccttgaaaccacctttta 1861 ttacatggggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcg 1921 gtgggttggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctct 1981 gctggcccagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaa 2041 tctcaccccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccac 2101 caagacttgttttatgctcagggtcaatttcttttttcttttttttttttttttttcttt 2161 ttctttgagactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggc 2221 ttactgcagcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgg 2281 gaccacaggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtc 2341 tcacagtgttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagc 2401 ctcccagagtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatc 2461 ttttacattctgcaagcacatctgcattttcaccccacccttcccctccttctccctttt 2521 tatatcccatttttatatcgatctcttattttacaataaaactttgctgccacctgtgtg 2581 tctgaggggtg SEQIDNO:87HumanTP53transcriptvariant2cDNASequence (NM_001276761.1;CDS:317-1381) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggccagac 181 tgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccctct 241 gagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtcccc 301 cttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatggtt 361 cactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgtggc 421 ccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccctgtc 481 atcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggcttctt 541 gcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagatgtt 601 ttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcccgg 661 cacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgtgag 721 gcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagcatct 781 tatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcgaca 841 tagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatccacta 901 caactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcaccat 961 catcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcgtgt 1021 ttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagggga 1081 gcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccagctc 1141 ctctccccagccaaagaagaaaccactggatggagaatatttcacccttcagatccgtgg 1201 gcgtgagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgccca 1261 ggctgggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaaggg 1321 tcagtctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcagactg 1381 acattctccacttcttgttccccactgacagcctcccacccccatctctccctcccctgc 1441 cattttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcaccca 1501 ggacttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgtttt 1561 gttgtggggaggaggatggggagtaggacataccagcttagattttaaggtttttactgt 1621 gagggatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatcagc 1681 cacattctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactgttg 1741 aattttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctcaca 1801 gagtgcattgtgagggttaatgaaataatgtacatctggccttgaaaccaccttttatta 1861 catggggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcggtg 1921 ggttggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctctgct 1981 ggcccagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaatct 2041 caccccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccaccaa 2101 gacttgttttatgctcagggtcaatttcttttttcttttttttttttttttttctttttc 2161 tttgagactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggctta 2221 ctgcagcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgggac 2281 cacaggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtctca 2341 cagtgttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagcctc 2401 ccagagtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatcttt 2461 tacattctgcaagcacatctgcattttcaccccacccttcccctccttctccctttttat 2521 atcccatttttatatcgatctcttattttacaataaaactttgctgccacctgtgtgtct 2581 gaggggtg SEQIDNO:88HumanTP53isoformhAminoAcidSequence(NP_001263624.1) 1 mddlmlspddieqwftedpgpdeaprmpeaappvapapaaptpaapapapswplsssvps 61 qktyqgsygfrlgflhsgtaksvtctyspalnkmfcqlaktcpvqlwvdstpppgtrvra 121 maiykqsqhmtevvrrcphhercsdsdglappqhlirvegnlrveylddrntfrhsvvvp 181 yeppevgsdcttihynymcnsscmggmnrrpiltiitledssgnllgrnsfevrvcacpg 241 rdrrteeenlrkkgephhelppgstkralpnntssspqpkkkpldgeyftlqmlldlrwc 301 yflinss SEQIDNO:89HumanTP53transcriptvariant4cDNASequence (NM_001276695.1;CDS:320-1243) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggcagcca 181 gactgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccc 241 tctgagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtc 301 ccccttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatg 361 gttcactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgt 421 ggcccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccct 481 gtcatcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggctt 541 cttgcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagat 601 gttttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcc 661 cggcacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgt 721 gaggcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagca 781 tcttatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcg 841 acatagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatcca 901 ctacaactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcac 961 catcatcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcg 1021 tgtttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagg 1081 ggagcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccag 1141 ctcctctccccagccaaagaagaaaccactggatggagaatatttcacccttcagatgct 1201 acttgacttacgatggtgttacttcctgataaactcgtcgtaagttgaaaatattatccg 1261 tgggcgtgagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgc 1321 ccaggctgggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaa 1381 gggtcagtctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcaga 1441 ctgacattctccacttcttgttccccactgacagcctcccacccccatctctccctcccc 1501 tgccattttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcac 1561 ccaggacttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgt 1621 tttgttgtggggaggaggatggggagtaggacataccagcttagattttaaggtttttac 1681 tgtgagggatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatc 1741 agccacattctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactg 1801 ttgaattttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctc 1861 acagagtgcattgtgagggttaatgaaataatgtacatctggccttgaaaccacctttta 1921 ttacatggggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcg 1981 gtgggttggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctct 2041 gctggcccagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaa 2101 tctcaccccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccac 2161 caagacttgttttatgctcagggtcaatttcttttttcttttttttttttttttttcttt 2221 ttctttgagactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggc 2281 ttactgcagcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgg 2341 gaccacaggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtc 2401 tcacagtgttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagc 2461 ctcccagagtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatc 2521 ttttacattctgcaagcacatctgcattttcaccccacccttcccctccttctccctttt 2581 tatatcccatttttatatcgatctcttattttacaataaaactttgctgccacctgtgtg 2641 tctgaggggtg SEQIDNO:90HumanTP53isoformiAminoAcidSequence(NP_001263625.1) 1 mddlmlspddieqwftedpgpdeaprmpeaappvapapaaptpaapapapswplsssvps 61 qktyqgsygfrlgflhsgtaksvtctyspalnkmfcqlaktcpvqlwvdstpppgtrvra 121 maiykqsqhmtevvrrcphhercsdsdglappqhlirvegnlrveylddrntfrhsvvvp 181 yeppevgsdcttihynymcnsscmggmnrrpiltiitledssgnllgrnsfevrvcacpg 241 rdrrteeenlrkkgephhelppgstkralpnntssspqpkkkpldgeyftlqdqtsfqke 301 nc SEQIDNO:91HumanTP53transcriptvariant3cDNAsequence (NM_001276696.1CDS:320-1228) 1 gatgggattggggttttcccctcccatgtgctcaagactggcgctaaaagttttgagctt 61 ctcaaaagtctagagccaccgtccagggagcaggtagctgctgggctccggggacacttt 121 gcgttcgggctgggagcgtgctttccacgacggtgacacgcttccctggattggcagcca 181 gactgccttccgggtcactgccatggaggagccgcagtcagatcctagcgtcgagccccc 241 tctgagtcaggaaacattttcagacctatggaaactacttcctgaaaacaacgttctgtc 301 ccccttgccgtcccaagcaatggatgatttgatgctgtccccggacgatattgaacaatg 361 gttcactgaagacccaggtccagatgaagctcccagaatgccagaggctgctccccccgt 421 ggcccctgcaccagcagctcctacaccggcggcccctgcaccagccccctcctggcccct 481 gtcatcttctgtcccttcccagaaaacctaccagggcagctacggtttccgtctgggctt 541 cttgcattctgggacagccaagtctgtgacttgcacgtactcccctgccctcaacaagat 601 gttttgccaactggccaagacctgccctgtgcagctgtgggttgattccacacccccgcc 661 cggcacccgcgtccgcgccatggccatctacaagcagtcacagcacatgacggaggttgt 721 gaggcgctgcccccaccatgagcgctgctcagatagcgatggtctggcccctcctcagca 781 tcttatccgagtggaaggaaatttgcgtgtggagtatttggatgacagaaacacttttcg 841 acatagtgtggtggtgccctatgagccgcctgaggttggctctgactgtaccaccatcca 901 ctacaactacatgtgtaacagttcctgcatgggcggcatgaaccggaggcccatcctcac 961 catcatcacactggaagactccagtggtaatctactgggacggaacagctttgaggtgcg 1021 tgtttgtgcctgtcctgggagagaccggcgcacagaggaagagaatctccgcaagaaagg 1081 ggagcctcaccacgagctgcccccagggagcactaagcgagcactgcccaacaacaccag 1141 ctcctctccccagccaaagaagaaaccactggatggagaatatttcacccttcaggacca 1201 gaccagctttcaaaaagaaaattgttaaagagagcatgaaaatggttctatgactttgcc 1261 tgatacagatgctacttgacttacgatggtgttacttcctgataaactcgtcgtaagttg 1321 aaaatattatccgtgggcgtgagcgcttcgagatgttccgagagctgaatgaggccttgg 1381 aactcaaggatgcccaggctgggaaggagccaggggggagcagggctcactccagccacc 1441 tgaagtccaaaaagggtcagtctacctcccgccataaaaaactcatgttcaagacagaag 1501 ggcctgactcagactgacattctccacttcttgttccccactgacagcctcccaccccca 1561 tctctccctcccctgccattttgggttttgggtctttgaacccttgcttgcaataggtgt 1621 gcgtcagaagcacccaggacttccatttgctttgtcccggggctccactgaacaagttgg 1681 cctgcactggtgttttgttgtggggaggaggatggggagtaggacataccagcttagatt 1741 ttaaggtttttactgtgagggatgtttgggagatgtaagaaatgttcttgcagttaaggg 1801 ttagtttacaatcagccacattctaggtaggggcccacttcaccgtactaaccagggaag 1861 ctgtccctcactgttgaattttctctaacttcaaggcccatatctgtgaaatgctggcat 1921 ttgcacctacctcacagagtgcattgtgagggttaatgaaataatgtacatctggccttg 1981 aaaccaccttttattacatggggtctagaacttgacccccttgagggtgcttgttccctc 2041 tccctgttggtcggtgggttggtagtttctacagttgggcagctggttaggtagagggag 2101 ttgtcaagtctctgctggcccagccaaaccctgtctgacaacctcttggtgaaccttagt 2161 acctaaaaggaaatctcaccccatcccacaccctggaggatttcatctcttgtatatgat 2221 gatctggatccaccaagacttgttttatgctcagggtcaatttcttttttcttttttttt 2281 tttttttttctttttctttgagactgggtctcgctttgttgcccaggctggagtggagtg 2341 gcgtgatcttggcttactgcagcctttgcctccccggctcgagcagtcctgcctcagcct 2401 ccggagtagctgggaccacaggttcatgccaccatggccagccaacttttgcatgttttg 2461 tagagatggggtctcacagtgttgcccaggctggtctcaaactcctgggctcaggcgatc 2521 cacctgtctcagcctcccagagtgctgggattacaattgtgagccaccacgtccagctgg 2581 aagggtcaacatcttttacattctgcaagcacatctgcattttcaccccacccttcccct 2641 ccttctccctttttatatcccatttttatatcgatctcttattttacaataaaactttgc 2701 tgccacctgtgtgtctgaggggtg SEQIDNO:92HumanTP53isoformjAminoAcidSequence(NP_001263626.1) 1 maiykqsqhmtevvrrcphhercsdsdglappqhlirvegnlrveylddrntfrhsvvvp 61 yeppevgsdcttihynymcnsscmggmnrrpiltiitledssgnllgrnsfevrvcacpg 121 rdrrteeenlrkkgephhelppgstkralpnntssspqpkkkpldgeyftlqirgrerfe 181 mfrelnealelkdaqagkepggsrahsshlkskkgqstsrhkklmfktegpdsd SEQIDNO:93HumanTP53transcriptvariant5cDNAsequence (NM_001276697.1;CDS:360-1064) 1 tgaggccaggagatggaggctgcagtgagctgtgatcacaccactgtgctccagcctgag 61 tgacagagcaagaccctatctcaaaaaaaaaaaaaaaaaagaaaagctcctgaggtgtag 121 acgccaactctctctagctcgctagtgggttgcaggaggtgcttacgcatgtttgtttct 181 ttgctgccgtcttccagttgctttatctgttcacttgtgccctgactttcaactctgtct 241 ccttcctcttcctacagtactcccctgccctcaacaagatgttttgccaactggccaaga 301 cctgccctgtgcagctgtgggttgattccacacccccgcccggcacccgcgtccgcgcca 361 tggccatctacaagcagtcacagcacatgacggaggttgtgaggcgctgcccccaccatg 421 agcgctgctcagatagcgatggtctggcccctcctcagcatcttatccgagtggaaggaa 481 atttgcgtgtggagtatttggatgacagaaacacttttcgacatagtgtggtggtgccct 541 atgagccgcctgaggttggctctgactgtaccaccatccactacaactacatgtgtaaca 601 gttcctgcatgggcggcatgaaccggaggcccatcctcaccatcatcacactggaagact 661 ccagtggtaatctactgggacggaacagctttgaggtgcgtgtttgtgcctgtcctggga 721 gagaccggcgcacagaggaagagaatctccgcaagaaaggggagcctcaccacgagctgc 781 ccccagggagcactaagcgagcactgcccaacaacaccagctcctctccccagccaaaga 841 agaaaccactggatggagaatatttcacccttcagatccgtgggcgtgagcgcttcgaga 901 tgttccgagagctgaatgaggccttggaactcaaggatgcccaggctgggaaggagccag 961 gggggagcagggctcactccagccacctgaagtccaaaaagggtcagtctacctcccgcc 1021 ataaaaaactcatgttcaagacagaagggcctgactcagactgacattctccacttcttg 1081 ttccccactgacagcctcccacccccatctctccctcccctgccattttgggttttgggt 1141 ctttgaacccttgcttgcaataggtgtgcgtcagaagcacccaggacttccatttgcttt 1201 gtcccggggctccactgaacaagttggcctgcactggtgttttgttgtggggaggaggat 1261 ggggagtaggacataccagcttagattttaaggtttttactgtgagggatgtttgggaga 1321 tgtaagaaatgttcttgcagttaagggttagtttacaatcagccacattctaggtagggg 1381 cccacttcaccgtactaaccagggaagctgtccctcactgttgaattttctctaacttca 1441 aggcccatatctgtgaaatgctggcatttgcacctacctcacagagtgcattgtgagggt 1501 taatgaaataatgtacatctggccttgaaaccaccttttattacatggggtctagaactt 1561 gacccccttgagggtgcttgttccctctccctgttggtcggtgggttggtagtttctaca 1621 gttgggcagctggttaggtagagggagttgtcaagtctctgctggcccagccaaaccctg 1681 tctgacaacctcttggtgaaccttagtacctaaaaggaaatctcaccccatcccacaccc 1741 tggaggatttcatctcttgtatatgatgatctggatccaccaagacttgttttatgctca 1801 gggtcaatttcttttttcttttttttttttttttttctttttctttgagactgggtctcg 1861 ctttgttgcccaggctggagtggagtggcgtgatcttggcttactgcagcctttgcctcc 1921 ccggctcgagcagtcctgcctcagcctccggagtagctgggaccacaggttcatgccacc 1981 atggccagccaacttttgcatgttttgtagagatggggtctcacagtgttgcccaggctg 2041 gtctcaaactcctgggctcaggcgatccacctgtctcagcctcccagagtgctgggatta 2101 caattgtgagccaccacgtccagctggaagggtcaacatcttttacattctgcaagcaca 2161 tctgcattttcaccccacccttcccctccttctccctttttatatcccatttttatatcg 2221 atctcttattttacaataaaactttgctgccacctgtgtgtctgaggggtg SEQIDNO:94HumanTP53isoformkAminoAcidSequence(NP_001263627.1) 1 maiykqsqhmtevvrrcphhercsdsdglappqhlirvegnlrveylddrntfrhsvvvp 61 yeppevgsdcttihynymcnsscmggmnrrpiltiitledssgnllgrnsfevrvcacpg 121 rdrrteeenlrkkgephhelppgstkralpnntssspqpkkkpldgeyftlqdqtsfqke 181 nc SEQIDNO:95HumanTP53transcriptvariant6cDNAsequence (NM_001276698.1;CDS:360-908) 1 tgaggccaggagatggaggctgcagtgagctgtgatcacaccactgtgctccagcctgag 61 tgacagagcaagaccctatctcaaaaaaaaaaaaaaaaaagaaaagctcctgaggtgtag 121 acgccaactctctctagctcgctagtgggttgcaggaggtgcttacgcatgtttgtttct 181 ttgctgccgtcttccagttgctttatctgttcacttgtgccctgactttcaactctgtct 241 ccttcctcttcctacagtactcccctgccctcaacaagatgttttgccaactggccaaga 301 cctgccctgtgcagctgtgggttgattccacacccccgcccggcacccgcgtccgcgcca 361 tggccatctacaagcagtcacagcacatgacggaggttgtgaggcgctgcccccaccatg 421 agcgctgctcagatagcgatggtctggcccctcctcagcatcttatccgagtggaaggaa 481 atttgcgtgtggagtatttggatgacagaaacacttttcgacatagtgtggtggtgccct 541 atgagccgcctgaggttggctctgactgtaccaccatccactacaactacatgtgtaaca 601 gttcctgcatgggcggcatgaaccggaggcccatcctcaccatcatcacactggaagact 661 ccagtggtaatctactgggacggaacagctttgaggtgcgtgtttgtgcctgtcctggga 721 gagaccggcgcacagaggaagagaatctccgcaagaaaggggagcctcaccacgagctgc 781 ccccagggagcactaagcgagcactgcccaacaacaccagctcctctccccagccaaaga 841 agaaaccactggatggagaatatttcacccttcaggaccagaccagctttcaaaaagaaa 901 attgttaaagagagcatgaaaatggttctatgactttgcctgatacagatgctacttgac 961 ttacgatggtgttacttcctgataaactcgtcgtaagttgaaaatattatccgtgggcgt 1021 gagcgcttcgagatgttccgagagctgaatgaggccttggaactcaaggatgcccaggct 1081 gggaaggagccaggggggagcagggctcactccagccacctgaagtccaaaaagggtcag 1141 tctacctcccgccataaaaaactcatgttcaagacagaagggcctgactcagactgacat 1201 tctccacttcttgttccccactgacagcctcccacccccatctctccctcccctgccatt 1261 ttgggttttgggtctttgaacccttgcttgcaataggtgtgcgtcagaagcacccaggac 1321 ttccatttgctttgtcccggggctccactgaacaagttggcctgcactggtgttttgttg 1381 tggggaggaggatggggagtaggacataccagcttagattttaaggtttttactgtgagg 1441 gatgtttgggagatgtaagaaatgttcttgcagttaagggttagtttacaatcagccaca 1501 ttctaggtaggggcccacttcaccgtactaaccagggaagctgtccctcactgttgaatt 1561 ttctctaacttcaaggcccatatctgtgaaatgctggcatttgcacctacctcacagagt 1621 gcattgtgagggttaatgaaataatgtacatctggccttgaaaccaccttttattacatg 1681 gggtctagaacttgacccccttgagggtgcttgttccctctccctgttggtcggtgggtt 1741 ggtagtttctacagttgggcagctggttaggtagagggagttgtcaagtctctgctggcc 1801 cagccaaaccctgtctgacaacctcttggtgaaccttagtacctaaaaggaaatctcacc 1861 ccatcccacaccctggaggatttcatctcttgtatatgatgatctggatccaccaagact 1921 tgttttatgctcagggtcaatttcttttttcttttttttttttttttttctttttctttg 1981 agactgggtctcgctttgttgcccaggctggagtggagtggcgtgatcttggcttactgc 2041 agcctttgcctccccggctcgagcagtcctgcctcagcctccggagtagctgggaccaca 2101 ggttcatgccaccatggccagccaacttttgcatgttttgtagagatggggtctcacagt 2161 gttgcccaggctggtctcaaactcctgggctcaggcgatccacctgtctcagcctcccag 2221 agtgctgggattacaattgtgagccaccacgtccagctggaagggtcaacatcttttaca 2281 ttctgcaagcacatctgcattttcaccccacccttcccctccttctccctttttatatcc 2341 catttttatatcgatctcttattttacaataaaactttgctgccacctgtgtgtctgagg 2401 ggtg SEQIDNO:96HumanTP53isoform1AminoAcidSequence(NP_0012636281) 1 maiykqsqhmtevvrrcphhercsdsdglappqhlirvegnlrveylddrntfrhsvvvp 61 yeppevgsdcttihynymcnsscmggmnrrpiltiitledssgnllgrnsfevrvcacpg 121 rdrrteeenlrkkgephhelppgstkralpnntssspqpkkkpldgeyftlqmlldlrwc 181 yflinss SEQIDNO:97HumanTP53transcriptvariant7cDNAsequence (NM_001276699.1;CDS:360-923) 1 tgaggccaggagatggaggctgcagtgagctgtgatcacaccactgtgctccagcctgag 61 tgacagagcaagaccctatctcaaaaaaaaaaaaaaaaaagaaaagctcctgaggtgtag 121 acgccaactctctctagctcgctagtgggttgcaggaggtgcttacgcatgtttgtttct 181 ttgctgccgtcttccagttgctttatctgttcacttgtgccctgactttcaactctgtct 241 ccttcctcttcctacagtactcccctgccctcaacaagatgttttgccaactggccaaga 301 cctgccctgtgcagctgtgggttgattccacacccccgcccggcacccgcgtccgcgcca 361 tggccatctacaagcagtcacagcacatgacggaggttgtgaggcgctgcccccaccatg 421 agcgctgctcagatagcgatggtctggcccctcctcagcatcttatccgagtggaaggaa 481 atttgcgtgtggagtatttggatgacagaaacacttttcgacatagtgtggtggtgccct 541 atgagccgcctgaggttggctctgactgtaccaccatccactacaactacatgtgtaaca 601 gttcctgcatgggcggcatgaaccggaggcccatcctcaccatcatcacactggaagact 661 ccagtggtaatctactgggacggaacagctttgaggtgcgtgtttgtgcctgtcctggga 721 gagaccggcgcacagaggaagagaatctccgcaagaaaggggagcctcaccacgagctgc 781 ccccagggagcactaagcgagcactgcccaacaacaccagctcctctccccagccaaaga 841 agaaaccactggatggagaatatttcacccttcagatgctacttgacttacgatggtgtt 901 acttcctgataaactcgtcgtaagttgaaaatattatccgtgggcgtgagcgcttcgaga 961 tgttccgagagctgaatgaggccttggaactcaaggatgcccaggctgggaaggagccag 1021 gggggagcagggctcactccagccacctgaagtccaaaaagggtcagtctacctcccgcc 1081 ataaaaaactcatgttcaagacagaagggcctgactcagactgacattctccacttcttg 1141 ttccccactgacagcctcccacccccatctctccctcccctgccattttgggttttgggt 1201 ctttgaacccttgcttgcaataggtgtgcgtcagaagcacccaggacttccatttgcttt 1261 gtcccggggctccactgaacaagttggcctgcactggtgttttgttgtggggaggaggat 1321 ggggagtaggacataccagcttagattttaaggtttttactgtgagggatgtttgggaga 1381 tgtaagaaatgttcttgcagttaagggttagtttacaatcagccacattctaggtagggg 1441 cccacttcaccgtactaaccagggaagctgtccctcactgttgaattttctctaacttca 1501 aggcccatatctgtgaaatgctggcatttgcacctacctcacagagtgcattgtgagggt 1561 taatgaaataatgtacatctggccttgaaaccaccttttattacatggggtctagaactt 1621 gacccccttgagggtgcttgttccctctccctgttggtcggtgggttggtagtttctaca 1681 gttgggcagctggttaggtagagggagttgtcaagtctctgctggcccagccaaaccctg 1741 tctgacaacctcttggtgaaccttagtacctaaaaggaaatctcaccccatcccacaccc 1801 tggaggatttcatctcttgtatatgatgatctggatccaccaagacttgttttatgctca 1861 gggtcaatttcttttttcttttttttttttttttttctttttctttgagactgggtctcg 1921 ctttgttgcccaggctggagtggagtggcgtgatcttggcttactgcagcctttgcctcc 1981 ccggctcgagcagtcctgcctcagcctccggagtagctgggaccacaggttcatgccacc 2041 atggccagccaacttttgcatgttttgtagagatggggtctcacagtgttgcccaggctg 2101 gtctcaaactcctgggctcaggcgatccacctgtctcagcctcccagagtgctgggatta 2161 caattgtgagccaccacgtccagctggaagggtcaacatcttttacattctgcaagcaca 2221 tctgcattttcaccccacccttcccctccttctccctttttatatcccatttttatatcg 2281 atctcttattttacaataaaactttgctgccacctgtgtgtctgaggggtg SEQIDNO:98MouseTP53isoformbAminoAcidSequence(NP_001120705.1) 1 mtameesqsdislelplsqetfsglwkllppedilpsphcmddlllpqdveeffegpsea 61 lrvsgapaaqdpvtetpgpvapapatpwplssfvpsqktyqgnygfhlgflqsgtaksvm 121 ctyspplnklfcqlaktcpvqlwvsatppagsrvramaiykksqhmtevvrrcphhercs 181 dgdglappqhlirvegnlypeyledrqtfrhsvvvpyeppeagseyttihykymcnsscm 241 ggmnrrpiltiitledssgnllgrdsfevrvcacpgrdrrteeenfrkkevlcpelppgs 301 akralptctsasppqkkkpldgeyftlkirgrkrfemfrelnealelkdahateesgdsr 361 ahsslqprafqalikeespnc SEQIDNO:99MouseTP53transcriptvariant2cDNAsequence (NM_001127233.1;CDS:158-1303) 1 tttcccctcccacgtgctcaccctggctaaagttctgtagcttcagttcattgggaccat 61 cctggctgtaggtagcgactacagttagggggcacctagcattcaggccctcatcctcct 121 ccttcccagcagggtgtcacgcttctccgaagactggatgactgccatggaggagtcaca 181 gtcggatatcagcctcgagctccctctgagccaggagacattttcaggcttatggaaact 241 acttcctccagaagatatcctgccatcacctcactgcatggacgatctgttgctgcccca 301 ggatgttgaggagttttttgaaggcccaagtgaagccctccgagtgtcaggagctcctgc 361 agcacaggaccctgtcaccgagacccctgggccagtggcccctgccccagccactccatg 421 gcccctgtcatcttttgtcccttctcaaaaaacttaccagggcaactatggcttccacct 481 gggcttcctgcagtctgggacagccaagtctgttatgtgcacgtactctcctcccctcaa 541 taagctattctgccagctggcgaagacgtgccctgtgcagttgtgggtcagcgccacacc 601 tccagctgggagccgtgtccgcgccatggccatctacaagaagtcacagcacatgacgga 661 ggtcgtgagacgctgcccccaccatgagcgctgctccgatggtgatggcctggctcctcc 721 ccagcatcttatccgggtggaaggaaatttgtatcccgagtatctggaagacaggcagac 781 ttttcgccacagcgtggtggtaccttatgagccacccgaggccggctctgagtataccac 841 catccactacaagtacatgtgtaatagctcctgcatggggggcatgaaccgccgacctat 901 ccttaccatcatcacactggaagactccagtgggaaccttctgggacgggacagctttga 961 ggttcgtgtttgtgcctgccctgggagagaccgccgtacagaagaagaaaatttccgcaa 1021 aaaggaagtcctttgccctgaactgcccccagggagcgcaaagagagcgctgcccacctg 1081 cacaagcgcctctcccccgcaaaagaaaaaaccacttgatggagagtatttcaccctcaa 1141 gatccgcgggcgtaaacgcttcgagatgttccgggagctgaatgaggccttagagttaaa 1201 ggatgcccatgctacagaggagtctggagacagcagggctcactccagcctccagcctag 1261 agccttccaagccttgatcaaggaggaaagcccaaactgctagctcccatcacttcatcc 1321 ctccccttttctgtcttcctatagctacctgaagaccaagaagggccagtctacttcccg 1381 ccataaaaaaacaatggtcaagaaagtggggcctgactcagactgactgcctctgcatcc 1441 cgtccccatcaccagcctccccctctccttgctgtcttatgacttcagggctgagacaca 1501 atcctcccggtcccttctgctgccttttttaccttgtagctagggctcagccccctctct 1561 gagtagtggttcctggcccaagttggggaataggttgatagttgtcaggtctctgctggc 1621 ccagcgaaattctatccagccagttgttggaccctggcacctacaatgaaatctcaccct 1681 accccacaccctgtaagattctatcttgggccctcatagggtccatatcctccagggcct 1741 actttccttccattctgcaaagcctgtctgcatttatccaccccccaccctgtctccctc 1801 ttttttttttttttacccctttttatatatcaatttcctattttacaataaaattttgtt 1861 atcacttaaaaaaaaaa SEQIDNO:100MouseTP53isoformaAminoAcidSequence(NP_035770.2) 1 mtameesqsdislelplsqetfsglwkllppedilpsphcmddlllpqdveeffegpsea 61 lrvsgapaaqdpvtetpgpvapapatpwplssfvpsqktyqgnygfhlgflqsgtaksvm 121 ctyspplnklfcqlaktcpvqlwvsatppagsrvramaiykksqhmtevvrrcphhercs 181 dgdglappqhlirvegnlypeyledrqtfrhsvvvpyeppeagseyttihykymcnsscm 241 ggmnrrpiltiitledssgnllgrdsfevrvcacpgrdrrteeenfrkkevlcpelppgs 301 akralptctsasppqkkkpldgeyftlkirgrkrfemfrelnealelkdahateesgdsr 361 ahssylktkkgqstsrhkktmvkkvgpdsd SEQIDNO:101MouseTP53transcriptvariant1cDNAsequence(NM_0116403; CDS:158-1330) 1 tttcccctcccacgtgctcaccctggctaaagttctgtagcttcagttcattgggaccat 61 cctggctgtaggtagcgactacagttagggggcacctagcattcaggccctcatcctcct 121 ccttcccagcagggtgtcacgcttctccgaagactggatgactgccatggaggagtcaca 181 gtcggatatcagcctcgagctccctctgagccaggagacattttcaggcttatggaaact 241 acttcctccagaagatatcctgccatcacctcactgcatggacgatctgttgctgcccca 301 ggatgttgaggagttttttgaaggcccaagtgaagccctccgagtgtcaggagctcctgc 361 agcacaggaccctgtcaccgagacccctgggccagtggcccctgccccagccactccatg 421 gcccctgtcatcttttgtcccttctcaaaaaacttaccagggcaactatggcttccacct 481 gggcttcctgcagtctgggacagccaagtctgttatgtgcacgtactctcctcccctcaa 541 taagctattctgccagctggcgaagacgtgccctgtgcagttgtgggtcagcgccacacc 601 tccagctgggagccgtgtccgcgccatggccatctacaagaagtcacagcacatgacgga 661 ggtcgtgagacgctgcccccaccatgagcgctgctccgatggtgatggcctggctcctcc 721 ccagcatcttatccgggtggaaggaaatttgtatcccgagtatctggaagacaggcagac 781 ttttcgccacagcgtggtggtaccttatgagccacccgaggccggctctgagtataccac 841 catccactacaagtacatgtgtaatagctcctgcatggggggcatgaaccgccgacctat 901 ccttaccatcatcacactggaagactccagtgggaaccttctgggacgggacagctttga 961 ggttcgtgtttgtgcctgccctgggagagaccgccgtacagaagaagaaaatttccgcaa 1021 aaaggaagtcctttgccctgaactgcccccagggagcgcaaagagagcgctgcccacctg 1081 cacaagcgcctctcccccgcaaaagaaaaaaccacttgatggagagtatttcaccctcaa 1141 gatccgcgggcgtaaacgcttcgagatgttccgggagctgaatgaggccttagagttaaa 1201 ggatgcccatgctacagaggagtctggagacagcagggctcactccagctacctgaagac 1261 caagaagggccagtctacttcccgccataaaaaaacaatggtcaagaaagtggggcctga 1321 ctcagactgactgcctctgcatcccgtccccatcaccagcctccccctctccttgctgtc 1381 ttatgacttcagggctgagacacaatcctcccggtcccttctgctgccttttttaccttg 1441 tagctagggctcagccccctctctgagtagtggttcctggcccaagttggggaataggtt 1501 gatagttgtcaggtctctgctggcccagcgaaattctatccagccagttgttggaccctg 1561 gcacctacaatgaaatctcaccctaccccacaccctgtaagattctatcttgggccctca 1621 tagggtccatatcctccagggcctactttccttccattctgcaaagcctgtctgcattta 1681 tccaccccccaccctgtctccctcttttttttttttttacccctttttatatatcaattt 1741 cctattttacaataaaattttgttatcacttaaaaaaaaaa SEQIDNO:102HumanTP73transcriptvariant1cDNAsequence(NM_005427.4; CDS:160-2070) 1 gccctgcctccccgcccgcgcacccgcccggaggctcgcgcgcccgcgaaggggacgcag 61 cgaaaccggggcccgcgccaggccagccgggacggacgccgatgcccggggctgcgacgg 121 ctgcagagcgagctgccctcggaggccggcgtggggaagatggcccagtccaccgccacc 181 tcccctgatgggggcaccacgtttgagcacctctggagctctctggaaccagacagcacc 241 tacttcgaccttccccagtcaagccgggggaataatgaggtggtgggcggaacggattcc 301 agcatggacgtcttccacctggagggcatgactacatctgtcatggcccagttcaatctg 361 ctgagcagcaccatggaccagatgagcagccgcgcggcctcggccagcccctacacccca 421 gagcacgccgccagcgtgcccacccactcgccctacgcacaacccagctccaccttcgac 481 accatgtcgccggcgcctgtcatcccctccaacaccgactaccccggaccccaccacttt 541 gaggtcactttccagcagtccagcacggccaagtcagccacctggacgtactccccgctc 601 ttgaagaaactctactgccagatcgccaagacatgccccatccagatcaaggtgtccacc 661 ccgccacccccaggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtg 721 accgacgtcgtgaaacgctgccccaaccacgagctcgggagggacttcaacgaaggacag 781 tctgctccagccagccacctcatccgcgtggaaggcaataatctctcgcagtatgtggat 841 gaccctgtcaccggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacg 901 gaattcaccaccatcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaac 961 cggcggcccatcctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgc 1021 cggtcctttgagggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggac 1081 cactaccgggagcagcaggccctgaacgagagctccgccaagaacggggccgccagcaag 1141 cgtgccttcaagcagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcgg 1201 cggcatggagacgaggacacgtactaccttcaggtgcgaggccgggagaactttgagatc 1261 ctgatgaagctgaaagagagcctggagctgatggagttggtgccgcagccactggtggac 1321 tcctatcggcagcagcagcagctcctacagaggccgagtcacctacagcccccgtcctac 1381 gggccggtcctctcgcccatgaacaaggtgcacgggggcatgaacaagctgccctccgtc 1441 aaccagctggtgggccagcctcccccgcacagttcggcagctacacccaacctggggccc 1501 gtgggccccgggatgctcaacaaccatggccacgcagtgccagccaacggcgagatgagc 1561 agcagccacagcgcccagtccatggtctcggggtcccactgcactccgccacccccctac 1621 cacgccgaccccagcctcgtcagttttttaacaggattggggtgtccaaactgcatcgag 1681 tatttcacctcccaagggttacagagcatttaccacctgcagaacctgaccattgaggac 1741 ctgggggccctgaagatccccgagcagtaccgcatgaccatctggcggggcctgcaggac 1801 ctgaagcagggccacgactacagcaccgcgcagcagctgctccgctctagcaacgcggcc 1861 accatctccatcggcggctcaggggaactgcagcgccagcgggtcatggaggccgtgcac 1921 ttccgcgtgcgccacaccatcaccatccccaaccgcggcggcccaggcggcggccctgac 1981 gagtgggcggacttcggcttcgacctgcccgactgcaaggcccgcaagcagcccatcaag 2041 gaggagttcacggaggccgagatccactgagggcctcgcctggctgcagcctgcgccacc 2101 gcccagagacccaagctgcctcccctctccttcctgtgtgtccaaaactgcctcaggagg 2161 caggaccttcgggctgtgcccggggaaaggcaaggtccggcccatccccaggcacctcac 2221 aggccccaggaaaggcccagccaccgaagccgcctgtggacagcctgagtcacctgcaga 2281 accttctggagctgccctagtgctgggcttgtggggcgggggctggcccactctcagccc 2341 tgccactgccccggcgtgctccatggcaggcgtgggtggggaccgcagcgtcggctccga 2401 cttccaggcttcatcctagagactgtcatctcccaaccaggcgaggtccttccaaaggaa 2461 aggatcctctttgctgatggactgccaaaaagtattttgcgacatcttttggttctggat 2521 agtagtgagcagccaagtgactgtgtctgaaacaccagtgtattttcagggaatgtccct 2581 aactgcgtcttgcccgcgccgggggctggggactctctctgctggacttgggactggcct 2641 ctgcccccagcacgctgtattctgcaggaccgcctccttcctgcccctaacaacaaccac 2701 agtgttgctgaaattggagaaaactggggagggcgcaaccccccccaggcgcggggaagc 2761 atgtggtaccgcctcagccagtgcccctcagcctggccacagtcgcctctcctcggggac 2821 ccctcagcagaaagggacagcctgtccttagaggactggaaattgtcaatatttgataaa 2881 atgatacccttttctacatggtgggtcagcttttttttttttttttttaactttctttct 2941 cagcattctctttggagttcaacctagcgcccatgagccaggctgaggaagctgagtgag 3001 aagccaggtgggcgggacttgttcccaggaaggccgggtggggaggaagcctagagggaa 3061 ccccaggaagggcaaatccaggcaaatctgcaggaatgctctgccatgggagcagctcct 3121 cccttgccacggccaccttctctagcactgcaaggtccacagggcattgctttcctttct 3181 aggcggtggcagtcagggaacagactgaggtaggtgtaggggggtctaggccttcgtgga 3241 gcaccccagggagttagtaggccccggggagacagagtctgcacaggccctttctggggc 3301 cacctccatccacgaggagcagcctgagccttggtggccgaaccttgaccgtcccggagc 3361 acagcttcagggcagggaaccggagcccctggggggcctcacgggtgtgacgaggccctt 3421 cattgcaggcaggtgggccaatgggagccctcacccacgcaagccgagacaccacccaga 3481 gtgcaggctgcctggccccttctggcacggccagctccacaccccctgcctagggtatgt 3541 gtggtcctaagggctaggagcttcccctactaacatctcccagaaaaagcagttaagccc 3601 ctcagggcacagcaaggttagacacagcccccatccccagatcaggactccatcttgcta 3661 agtggcatcaccgtcaccagcctccccttatttaaaagcagcgactggtgttgccgcagg 3721 tacctggtctacgaagacgcaggcatccctctcccaccgtccacctccccgggggccgct 3781 gacagcacagtcgcctgggtgcacgcttgtgggggcagcaggaacggggctgtcggctct 3841 caggggatctggctgcagccagggcgagggcctggcccttccttccagctccttccggct 3901 ccttccagctgaagggcaggaagctctggccgcttagcttctagggttccatctccctag 3961 aaaggtgcccacgcccagggcatcagtcagtagcggcagcagcagcagactcggggcttt 4021 cccagggtggcgcagccaccccagctgcatgtcacctcagctctccatcttattgccatt 4081 ttgtagatgaggaagctgagaccagaaaggctaagacccatgccccaggcaccacaccca 4141 tctcttgggggctgggcacctgctacccgaggccacctcctgaagcccccactcttcccc 4201 catgttccacttcaggagccgcgggggcccatcctgacacccggggttcctcagcccagc 4261 gcagatgtgcttcagttccagagggcttgttgatttgtttcttaggtacgttacctgtcc 4321 accctgagtccagtgaggctgtcccaagagcccctgtagtgtgctcctgggaagggctgg 4381 gggggctgggggggctgggagaggcccaggggcagctgtcactggaaccccagccagatg 4441 tccaaggaagccggccagaacacggagcagccagatggccccagctgcacctgtctaggg 4501 agcccatgcagcctccttgcactggagaagcagctgtgaaagtagacagagttgagactt 4561 cgccgtggtcaggagaaaatgcaaattcccaggaacaagaatcctttaagtgatatgttt 4621 ttataaaactaaacaaatcaacaaataaatcttgaaggcggatggttttcccagcagtgc 4681 aggggttggagggaggctgctggcactcctggggccaagggggacaggcagtggtcctga 4741 gtctgctcagagaggcaaggcagaaggagctcgccaggcaggtcagctcacatctgtcca 4801 agtcgctctggtcagaaacagcgactctcccccattcccccagcgttcccaccaggcctg 4861 ggctgctgggaagcccttgctgtacccaggagcccgacccgcagtatcctggcacagagc 4921 cacttgtcactcagaacagtcagtgtctccaacgcacaaacatccactcctctgttacca 4981 gttaaagcactttaatgctttaaggtgaaaacgaaatcccatccgtgtttttcgtgtaag 5041 atcgtgcttctccgagcagtattaatggacgccctccaatgacataacaactgtttttgg 5101 taatgtaatcttgggaaaatgtgttatttttttagctgtgtttcagtggggatttttgtt 5161 tttgtaacataataaagtgtatgttccaatga SEQIDNO:103HumanTP73isoform1aminoacidsequence(NP_005418.1) 1 maqstatspdggttfehlwsslepdstyfdlpqssrgnnevvggtdssmdvfhlegmtts 61 vmaqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntd 121 ypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampv 181 ykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpy 241 eppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgr 301 drkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvr 361 grenfeilmklkeslelmelvpqplvdsyrqqqqllqrpshlqppsygpvlspmnkvhgg 421 mnklpsvnqlvgqppphssaatpnlgpvgpgmlnnhghavpangemssshsaqsmvsgsh 481 ctppppyhadpslvsfltglgcpncieyftsqglqsiyhlqnltiedlgalkipeqyrmt 541 iwrglqdlkqghdystaqqllrssnaatisiggsgelqrqrvmeavhfrvrhtitipnrg 601 gpgggpdewadfgfdlpdckarkqpikeefteaeih SEQIDNO:104HumanTP73transcriptvariant2cDNAsequence (NM_001126240.3;CDS:235-1998) 1 ggattcagccagttgacagaactaagggagatgggaaaagcgaaaatgccaacaaacggc 61 ccgcatgttccccagcatcctcggctcctgcctcactagctgcggagcctctcccgctcg 121 gtccacgctgccgggcggccacgaccgtgacccttcccctcgggccgcccagatccatgc 181 ctcgtcccacgggacaccagttccctggcgtgtgcagaccccccggcgcctaccatgctg 241 tacgtcggtgaccccgcacggcacctcgccacggcccagttcaatctgctgagcagcacc 301 atggaccagatgagcagccgcgcggcctcggccagcccctacaccccagagcacgccgcc 361 agcgtgcccacccactcgccctacgcacaacccagctccaccttcgacaccatgtcgccg 421 gcgcctgtcatcccctccaacaccgactaccccggaccccaccactttgaggtcactttc 481 cagcagtccagcacggccaagtcagccacctggacgtactccccgctcttgaagaaactc 541 tactgccagatcgccaagacatgccccatccagatcaaggtgtccaccccgccaccccca 601 ggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtgaccgacgtcgtg 661 aaacgctgccccaaccacgagctcgggagggacttcaacgaaggacagtctgctccagcc 721 agccacctcatccgcgtggaaggcaataatctctcgcagtatgtggatgaccctgtcacc 781 ggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacggaattcaccacc 841 atcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaaccggcggcccatc 901 ctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgccggtcctttgag 961 ggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggaccactaccgggag 1021 cagcaggccctgaacgagagctccgccaagaacggggccgccagcaagcgtgccttcaag 1081 cagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcggcggcatggagac 1141 gaggacacgtactaccttcaggtgcgaggccgggagaactttgagatcctgatgaagctg 1201 aaagagagcctggagctgatggagttggtgccgcagccactggtggactcctatcggcag 1261 cagcagcagctcctacagaggccgagtcacctacagcccccgtcctacgggccggtcctc 1321 tcgcccatgaacaaggtgcacgggggcatgaacaagctgccctccgtcaaccagctggtg 1381 ggccagcctcccccgcacagttcggcagctacacccaacctggggcccgtgggccccggg 1441 atgctcaacaaccatggccacgcagtgccagccaacggcgagatgagcagcagccacagc 1501 gcccagtccatggtctcggggtcccactgcactccgccacccccctaccacgccgacccc 1561 agcctcgtcagttttttaacaggattggggtgtccaaactgcatcgagtatttcacctcc 1621 caagggttacagagcatttaccacctgcagaacctgaccattgaggacctgggggccctg 1681 aagatccccgagcagtaccgcatgaccatctggcggggcctgcaggacctgaagcagggc 1741 cacgactacagcaccgcgcagcagctgctccgctctagcaacgcggccaccatctccatc 1801 ggcggctcaggggaactgcagcgccagcgggtcatggaggccgtgcacttccgcgtgcgc 1861 cacaccatcaccatccccaaccgcggcggcccaggcggcggccctgacgagtgggcggac 1921 ttcggcttcgacctgcccgactgcaaggcccgcaagcagcccatcaaggaggagttcacg 1981 gaggccgagatccactgagggcctcgcctggctgcagcctgcgccaccgcccagagaccc 2041 aagctgcctcccctctccttcctgtgtgtccaaaactgcctcaggaggcaggaccttcgg 2101 gctgtgcccggggaaaggcaaggtccggcccatccccaggcacctcacaggccccaggaa 2161 aggcccagccaccgaagccgcctgtggacagcctgagtcacctgcagaaccttctggagc 2221 tgccctagtgctgggcttgtggggcgggggctggcccactctcagccctgccactgcccc 2281 ggcgtgctccatggcaggcgtgggtggggaccgcagcgtcggctccgacttccaggcttc 2341 atcctagagactgtcatctcccaaccaggcgaggtccttccaaaggaaaggatcctcttt 2401 gctgatggactgccaaaaagtattttgcgacatcttttggttctggatagtagtgagcag 2461 ccaagtgactgtgtctgaaacaccagtgtattttcagggaatgtccctaactgcgtcttg 2521 cccgcgccgggggctggggactctctctgctggacttgggactggcctctgcccccagca 2581 cgctgtattctgcaggaccgcctccttcctgcccctaacaacaaccacagtgttgctgaa 2641 attggagaaaactggggagggcgcaaccccccccaggcgcggggaagcatgtggtaccgc 2701 ctcagccagtgcccctcagcctggccacagtcgcctctcctcggggacccctcagcagaa 2761 agggacagcctgtccttagaggactggaaattgtcaatatttgataaaatgatacccttt 2821 tctacatggtgggtcagcttttttttttttttttttaactttctttctcagcattctctt 2881 tggagttcaacctagcgcccatgagccaggctgaggaagctgagtgagaagccaggtggg 2941 cgggacttgttcccaggaaggccgggtggggaggaagcctagagggaaccccaggaaggg 3001 caaatccaggcaaatctgcaggaatgctctgccatgggagcagctcctcccttgccacgg 3061 ccaccttctctagcactgcaaggtccacagggcattgctttcctttctaggcggtggcag 3121 tcagggaacagactgaggtaggtgtaggggggtctaggccttcgtggagcaccccaggga 3181 gttagtaggccccggggagacagagtctgcacaggccctttctggggccacctccatcca 3241 cgaggagcagcctgagccttggtggccgaaccttgaccgtcccggagcacagcttcaggg 3301 cagggaaccggagcccctggggggcctcacgggtgtgacgaggcccttcattgcaggcag 3361 gtgggccaatgggagccctcacccacgcaagccgagacaccacccagagtgcaggctgcc 3421 tggccccttctggcacggccagctccacaccccctgcctagggtatgtgtggtcctaagg 3481 gctaggagcttcccctactaacatctcccagaaaaagcagttaagcccctcagggcacag 3541 caaggttagacacagcccccatccccagatcaggactccatcttgctaagtggcatcacc 3601 gtcaccagcctccccttatttaaaagcagcgactggtgttgccgcaggtacctggtctac 3661 gaagacgcaggcatccctctcccaccgtccacctccccgggggccgctgacagcacagtc 3721 gcctgggtgcacgcttgtgggggcagcaggaacggggctgtcggctctcaggggatctgg 3781 ctgcagccagggcgagggcctggcccttccttccagctccttccggctccttccagctga 3841 agggcaggaagctctggccgcttagcttctagggttccatctccctagaaaggtgcccac 3901 gcccagggcatcagtcagtagcggcagcagcagcagactcggggctttcccagggtggcg 3961 cagccaccccagctgcatgtcacctcagctctccatcttattgccattttgtagatgagg 4021 aagctgagaccagaaaggctaagacccatgccccaggcaccacacccatctcttgggggc 4081 tgggcacctgctacccgaggccacctcctgaagcccccactcttcccccatgttccactt 4141 caggagccgcgggggcccatcctgacacccggggttcctcagcccagcgcagatgtgctt 4201 cagttccagagggcttgttgatttgtttcttaggtacgttacctgtccaccctgagtcca 4261 gtgaggctgtcccaagagcccctgtagtgtgctcctgggaagggctgggggggctggggg 4321 ggctgggagaggcccaggggcagctgtcactggaaccccagccagatgtccaaggaagcc 4381 ggccagaacacggagcagccagatggccccagctgcacctgtctagggagcccatgcagc 4441 ctccttgcactggagaagcagctgtgaaagtagacagagttgagacttcgccgtggtcag 4501 gagaaaatgcaaattcccaggaacaagaatcctttaagtgatatgtttttataaaactaa 4561 acaaatcaacaaataaatcttgaaggcggatggttttcccagcagtgcaggggttggagg 4621 gaggctgctggcactcctggggccaagggggacaggcagtggtcctgagtctgctcagag 4681 aggcaaggcagaaggagctcgccaggcaggtcagctcacatctgtccaagtcgctctggt 4741 cagaaacagcgactctcccccattcccccagcgttcccaccaggcctgggctgctgggaa 4801 gcccttgctgtacccaggagcccgacccgcagtatcctggcacagagccacttgtcactc 4861 agaacagtcagtgtctccaacgcacaaacatccactcctctgttaccagttaaagcactt 4921 taatgctttaaggtgaaaacgaaatcccatccgtgtttttcgtgtaagatcgtgcttctc 4981 cgagcagtattaatggacgccctccaatgacataacaactgtttttggtaatgtaatctt 5041 gggaaaatgtgttatttttttagctgtgtttcagtggggatttttgtttttgtaacataa 5101 taaagtgtatgttccaatga SEQIDNO:105HumanTP73isoform2aminoacidsequence(NP_001119712.1) 1 mlyvgdparhlataqfnilsstmdqmssraasaspytpehaasvpthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrh 301 gdedtyylqvrgrenfeilmklkeslelmelvpqplvdsyrqqqqllqrpshlqppsygp 361 vlspmnkvhggmnklpsvnqlvgqppphssaatpnlgpvgpgmlnnhghavpangemsss 421 hsaqsmvsgshctppppyhadpslvsfltglgcpncieyftsqglqsiyhlqnitiedlg 481 alkipeqyrmtiwrglqdlkqghdystaqqllrssnaatisiggsgelqrqrvmeavhfr 541 vrhtitipnrggpgggpdewadfgfdlpdckarkqpikeefteaeih SEQIDNO:106HumanTP73transcriptvariant3cDNAsequence (NM_001126241.3;CDS:235-1587) 1 ggattcagccagttgacagaactaagggagatgggaaaagcgaaaatgccaacaaacggc 61 ccgcatgttccccagcatcctcggctcctgcctcactagctgcggagcctctcccgctcg 121 gtccacgctgccgggcggccacgaccgtgacccttcccctcgggccgcccagatccatgc 181 ctcgtcccacgggacaccagttccctggcgtgtgcagaccccccggcgcctaccatgctg 241 tacgtcggtgaccccgcacggcacctcgccacggcccagttcaatctgctgagcagcacc 301 atggaccagatgagcagccgcgcggcctcggccagcccctacaccccagagcacgccgcc 361 agcgtgcccacccactcgccctacgcacaacccagctccaccttcgacaccatgtcgccg 421 gcgcctgtcatcccctccaacaccgactaccccggaccccaccactttgaggtcactttc 481 cagcagtccagcacggccaagtcagccacctggacgtactccccgctcttgaagaaactc 541 tactgccagatcgccaagacatgccccatccagatcaaggtgtccaccccgccaccccca 601 ggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtgaccgacgtcgtg 661 aaacgctgccccaaccacgagctcgggagggacttcaacgaaggacagtctgctccagcc 721 agccacctcatccgcgtggaaggcaataatctctcgcagtatgtggatgaccctgtcacc 781 ggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacggaattcaccacc 841 atcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaaccggcggcccatc 901 ctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgccggtcctttgag 961 ggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggaccactaccgggag 1021 cagcaggccctgaacgagagctccgccaagaacggggccgccagcaagcgtgccttcaag 1081 cagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcggcggcatggagac 1141 gaggacacgtactaccttcaggtgcgaggccgggagaactttgagatcctgatgaagctg 1201 aaagagagcctggagctgatggagttggtgccgcagccactggtggactcctatcggcag 1261 cagcagcagctcctacagaggccgagtcacctacagcccccgtcctacgggccggtcctc 1321 tcgcccatgaacaaggtgcacgggggcatgaacaagctgccctccgtcaaccagctggtg 1381 ggccagcctcccccgcacagttcggcagctacacccaacctggggcccgtgggccccggg 1441 atgctcaacaaccatggccacgcagtgccagccaacggcgagatgagcagcagccacagc 1501 gcccagtccatggtctcggggtcccactgcactccgccacccccctaccacgccgacccc 1561 agcctcgtcaggacctgggggccctgaagatccccgagcagtaccgcatgaccatctggc 1621 ggggcctgcaggacctgaagcagggccacgactacagcaccgcgcagcagctgctccgct 1681 ctagcaacgcggccaccatctccatcggcggctcaggggaactgcagcgccagcgggtca 1741 tggaggccgtgcacttccgcgtgcgccacaccatcaccatccccaaccgcggcggcccag 1801 gcggcggccctgacgagtgggcggacttcggcttcgacctgcccgactgcaaggcccgca 1861 agcagcccatcaaggaggagttcacggaggccgagatccactgagggcctcgcctggctg 1921 cagcctgcgccaccgcccagagacccaagctgcctcccctctccttcctgtgtgtccaaa 1981 actgcctcaggaggcaggaccttcgggctgtgcccggggaaaggcaaggtccggcccatc 2041 cccaggcacctcacaggccccaggaaaggcccagccaccgaagccgcctgtggacagcct 2101 gagtcacctgcagaaccttctggagctgccctagtgctgggcttgtggggcgggggctgg 2161 cccactctcagccctgccactgccccggcgtgctccatggcaggcgtgggtggggaccgc 2221 agcgtcggctccgacttccaggcttcatcctagagactgtcatctcccaaccaggcgagg 2281 tccttccaaaggaaaggatcctctttgctgatggactgccaaaaagtattttgcgacatc 2341 ttttggttctggatagtagtgagcagccaagtgactgtgtctgaaacaccagtgtatttt 2401 cagggaatgtccctaactgcgtcttgcccgcgccgggggctggggactctctctgctgga 2461 cttgggactggcctctgcccccagcacgctgtattctgcaggaccgcctccttcctgccc 2521 ctaacaacaaccacagtgttgctgaaattggagaaaactggggagggcgcaacccccccc 2581 aggcgcggggaagcatgtggtaccgcctcagccagtgcccctcagcctggccacagtcgc 2641 ctctcctcggggacccctcagcagaaagggacagcctgtccttagaggactggaaattgt 2701 caatatttgataaaatgatacccttttctacatggtgggtcagctttttttttttttttt 2761 ttaactttctttctcagcattctctttggagttcaacctagcgcccatgagccaggctga 2821 ggaagctgagtgagaagccaggtgggcgggacttgttcccaggaaggccgggtggggagg 2881 aagcctagagggaaccccaggaagggcaaatccaggcaaatctgcaggaatgctctgcca 2941 tgggagcagctcctcccttgccacggccaccttctctagcactgcaaggtccacagggca 3001 ttgctttcctttctaggcggtggcagtcagggaacagactgaggtaggtgtaggggggtc 3061 taggccttcgtggagcaccccagggagttagtaggccccggggagacagagtctgcacag 3121 gccctttctggggccacctccatccacgaggagcagcctgagccttggtggccgaacctt 3181 gaccgtcccggagcacagcttcagggcagggaaccggagcccctggggggcctcacgggt 3241 gtgacgaggcccttcattgcaggcaggtgggccaatgggagccctcacccacgcaagccg 3301 agacaccacccagagtgcaggctgcctggccccttctggcacggccagctccacaccccc 3361 tgcctagggtatgtgtggtcctaagggctaggagcttcccctactaacatctcccagaaa 3421 aagcagttaagcccctcagggcacagcaaggttagacacagcccccatccccagatcagg 3481 actccatcttgctaagtggcatcaccgtcaccagcctccccttatttaaaagcagcgact 3541 ggtgttgccgcaggtacctggtctacgaagacgcaggcatccctctcccaccgtccacct 3601 ccccgggggccgctgacagcacagtcgcctgggtgcacgcttgtgggggcagcaggaacg 3661 gggctgtcggctctcaggggatctggctgcagccagggcgagggcctggcccttccttcc 3721 agctccttccggctccttccagctgaagggcaggaagctctggccgcttagcttctaggg 3781 ttccatctccctagaaaggtgcccacgcccagggcatcagtcagtagcggcagcagcagc 3841 agactcggggctttcccagggtggcgcagccaccccagctgcatgtcacctcagctctcc 3901 atcttattgccattttgtagatgaggaagctgagaccagaaaggctaagacccatgcccc 3961 aggcaccacacccatctcttgggggctgggcacctgctacccgaggccacctcctgaagc 4021 ccccactcttcccccatgttccacttcaggagccgcgggggcccatcctgacacccgggg 4081 ttcctcagcccagcgcagatgtgcttcagttccagagggcttgttgatttgtttcttagg 4141 tacgttacctgtccaccctgagtccagtgaggctgtcccaagagcccctgtagtgtgctc 4201 ctgggaagggctgggggggctgggggggctgggagaggcccaggggcagctgtcactgga 4261 accccagccagatgtccaaggaagccggccagaacacggagcagccagatggccccagct 4321 gcacctgtctagggagcccatgcagcctccttgcactggagaagcagctgtgaaagtaga 4381 cagagttgagacttcgccgtggtcaggagaaaatgcaaattcccaggaacaagaatcctt 4441 taagtgatatgtttttataaaactaaacaaatcaacaaataaatcttgaaggcggatggt 4501 tttcccagcagtgcaggggttggagggaggctgctggcactcctggggccaagggggaca 4561 ggcagtggtcctgagtctgctcagagaggcaaggcagaaggagctcgccaggcaggtcag 4621 ctcacatctgtccaagtcgctctggtcagaaacagcgactctcccccattcccccagcgt 4681 tcccaccaggcctgggctgctgggaagcccttgctgtacccaggagcccgacccgcagta 4741 tcctggcacagagccacttgtcactcagaacagtcagtgtctccaacgcacaaacatcca 4801 ctcctctgttaccagttaaagcactttaatgctttaaggtgaaaacgaaatcccatccgt 4861 gtttttcgtgtaagatcgtgcttctccgagcagtattaatggacgccctccaatgacata 4921 acaactgtttttggtaatgtaatcttgggaaaatgtgttatttttttagctgtgtttcag 4981 tggggatttttgtttttgtaacataataaagtgtatgttccaatga SEQIDNO:107HumanTP73isoform3aminoacidsequence(NP_001119713.1) 1 mlyvgdparhlataqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrh 301 gdedtyylqvrgrenfeilmklkeslelmelvpqplvdsyrqqqqllqrpshlqppsygp 361 vlspmnkvhggmnklpsvnqlvgqppphssaatpnlgpvgpgmlnnhghavpangemsss 421 hsaqsmvsgshctppppyhadpslvrtwgp SEQIDNO:108HumanTP73transcriptvariant4cDNAsequence (NM_001126242.3;CDS:235-1515) 1 ggattcagccagttgacagaactaagggagatgggaaaagcgaaaatgccaacaaacggc 61 ccgcatgttccccagcatcctcggctcctgcctcactagctgcggagcctctcccgctcg 121 gtccacgctgccgggcggccacgaccgtgacccttcccctcgggccgcccagatccatgc 181 ctcgtcccacgggacaccagttccctggcgtgtgcagaccccccggcgcctaccatgctg 241 tacgtcggtgaccccgcacggcacctcgccacggcccagttcaatctgctgagcagcacc 301 atggaccagatgagcagccgcgcggcctcggccagcccctacaccccagagcacgccgcc 361 agcgtgcccacccactcgccctacgcacaacccagctccaccttcgacaccatgtcgccg 421 gcgcctgtcatcccctccaacaccgactaccccggaccccaccactttgaggtcactttc 481 cagcagtccagcacggccaagtcagccacctggacgtactccccgctcttgaagaaactc 541 tactgccagatcgccaagacatgccccatccagatcaaggtgtccaccccgccaccccca 601 ggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtgaccgacgtcgtg 661 aaacgctgccccaaccacgagctcgggagggacttcaacgaaggacagtctgctccagcc 721 agccacctcatccgcgtggaaggcaataatctctcgcagtatgtggatgaccctgtcacc 781 ggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacggaattcaccacc 841 atcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaaccggcggcccatc 901 ctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgccggtcctttgag 961 ggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggaccactaccgggag 1021 cagcaggccctgaacgagagctccgccaagaacggggccgccagcaagcgtgccttcaag 1081 cagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcggcggcatggagac 1141 gaggacacgtactaccttcaggtgcgaggccgggagaactttgagatcctgatgaagctg 1201 aaagagagcctggagctgatggagttggtgccgcagccactggtggactcctatcggcag 1261 cagcagcagctcctacagaggccgccccgggatgctcaacaaccatggccacgcagtgcc 1321 agccaacggcgagatgagcagcagccacagcgcccagtccatggtctcggggtcccactg 1381 cactccgccacccccctaccacgccgaccccagcctcgtcagttttttaacaggattggg 1441 gtgtccaaactgcatcgagtatttcacctcccaagggttacagagcatttaccacctgca 1501 gaacctgaccattgaggacctgggggccctgaagatccccgagcagtaccgcatgaccat 1561 ctggcggggcctgcaggacctgaagcagggccacgactacagcaccgcgcagcagctgct 1621 ccgctctagcaacgcggccaccatctccatcggcggctcaggggaactgcagcgccagcg 1681 ggtcatggaggccgtgcacttccgcgtgcgccacaccatcaccatccccaaccgcggcgg 1741 cccaggcggcggccctgacgagtgggcggacttcggcttcgacctgcccgactgcaaggc 1801 ccgcaagcagcccatcaaggaggagttcacggaggccgagatccactgagggcctcgcct 1861 ggctgcagcctgcgccaccgcccagagacccaagctgcctcccctctccttcctgtgtgt 1921 ccaaaactgcctcaggaggcaggaccttcgggctgtgcccggggaaaggcaaggtccggc 1981 ccatccccaggcacctcacaggccccaggaaaggcccagccaccgaagccgcctgtggac 2041 agcctgagtcacctgcagaaccttctggagctgccctagtgctgggcttgtggggcgggg 2101 gctggcccactctcagccctgccactgccccggcgtgctccatggcaggcgtgggtgggg 2161 accgcagcgtcggctccgacttccaggcttcatcctagagactgtcatctcccaaccagg 2221 cgaggtccttccaaaggaaaggatcctctttgctgatggactgccaaaaagtattttgcg 2281 acatcttttggttctggatagtagtgagcagccaagtgactgtgtctgaaacaccagtgt 2341 attttcagggaatgtccctaactgcgtcttgcccgcgccgggggctggggactctctctg 2401 ctggacttgggactggcctctgcccccagcacgctgtattctgcaggaccgcctccttcc 2461 tgcccctaacaacaaccacagtgttgctgaaattggagaaaactggggagggcgcaaccc 2521 cccccaggcgcggggaagcatgtggtaccgcctcagccagtgcccctcagcctggccaca 2581 gtcgcctctcctcggggacccctcagcagaaagggacagcctgtccttagaggactggaa 2641 attgtcaatatttgataaaatgatacccttttctacatggtgggtcagcttttttttttt 2701 tttttttaactttctttctcagcattctctttggagttcaacctagcgcccatgagccag 2761 gctgaggaagctgagtgagaagccaggtgggcgggacttgttcccaggaaggccgggtgg 2821 ggaggaagcctagagggaaccccaggaagggcaaatccaggcaaatctgcaggaatgctc 2881 tgccatgggagcagctcctcccttgccacggccaccttctctagcactgcaaggtccaca 2941 gggcattgctttcctttctaggcggtggcagtcagggaacagactgaggtaggtgtaggg 3001 gggtctaggccttcgtggagcaccccagggagttagtaggccccggggagacagagtctg 3061 cacaggccctttctggggccacctccatccacgaggagcagcctgagccttggtggccga 3121 accttgaccgtcccggagcacagcttcagggcagggaaccggagcccctggggggcctca 3181 cgggtgtgacgaggcccttcattgcaggcaggtgggccaatgggagccctcacccacgca 3241 agccgagacaccacccagagtgcaggctgcctggccccttctggcacggccagctccaca 3301 ccccctgcctagggtatgtgtggtcctaagggctaggagcttcccctactaacatctccc 3361 agaaaaagcagttaagcccctcagggcacagcaaggttagacacagcccccatccccaga 3421 tcaggactccatcttgctaagtggcatcaccgtcaccagcctccccttatttaaaagcag 3481 cgactggtgttgccgcaggtacctggtctacgaagacgcaggcatccctctcccaccgtc 3541 cacctccccgggggccgctgacagcacagtcgcctgggtgcacgcttgtgggggcagcag 3601 gaacggggctgtcggctctcaggggatctggctgcagccagggcgagggcctggcccttc 3661 cttccagctccttccggctccttccagctgaagggcaggaagctctggccgcttagcttc 3721 tagggttccatctccctagaaaggtgcccacgcccagggcatcagtcagtagcggcagca 3781 gcagcagactcggggctttcccagggtggcgcagccaccccagctgcatgtcacctcagc 3841 tctccatcttattgccattttgtagatgaggaagctgagaccagaaaggctaagacccat 3901 gccccaggcaccacacccatctcttgggggctgggcacctgctacccgaggccacctcct 3961 gaagcccccactcttcccccatgttccacttcaggagccgcgggggcccatcctgacacc 4021 cggggttcctcagcccagcgcagatgtgcttcagttccagagggcttgttgatttgtttc 4081 ttaggtacgttacctgtccaccctgagtccagtgaggctgtcccaagagcccctgtagtg 4141 tgctcctgggaagggctgggggggctgggggggctgggagaggcccaggggcagctgtca 4201 ctggaaccccagccagatgtccaaggaagccggccagaacacggagcagccagatggccc 4261 cagctgcacctgtctagggagcccatgcagcctccttgcactggagaagcagctgtgaaa 4321 gtagacagagttgagacttcgccgtggtcaggagaaaatgcaaattcccaggaacaagaa 4381 tcctttaagtgatatgtttttataaaactaaacaaatcaacaaataaatcttgaaggcgg 4441 atggttttcccagcagtgcaggggttggagggaggctgctggcactcctggggccaaggg 4501 ggacaggcagtggtcctgagtctgctcagagaggcaaggcagaaggagctcgccaggcag 4561 gtcagctcacatctgtccaagtcgctctggtcagaaacagcgactctcccccattccccc 4621 agcgttcccaccaggcctgggctgctgggaagcccttgctgtacccaggagcccgacccg 4681 cagtatcctggcacagagccacttgtcactcagaacagtcagtgtctccaacgcacaaac 4741 atccactcctctgttaccagttaaagcactttaatgctttaaggtgaaaacgaaatccca 4801 tccgtgtttttcgtgtaagatcgtgcttctccgagcagtattaatggacgccctccaatg 4861 acataacaactgtttttggtaatgtaatcttgggaaaatgtgttatttttttagctgtgt 4921 ttcagtggggatttttgtttttgtaacataataaagtgtatgttccaatga SEQIDNO:109HumanTP73isoform4aminoacidsequence(NP_001119714.1) 1 mlyvgdparhlataqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrh 301 gdedtyylqvrgrenfeilmklkesleimeivpqpivdsyrqqqqllqrpprdaqqpwpr 361 sasqrrdeqqpqrpvhglgvplhsatplprrpqprqffnrigvsklhrvfhlprvtehlp 421 paepdh SEQIDNO:110HumanTP73transcriptvariant5cDNAsequence (NM_001204189.2;CDS:235-1299) 1 ggattcagccagttgacagaactaagggagatgggaaaagcgaaaatgccaacaaacggc 61 ccgcatgttccccagcatcctcggctcctgcctcactagctgcggagcctctcccgctcg 121 gtccacgctgccgggcggccacgaccgtgacccttcccctcgggccgcccagatccatgc 181 ctcgtcccacgggacaccagttccctggcgtgtgcagaccccccggcgcctaccatgctg 241 tacgtcggtgaccccgcacggcacctcgccacggcccagttcaatctgctgagcagcacc 301 atggaccagatgagcagccgcgcggcctcggccagcccctacaccccagagcacgccgcc 361 agcgtgcccacccactcgccctacgcacaacccagctccaccttcgacaccatgtcgccg 421 gcgcctgtcatcccctccaacaccgactaccccggaccccaccactttgaggtcactttc 481 cagcagtccagcacggccaagtcagccacctggacgtactccccgctcttgaagaaactc 541 tactgccagatcgccaagacatgccccatccagatcaaggtgtccaccccgccaccccca 601 ggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtgaccgacgtcgtg 661 aaacgctgccccaaccacgagctcgggagggacttcaacgaaggacagtctgctccagcc 721 agccacctcatccgcgtggaaggcaataatctctcgcagtatgtggatgaccctgtcacc 781 ggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacggaattcaccacc 841 atcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaaccggcggcccatc 901 ctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgccggtcctttgag 961 ggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggaccactaccgggag 1021 cagcaggccctgaacgagagctccgccaagaacggggccgccagcaagcgtgccttcaag 1081 cagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcggcggcatggagac 1141 gaggacacgtactaccttcaggtgcgaggccgggagaactttgagatcctgatgaagctg 1201 aaagagagcctggagctgatggagttggtgccgcagccactggtggactcctatcggcag 1261 cagcagcagctcctacagaggccgacctgggggccctgaagatccccgagcagtaccgca 1321 tgaccatctggcggggcctgcaggacctgaagcagggccacgactacagcaccgcgcagc 1381 agctgctccgctctagcaacgcggccaccatctccatcggcggctcaggggaactgcagc 1441 gccagcgggtcatggaggccgtgcacttccgcgtgcgccacaccatcaccatccccaacc 1501 gcggcggcccaggcggcggccctgacgagtgggcggacttcggcttcgacctgcccgact 1561 gcaaggcccgcaagcagcccatcaaggaggagttcacggaggccgagatccactgagggc 1621 ctcgcctggctgcagcctgcgccaccgcccagagacccaagctgcctcccctctccttcc 1681 tgtgtgtccaaaactgcctcaggaggcaggaccttcgggctgtgcccggggaaaggcaag 1741 gtccggcccatccccaggcacctcacaggccccaggaaaggcccagccaccgaagccgcc 1801 tgtggacagcctgagtcacctgcagaaccttctggagctgccctagtgctgggcttgtgg 1861 ggcgggggctggcccactctcagccctgccactgccccggcgtgctccatggcaggcgtg 1921 ggtggggaccgcagcgtcggctccgacttccaggcttcatcctagagactgtcatctccc 1981 aaccaggcgaggtccttccaaaggaaaggatcctctttgctgatggactgccaaaaagta 2041 ttttgcgacatcttttggttctggatagtagtgagcagccaagtgactgtgtctgaaaca 2101 ccagtgtattttcagggaatgtccctaactgcgtcttgcccgcgccgggggctggggact 2161 ctctctgctggacttgggactggcctctgcccccagcacgctgtattctgcaggaccgcc 2221 tccttcctgcccctaacaacaaccacagtgttgctgaaattggagaaaactggggagggc 2281 gcaaccccccccaggcgcggggaagcatgtggtaccgcctcagccagtgcccctcagcct 2341 ggccacagtcgcctctcctcggggacccctcagcagaaagggacagcctgtccttagagg 2401 actggaaattgtcaatatttgataaaatgatacccttttctacatggtgggtcagctttt 2461 ttttttttttttttaactttctttctcagcattctctttggagttcaacctagcgcccat 2521 gagccaggctgaggaagctgagtgagaagccaggtgggcgggacttgttcccaggaaggc 2581 cgggtggggaggaagcctagagggaaccccaggaagggcaaatccaggcaaatctgcagg 2641 aatgctctgccatgggagcagctcctcccttgccacggccaccttctctagcactgcaag 2701 gtccacagggcattgctttcctttctaggcggtggcagtcagggaacagactgaggtagg 2761 tgtaggggggtctaggccttcgtggagcaccccagggagttagtaggccccggggagaca 2821 gagtctgcacaggccctttctggggccacctccatccacgaggagcagcctgagccttgg 2881 tggccgaaccttgaccgtcccggagcacagcttcagggcagggaaccggagcccctgggg 2941 ggcctcacgggtgtgacgaggcccttcattgcaggcaggtgggccaatgggagccctcac 3001 ccacgcaagccgagacaccacccagagtgcaggctgcctggccccttctggcacggccag 3061 ctccacaccccctgcctagggtatgtgtggtcctaagggctaggagcttcccctactaac 3121 atctcccagaaaaagcagttaagcccctcagggcacagcaaggttagacacagcccccat 3181 ccccagatcaggactccatcttgctaagtggcatcaccgtcaccagcctccccttattta 3241 aaagcagcgactggtgttgccgcaggtacctggtctacgaagacgcaggcatccctctcc 3301 caccgtccacctccccgggggccgctgacagcacagtcgcctgggtgcacgcttgtgggg 3361 gcagcaggaacggggctgtcggctctcaggggatctggctgcagccagggcgagggcctg 3421 gcccttccttccagctccttccggctccttccagctgaagggcaggaagctctggccgct 3481 tagcttctagggttccatctccctagaaaggtgcccacgcccagggcatcagtcagtagc 3541 ggcagcagcagcagactcggggctttcccagggtggcgcagccaccccagctgcatgtca 3601 cctcagctctccatcttattgccattttgtagatgaggaagctgagaccagaaaggctaa 3661 gacccatgccccaggcaccacacccatctcttgggggctgggcacctgctacccgaggcc 3721 acctcctgaagcccccactcttcccccatgttccacttcaggagccgcgggggcccatcc 3781 tgacacccggggttcctcagcccagcgcagatgtgcttcagttccagagggcttgttgat 3841 ttgtttcttaggtacgttacctgtccaccctgagtccagtgaggctgtcccaagagcccc 3901 tgtagtgtgctcctgggaagggctgggggggctgggggggctgggagaggcccaggggca 3961 gctgtcactggaaccccagccagatgtccaaggaagccggccagaacacggagcagccag 4021 atggccccagctgcacctgtctagggagcccatgcagcctccttgcactggagaagcagc 4081 tgtgaaagtagacagagttgagacttcgccgtggtcaggagaaaatgcaaattcccagga 4141 acaagaatcctttaagtgatatgtttttataaaactaaacaaatcaacaaataaatcttg 4201 aaggcggatggttttcccagcagtgcaggggttggagggaggctgctggcactcctgggg 4261 ccaagggggacaggcagtggtcctgagtctgctcagagaggcaaggcagaaggagctcgc 4321 caggcaggtcagctcacatctgtccaagtcgctctggtcagaaacagcgactctccccca 4381 ttcccccagcgttcccaccaggcctgggctgctgggaagcccttgctgtacccaggagcc 4441 cgacccgcagtatcctggcacagagccacttgtcactcagaacagtcagtgtctccaacg 4501 cacaaacatccactcctctgttaccagttaaagcactttaatgctttaaggtgaaaacga 4561 aatcccatccgtgtttttcgtgtaagatcgtgcttctccgagcagtattaatggacgccc 4621 tccaatgacataacaactgtttttggtaatgtaatcttgggaaaatgtgttattttttta 4681 gctgtgtttcagtggggatttttgtttttgtaacataataaagtgtatgttccaatga SEQIDNO:111HumanTP73isoform5aminoacidsequence(NP_001191118.1) 1 mlyvgdparhlataqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrh 301 gdedtyylqvrgrenfeilmklkeslelmelvpqplvdsyrqqqqllqrptwgp SEQIDNO:112HumanTP73transcriptvariant6cDNAsequence (NM_001204190.2;CDS:235-1755) 1 ggattcagccagttgacagaactaagggagatgggaaaagcgaaaatgccaacaaacggc 61 ccgcatgttccccagcatcctcggctcctgcctcactagctgcggagcctctcccgctcg 121 gtccacgctgccgggcggccacgaccgtgacccttcccctcgggccgcccagatccatgc 181 ctcgtcccacgggacaccagttccctggcgtgtgcagaccccccggcgcctaccatgctg 241 tacgtcggtgaccccgcacggcacctcgccacggcccagttcaatctgctgagcagcacc 301 atggaccagatgagcagccgcgcggcctcggccagcccctacaccccagagcacgccgcc 361 agcgtgcccacccactcgccctacgcacaacccagctccaccttcgacaccatgtcgccg 421 gcgcctgtcatcccctccaacaccgactaccccggaccccaccactttgaggtcactttc 481 cagcagtccagcacggccaagtcagccacctggacgtactccccgctcttgaagaaactc 541 tactgccagatcgccaagacatgccccatccagatcaaggtgtccaccccgccaccccca 601 ggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtgaccgacgtcgtg 661 aaacgctgccccaaccacgagctcgggagggacttcaacgaaggacagtctgctccagcc 721 agccacctcatccgcgtggaaggcaataatctctcgcagtatgtggatgaccctgtcacc 781 ggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacggaattcaccacc 841 atcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaaccggcggcccatc 901 ctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgccggtcctttgag 961 ggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggaccactaccgggag 1021 cagcaggccctgaacgagagctccgccaagaacggggccgccagcaagcgtgccttcaag 1081 cagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcggcggcatggagac 1141 gaggacacgtactaccttcaggtgcgaggccgggagaactttgagatcctgatgaagctg 1201 aaagagagcctggagctgatggagttggtgccgcagccactggtggactcctatcggcag 1261 cagcagcagctcctacagaggccgccccgggatgctcaacaaccatggccacgcagtgcc 1321 agccaacggcgagatgagcagcagccacagcgcccagtccatggtctcggggtcccactg 1381 cactccgccacccccctaccacgccgaccccagcctcgtcaggacctgggggccctgaag 1441 atccccgagcagtaccgcatgaccatctggcggggcctgcaggacctgaagcagggccac 1501 gactacagcaccgcgcagcagctgctccgctctagcaacgcggccaccatctccatcggc 1561 ggctcaggggaactgcagcgccagcgggtcatggaggccgtgcacttccgcgtgcgccac 1621 accatcaccatccccaaccgcggcggcccaggcggcggccctgacgagtgggcggacttc 1681 ggcttcgacctgcccgactgcaaggcccgcaagcagcccatcaaggaggagttcacggag 1741 gccgagatccactgagggcctcgcctggctgcagcctgcgccaccgcccagagacccaag 1801 ctgcctcccctctccttcctgtgtgtccaaaactgcctcaggaggcaggaccttcgggct 1861 gtgcccggggaaaggcaaggtccggcccatccccaggcacctcacaggccccaggaaagg 1921 cccagccaccgaagccgcctgtggacagcctgagtcacctgcagaaccttctggagctgc 1981 cctagtgctgggcttgtggggcgggggctggcccactctcagccctgccactgccccggc 2041 gtgctccatggcaggcgtgggtggggaccgcagcgtcggctccgacttccaggcttcatc 2101 ctagagactgtcatctcccaaccaggcgaggtccttccaaaggaaaggatcctctttgct 2161 gatggactgccaaaaagtattttgcgacatcttttggttctggatagtagtgagcagcca 2221 agtgactgtgtctgaaacaccagtgtattttcagggaatgtccctaactgcgtcttgccc 2281 gcgccgggggctggggactctctctgctggacttgggactggcctctgcccccagcacgc 2341 tgtattctgcaggaccgcctccttcctgcccctaacaacaaccacagtgttgctgaaatt 2401 ggagaaaactggggagggcgcaaccccccccaggcgcggggaagcatgtggtaccgcctc 2461 agccagtgcccctcagcctggccacagtcgcctctcctcggggacccctcagcagaaagg 2521 gacagcctgtccttagaggactggaaattgtcaatatttgataaaatgatacccttttct 2581 acatggtgggtcagcttttttttttttttttttaactttctttctcagcattctctttgg 2641 agttcaacctagcgcccatgagccaggctgaggaagctgagtgagaagccaggtgggcgg 2701 gacttgttcccaggaaggccgggtggggaggaagcctagagggaaccccaggaagggcaa 2761 atccaggcaaatctgcaggaatgctctgccatgggagcagctcctcccttgccacggcca 2821 ccttctctagcactgcaaggtccacagggcattgctttcctttctaggcggtggcagtca 2881 gggaacagactgaggtaggtgtaggggggtctaggccttcgtggagcaccccagggagtt 2941 agtaggccccggggagacagagtctgcacaggccctttctggggccacctccatccacga 3001 ggagcagcctgagccttggtggccgaaccttgaccgtcccggagcacagcttcagggcag 3061 ggaaccggagcccctggggggcctcacgggtgtgacgaggcccttcattgcaggcaggtg 3121 ggccaatgggagccctcacccacgcaagccgagacaccacccagagtgcaggctgcctgg 3181 ccccttctggcacggccagctccacaccccctgcctagggtatgtgtggtcctaagggct 3241 aggagcttcccctactaacatctcccagaaaaagcagttaagcccctcagggcacagcaa 3301 ggttagacacagcccccatccccagatcaggactccatcttgctaagtggcatcaccgtc 3361 accagcctccccttatttaaaagcagcgactggtgttgccgcaggtacctggtctacgaa 3421 gacgcaggcatccctctcccaccgtccacctccccgggggccgctgacagcacagtcgcc 3481 tgggtgcacgcttgtgggggcagcaggaacggggctgtcggctctcaggggatctggctg 3541 cagccagggcgagggcctggcccttccttccagctccttccggctccttccagctgaagg 3601 gcaggaagctctggccgcttagcttctagggttccatctccctagaaaggtgcccacgcc 3661 cagggcatcagtcagtagcggcagcagcagcagactcggggctttcccagggtggcgcag 3721 ccaccccagctgcatgtcacctcagctctccatcttattgccattttgtagatgaggaag 3781 ctgagaccagaaaggctaagacccatgccccaggcaccacacccatctcttgggggctgg 3841 gcacctgctacccgaggccacctcctgaagcccccactcttcccccatgttccacttcag 3901 gagccgcgggggcccatcctgacacccggggttcctcagcccagcgcagatgtgcttcag 3961 ttccagagggcttgttgatttgtttcttaggtacgttacctgtccaccctgagtccagtg 4021 aggctgtcccaagagcccctgtagtgtgctcctgggaagggctgggggggctgggggggc 4081 tgggagaggcccaggggcagctgtcactggaaccccagccagatgtccaaggaagccggc 4141 cagaacacggagcagccagatggccccagctgcacctgtctagggagcccatgcagcctc 4201 cttgcactggagaagcagctgtgaaagtagacagagttgagacttcgccgtggtcaggag 4261 aaaatgcaaattcccaggaacaagaatcctttaagtgatatgtttttataaaactaaaca 4321 aatcaacaaataaatcttgaaggcggatggttttcccagcagtgcaggggttggagggag 4381 gctgctggcactcctggggccaagggggacaggcagtggtcctgagtctgctcagagagg 4441 caaggcagaaggagctcgccaggcaggtcagctcacatctgtccaagtcgctctggtcag 4501 aaacagcgactctcccccattcccccagcgttcccaccaggcctgggctgctgggaagcc 4561 cttgctgtacccaggagcccgacccgcagtatcctggcacagagccacttgtcactcaga 4621 acagtcagtgtctccaacgcacaaacatccactcctctgttaccagttaaagcactttaa 4681 tgctttaaggtgaaaacgaaatcccatccgtgtttttcgtgtaagatcgtgcttctccga 4741 gcagtattaatggacgccctccaatgacataacaactgtttttggtaatgtaatcttggg 4801 aaaatgtgttatttttttagctgtgtttcagtggggatttttgtttttgtaacataataa 4861 agtgtatgttccaatga SEQIDNO:113HumanTP73isoform6aminoacidsequence(NP_001191119.1) 1 mlyvgdparhlataqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrh 301 gdedtyylqvrgrenfeilmklkesleimelvpqplvdsyrqqqqllqrpprdaqqpwpr 361 sasqrrdeqqpqrpvhglgvplhsatplprrpqprqdlgalkipeqyrmtiwrglqdlkq 421 ghdystaqqllrssnaatisiggsgelqrqrvmeavhfrvrhtitipnrggpgggpdewa 481 dfgfdlpdckarkqpikeefteaeih SEQIDNO:114HumanTP73transcriptvariant7cDNAsequence (NM_001204191.2;CDS:235-1710) 1 ggattcagccagttgacagaactaagggagatgggaaaagcgaaaatgccaacaaacggc 61 ccgcatgttccccagcatcctcggctcctgcctcactagctgcggagcctctcccgctcg 121 gtccacgctgccgggcggccacgaccgtgacccttcccctcgggccgcccagatccatgc 181 ctcgtcccacgggacaccagttccctggcgtgtgcagaccccccggcgcctaccatgctg 241 tacgtcggtgaccccgcacggcacctcgccacggcccagttcaatctgctgagcagcacc 301 atggaccagatgagcagccgcgcggcctcggccagcccctacaccccagagcacgccgcc 361 agcgtgcccacccactcgccctacgcacaacccagctccaccttcgacaccatgtcgccg 421 gcgcctgtcatcccctccaacaccgactaccccggaccccaccactttgaggtcactttc 481 cagcagtccagcacggccaagtcagccacctggacgtactccccgctcttgaagaaactc 541 tactgccagatcgccaagacatgccccatccagatcaaggtgtccaccccgccaccccca 601 ggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtgaccgacgtcgtg 661 aaacgctgccccaaccacgagctcgggagggacttcaacgaaggacagtctgctccagcc 721 agccacctcatccgcgtggaaggcaataatctctcgcagtatgtggatgaccctgtcacc 781 ggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacggaattcaccacc 841 atcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaaccggcggcccatc 901 ctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgccggtcctttgag 961 ggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggaccactaccgggag 1021 cagcaggccctgaacgagagctccgccaagaacggggccgccagcaagcgtgccttcaag 1081 cagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcggcggcatggagac 1141 gaggacacgtactaccttcaggtgcgaggccgggagaactttgagatcctgatgaagctg 1201 aaagagagcctggagctgatggagttggtgccgcagccactggtggactcctatcggcag 1261 cagcagcagctcctacagaggccttttttaacaggattggggtgtccaaactgcatcgag 1321 tatttcacctcccaagggttacagagcatttaccacctgcagaacctgaccattgaggac 1381 ctgggggccctgaagatccccgagcagtaccgcatgaccatctggcggggcctgcaggac 1441 ctgaagcagggccacgactacagcaccgcgcagcagctgctccgctctagcaacgcggcc 1501 accatctccatcggcggctcaggggaactgcagcgccagcgggtcatggaggccgtgcac 1561 ttccgcgtgcgccacaccatcaccatccccaaccgcggcggcccaggcggcggccctgac 1621 gagtgggcggacttcggcttcgacctgcccgactgcaaggcccgcaagcagcccatcaag 1681 gaggagttcacggaggccgagatccactgagggcctcgcctggctgcagcctgcgccacc 1741 gcccagagacccaagctgcctcccctctccttcctgtgtgtccaaaactgcctcaggagg 1801 caggaccttcgggctgtgcccggggaaaggcaaggtccggcccatccccaggcacctcac 1861 aggccccaggaaaggcccagccaccgaagccgcctgtggacagcctgagtcacctgcaga 1921 accttctggagctgccctagtgctgggcttgtggggcgggggctggcccactctcagccc 1981 tgccactgccccggcgtgctccatggcaggcgtgggtggggaccgcagcgtcggctccga 2041 cttccaggcttcatcctagagactgtcatctcccaaccaggcgaggtccttccaaaggaa 2101 aggatcctctttgctgatggactgccaaaaagtattttgcgacatcttttggttctggat 2161 agtagtgagcagccaagtgactgtgtctgaaacaccagtgtattttcagggaatgtccct 2221 aactgcgtcttgcccgcgccgggggctggggactctctctgctggacttgggactggcct 2281 ctgcccccagcacgctgtattctgcaggaccgcctccttcctgcccctaacaacaaccac 2341 agtgttgctgaaattggagaaaactggggagggcgcaaccccccccaggcgcggggaagc 2401 atgtggtaccgcctcagccagtgcccctcagcctggccacagtcgcctctcctcggggac 2461 ccctcagcagaaagggacagcctgtccttagaggactggaaattgtcaatatttgataaa 2521 atgatacccttttctacatggtgggtcagcttttttttttttttttttaactttctttct 2581 cagcattctctttggagttcaacctagcgcccatgagccaggctgaggaagctgagtgag 2641 aagccaggtgggcgggacttgttcccaggaaggccgggtggggaggaagcctagagggaa 2701 ccccaggaagggcaaatccaggcaaatctgcaggaatgctctgccatgggagcagctcct 2761 cccttgccacggccaccttctctagcactgcaaggtccacagggcattgctttcctttct 2821 aggcggtggcagtcagggaacagactgaggtaggtgtaggggggtctaggccttcgtgga 2881 gcaccccagggagttagtaggccccggggagacagagtctgcacaggccctttctggggc 2941 cacctccatccacgaggagcagcctgagccttggtggccgaaccttgaccgtcccggagc 3001 acagcttcagggcagggaaccggagcccctggggggcctcacgggtgtgacgaggccctt 3061 cattgcaggcaggtgggccaatgggagccctcacccacgcaagccgagacaccacccaga 3121 gtgcaggctgcctggccccttctggcacggccagctccacaccccctgcctagggtatgt 3181 gtggtcctaagggctaggagcttcccctactaacatctcccagaaaaagcagttaagccc 3241 ctcagggcacagcaaggttagacacagcccccatccccagatcaggactccatcttgcta 3301 agtggcatcaccgtcaccagcctccccttatttaaaagcagcgactggtgttgccgcagg 3361 tacctggtctacgaagacgcaggcatccctctcccaccgtccacctccccgggggccgct 3421 gacagcacagtcgcctgggtgcacgcttgtgggggcagcaggaacggggctgtcggctct 3481 caggggatctggctgcagccagggcgagggcctggcccttccttccagctccttccggct 3541 ccttccagctgaagggcaggaagctctggccgcttagcttctagggttccatctccctag 3601 aaaggtgcccacgcccagggcatcagtcagtagcggcagcagcagcagactcggggcttt 3661 cccagggtggcgcagccaccccagctgcatgtcacctcagctctccatcttattgccatt 3721 ttgtagatgaggaagctgagaccagaaaggctaagacccatgccccaggcaccacaccca 3781 tctcttgggggctgggcacctgctacccgaggccacctcctgaagcccccactcttcccc 3841 catgttccacttcaggagccgcgggggcccatcctgacacccggggttcctcagcccagc 3901 gcagatgtgcttcagttccagagggcttgttgatttgtttcttaggtacgttacctgtcc 3961 accctgagtccagtgaggctgtcccaagagcccctgtagtgtgctcctgggaagggctgg 4021 gggggctgggggggctgggagaggcccaggggcagctgtcactggaaccccagccagatg 4081 tccaaggaagccggccagaacacggagcagccagatggccccagctgcacctgtctaggg 4141 agcccatgcagcctccttgcactggagaagcagctgtgaaagtagacagagttgagactt 4201 cgccgtggtcaggagaaaatgcaaattcccaggaacaagaatcctttaagtgatatgttt 4261 ttataaaactaaacaaatcaacaaataaatcttgaaggcggatggttttcccagcagtgc 4321 aggggttggagggaggctgctggcactcctggggccaagggggacaggcagtggtcctga 4381 gtctgctcagagaggcaaggcagaaggagctcgccaggcaggtcagctcacatctgtcca 4441 agtcgctctggtcagaaacagcgactctcccccattcccccagcgttcccaccaggcctg 4501 ggctgctgggaagcccttgctgtacccaggagcccgacccgcagtatcctggcacagagc 4561 cacttgtcactcagaacagtcagtgtctccaacgcacaaacatccactcctctgttacca 4621 gttaaagcactttaatgctttaaggtgaaaacgaaatcccatccgtgtttttcgtgtaag 4681 atcgtgcttctccgagcagtattaatggacgccctccaatgacataacaactgtttttgg 4741 taatgtaatcttgggaaaatgtgttatttttttagctgtgtttcagtggggatttttgtt 4801 tttgtaacataataaagtgtatgttccaatga SEQIDNO:115HumanTP73isoform7aminoacidsequence(NP_001191120.1) 1 mlyvgdparhlataqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrh 301 gdedtyylqvrgrenfeilmklkesleimelvpqplvdsyrqqqqllqrpfltglgcpnc 361 ieyftsqglqsiyhlqnltiedlgalkipeqyrmtiwrglqdlkqghdystaqqllrssn 421 aatisiggsgelqrqrvmeavhfrvrhtitipnrggpgggpdewadfgfdlpdckarkqp 481 ikeefteaeih SEQIDNO:116HumanTP73transcriptvariant8cDNAsequence (NM_001204184.2;CDS:160-1659) 1 gccctgcctccccgcccgcgcacccgcccggaggctcgcgcgcccgcgaaggggacgcag 61 cgaaaccggggcccgcgccaggccagccgggacggacgccgatgcccggggctgcgacgg 121 ctgcagagcgagctgccctcggaggccggcgtggggaagatggcccagtccaccgccacc 181 tcccctgatgggggcaccacgtttgagcacctctggagctctctggaaccagacagcacc 241 tacttcgaccttccccagtcaagccgggggaataatgaggtggtgggcggaacggattcc 301 agcatggacgtcttccacctggagggcatgactacatctgtcatggcccagttcaatctg 361 ctgagcagcaccatggaccagatgagcagccgcgcggcctcggccagcccctacacccca 421 gagcacgccgccagcgtgcccacccactcgccctacgcacaacccagctccaccttcgac 481 accatgtcgccggcgcctgtcatcccctccaacaccgactaccccggaccccaccacttt 541 gaggtcactttccagcagtccagcacggccaagtcagccacctggacgtactccccgctc 601 ttgaagaaactctactgccagatcgccaagacatgccccatccagatcaaggtgtccacc 661 ccgccacccccaggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtg 721 accgacgtcgtgaaacgctgccccaaccacgagctcgggagggacttcaacgaaggacag 781 tctgctccagccagccacctcatccgcgtggaaggcaataatctctcgcagtatgtggat 841 gaccctgtcaccggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacg 901 gaattcaccaccatcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaac 961 cggcggcccatcctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgc 1021 cggtcctttgagggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggac 1081 cactaccgggagcagcaggccctgaacgagagctccgccaagaacggggccgccagcaag 1141 cgtgccttcaagcagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcgg 1201 cggcatggagacgaggacacgtactaccttcaggtgcgaggccgggagaactttgagatc 1261 ctgatgaagctgaaagagagcctggagctgatggagttggtgccgcagccactggtggac 1321 tcctatcggcagcagcagcagctcctacagaggccgagtcacctacagcccccgtcctac 1381 gggccggtcctctcgcccatgaacaaggtgcacgggggcatgaacaagctgccctccgtc 1441 aaccagctggtgggccagcctcccccgcacagttcggcagctacacccaacctggggccc 1501 gtgggccccgggatgctcaacaaccatggccacgcagtgccagccaacggcgagatgagc 1561 agcagccacagcgcccagtccatggtctcggggtcccactgcactccgccacccccctac 1621 cacgccgaccccagcctcgtcaggacctgggggccctgaagatccccgagcagtaccgca 1681 tgaccatctggcggggcctgcaggacctgaagcagggccacgactacagcaccgcgcagc 1741 agctgctccgctctagcaacgcggccaccatctccatcggcggctcaggggaactgcagc 1801 gccagcgggtcatggaggccgtgcacttccgcgtgcgccacaccatcaccatccccaacc 1861 gcggcggcccaggcggcggccctgacgagtgggcggacttcggcttcgacctgcccgact 1921 gcaaggcccgcaagcagcccatcaaggaggagttcacggaggccgagatccactgagggc 1981 ctcgcctggctgcagcctgcgccaccgcccagagacccaagctgcctcccctctccttcc 2041 tgtgtgtccaaaactgcctcaggaggcaggaccttcgggctgtgcccggggaaaggcaag 2101 gtccggcccatccccaggcacctcacaggccccaggaaaggcccagccaccgaagccgcc 2161 tgtggacagcctgagtcacctgcagaaccttctggagctgccctagtgctgggcttgtgg 2221 ggcgggggctggcccactctcagccctgccactgccccggcgtgctccatggcaggcgtg 2281 ggtggggaccgcagcgtcggctccgacttccaggcttcatcctagagactgtcatctccc 2341 aaccaggcgaggtccttccaaaggaaaggatcctctttgctgatggactgccaaaaagta 2401 ttttgcgacatcttttggttctggatagtagtgagcagccaagtgactgtgtctgaaaca 2461 ccagtgtattttcagggaatgtccctaactgcgtcttgcccgcgccgggggctggggact 2521 ctctctgctggacttgggactggcctctgcccccagcacgctgtattctgcaggaccgcc 2581 tccttcctgcccctaacaacaaccacagtgttgctgaaattggagaaaactggggagggc 2641 gcaaccccccccaggcgcggggaagcatgtggtaccgcctcagccagtgcccctcagcct 2701 ggccacagtcgcctctcctcggggacccctcagcagaaagggacagcctgtccttagagg 2761 actggaaattgtcaatatttgataaaatgatacccttttctacatggtgggtcagctttt 2821 ttttttttttttttaactttctttctcagcattctctttggagttcaacctagcgcccat 2881 gagccaggctgaggaagctgagtgagaagccaggtgggcgggacttgttcccaggaaggc 2941 cgggtggggaggaagcctagagggaaccccaggaagggcaaatccaggcaaatctgcagg 3001 aatgctctgccatgggagcagctcctcccttgccacggccaccttctctagcactgcaag 3061 gtccacagggcattgctttcctttctaggcggtggcagtcagggaacagactgaggtagg 3121 tgtaggggggtctaggccttcgtggagcaccccagggagttagtaggccccggggagaca 3181 gagtctgcacaggccctttctggggccacctccatccacgaggagcagcctgagccttgg 3241 tggccgaaccttgaccgtcccggagcacagcttcagggcagggaaccggagcccctgggg 3301 ggcctcacgggtgtgacgaggcccttcattgcaggcaggtgggccaatgggagccctcac 3361 ccacgcaagccgagacaccacccagagtgcaggctgcctggccccttctggcacggccag 3421 ctccacaccccctgcctagggtatgtgtggtcctaagggctaggagcttcccctactaac 3481 atctcccagaaaaagcagttaagcccctcagggcacagcaaggttagacacagcccccat 3541 ccccagatcaggactccatcttgctaagtggcatcaccgtcaccagcctccccttattta 3601 aaagcagcgactggtgttgccgcaggtacctggtctacgaagacgcaggcatccctctcc 3661 caccgtccacctccccgggggccgctgacagcacagtcgcctgggtgcacgcttgtgggg 3721 gcagcaggaacggggctgtcggctctcaggggatctggctgcagccagggcgagggcctg 3781 gcccttccttccagctccttccggctccttccagctgaagggcaggaagctctggccgct 3841 tagcttctagggttccatctccctagaaaggtgcccacgcccagggcatcagtcagtagc 3901 ggcagcagcagcagactcggggctttcccagggtggcgcagccaccccagctgcatgtca 3961 cctcagctctccatcttattgccattttgtagatgaggaagctgagaccagaaaggctaa 4021 gacccatgccccaggcaccacacccatctcttgggggctgggcacctgctacccgaggcc 4081 acctcctgaagcccccactcttcccccatgttccacttcaggagccgcgggggcccatcc 4141 tgacacccggggttcctcagcccagcgcagatgtgcttcagttccagagggcttgttgat 4201 ttgtttcttaggtacgttacctgtccaccctgagtccagtgaggctgtcccaagagcccc 4261 tgtagtgtgctcctgggaagggctgggggggctgggggggctgggagaggcccaggggca 4321 gctgtcactggaaccccagccagatgtccaaggaagccggccagaacacggagcagccag 4381 atggccccagctgcacctgtctagggagcccatgcagcctccttgcactggagaagcagc 4441 tgtgaaagtagacagagttgagacttcgccgtggtcaggagaaaatgcaaattcccagga 4501 acaagaatcctttaagtgatatgtttttataaaactaaacaaatcaacaaataaatcttg 4561 aaggcggatggttttcccagcagtgcaggggttggagggaggctgctggcactcctgggg 4621 ccaagggggacaggcagtggtcctgagtctgctcagagaggcaaggcagaaggagctcgc 4681 caggcaggtcagctcacatctgtccaagtcgctctggtcagaaacagcgactctccccca 4741 ttcccccagcgttcccaccaggcctgggctgctgggaagcccttgctgtacccaggagcc 4801 cgacccgcagtatcctggcacagagccacttgtcactcagaacagtcagtgtctccaacg 4861 cacaaacatccactcctctgttaccagttaaagcactttaatgctttaaggtgaaaacga 4921 aatcccatccgtgtttttcgtgtaagatcgtgcttctccgagcagtattaatggacgccc 4981 tccaatgacataacaactgtttttggtaatgtaatcttgggaaaatgtgttattttttta 5041 gctgtgtttcagtggggatttttgtttttgtaacataataaagtgtatgttccaatga SEQIDNO:117HumanTP73isoform8aminoacidsequence(NP_001191113.1) 1 maqstatspdggttfehlwsslepdstyfdlpqssrgnnevvggtdssmdvfhlegmtts 61 vmaqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntd 121 ypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampv 181 ykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpy 241 eppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgr 301 drkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvr 361 grenfeilmklkeslelmelvpqplvdsyrqqqqllqrpshlqppsygpvlspmnkvhgg 421 mnklpsvnqlvgqppphssaatpnlgpvgpgmlnnhghavpangemssshsaqsmvsgsh 481 ctppppyhadpslvrtwgp SEQIDNO:118HumanTP73transcriptvariant9cDNAsequence (NM_001204185.2;CDS:160-1587) 1 gccctgcctccccgcccgcgcacccgcccggaggctcgcgcgcccgcgaaggggacgcag 61 cgaaaccggggcccgcgccaggccagccgggacggacgccgatgcccggggctgcgacgg 121 ctgcagagcgagctgccctcggaggccggcgtggggaagatggcccagtccaccgccacc 181 tcccctgatgggggcaccacgtttgagcacctctggagctctctggaaccagacagcacc 241 tacttcgaccttccccagtcaagccgggggaataatgaggtggtgggcggaacggattcc 301 agcatggacgtcttccacctggagggcatgactacatctgtcatggcccagttcaatctg 361 ctgagcagcaccatggaccagatgagcagccgcgcggcctcggccagcccctacacccca 421 gagcacgccgccagcgtgcccacccactcgccctacgcacaacccagctccaccttcgac 481 accatgtcgccggcgcctgtcatcccctccaacaccgactaccccggaccccaccacttt 541 gaggtcactttccagcagtccagcacggccaagtcagccacctggacgtactccccgctc 601 ttgaagaaactctactgccagatcgccaagacatgccccatccagatcaaggtgtccacc 661 ccgccacccccaggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtg 721 accgacgtcgtgaaacgctgccccaaccacgagctcgggagggacttcaacgaaggacag 781 tctgctccagccagccacctcatccgcgtggaaggcaataatctctcgcagtatgtggat 841 gaccctgtcaccggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacg 901 gaattcaccaccatcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaac 961 cggcggcccatcctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgc 1021 cggtcctttgagggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggac 1081 cactaccgggagcagcaggccctgaacgagagctccgccaagaacggggccgccagcaag 1141 cgtgccttcaagcagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcgg 1201 cggcatggagacgaggacacgtactaccttcaggtgcgaggccgggagaactttgagatc 1261 ctgatgaagctgaaagagagcctggagctgatggagttggtgccgcagccactggtggac 1321 tcctatcggcagcagcagcagctcctacagaggccgccccgggatgctcaacaaccatgg 1381 ccacgcagtgccagccaacggcgagatgagcagcagccacagcgcccagtccatggtctc 1441 ggggtcccactgcactccgccacccccctaccacgccgaccccagcctcgtcagtttttt 1501 aacaggattggggtgtccaaactgcatcgagtatttcacctcccaagggttacagagcat 1561 ttaccacctgcagaacctgaccattgaggacctgggggccctgaagatccccgagcagta 1621 ccgcatgaccatctggcggggcctgcaggacctgaagcagggccacgactacagcaccgc 1681 gcagcagctgctccgctctagcaacgcggccaccatctccatcggcggctcaggggaact 1741 gcagcgccagcgggtcatggaggccgtgcacttccgcgtgcgccacaccatcaccatccc 1801 caaccgcggcggcccaggcggcggccctgacgagtgggcggacttcggcttcgacctgcc 1861 cgactgcaaggcccgcaagcagcccatcaaggaggagttcacggaggccgagatccactg 1921 agggcctcgcctggctgcagcctgcgccaccgcccagagacccaagctgcctcccctctc 1981 cttcctgtgtgtccaaaactgcctcaggaggcaggaccttcgggctgtgcccggggaaag 2041 gcaaggtccggcccatccccaggcacctcacaggccccaggaaaggcccagccaccgaag 2101 ccgcctgtggacagcctgagtcacctgcagaaccttctggagctgccctagtgctgggct 2161 tgtggggcgggggctggcccactctcagccctgccactgccccggcgtgctccatggcag 2221 gcgtgggtggggaccgcagcgtcggctccgacttccaggcttcatcctagagactgtcat 2281 ctcccaaccaggcgaggtccttccaaaggaaaggatcctctttgctgatggactgccaaa 2341 aagtattttgcgacatcttttggttctggatagtagtgagcagccaagtgactgtgtctg 2401 aaacaccagtgtattttcagggaatgtccctaactgcgtcttgcccgcgccgggggctgg 2461 ggactctctctgctggacttgggactggcctctgcccccagcacgctgtattctgcagga 2521 ccgcctccttcctgcccctaacaacaaccacagtgttgctgaaattggagaaaactgggg 2581 agggcgcaaccccccccaggcgcggggaagcatgtggtaccgcctcagccagtgcccctc 2641 agcctggccacagtcgcctctcctcggggacccctcagcagaaagggacagcctgtcctt 2701 agaggactggaaattgtcaatatttgataaaatgatacccttttctacatggtgggtcag 2761 cttttttttttttttttttaactttctttctcagcattctctttggagttcaacctagcg 2821 cccatgagccaggctgaggaagctgagtgagaagccaggtgggcgggacttgttcccagg 2881 aaggccgggtggggaggaagcctagagggaaccccaggaagggcaaatccaggcaaatct 2941 gcaggaatgctctgccatgggagcagctcctcccttgccacggccaccttctctagcact 3001 gcaaggtccacagggcattgctttcctttctaggcggtggcagtcagggaacagactgag 3061 gtaggtgtaggggggtctaggccttcgtggagcaccccagggagttagtaggccccgggg 3121 agacagagtctgcacaggccctttctggggccacctccatccacgaggagcagcctgagc 3181 cttggtggccgaaccttgaccgtcccggagcacagcttcagggcagggaaccggagcccc 3241 tggggggcctcacgggtgtgacgaggcccttcattgcaggcaggtgggccaatgggagcc 3301 ctcacccacgcaagccgagacaccacccagagtgcaggctgcctggccccttctggcacg 3361 gccagctccacaccccctgcctagggtatgtgtggtcctaagggctaggagcttccccta 3421 ctaacatctcccagaaaaagcagttaagcccctcagggcacagcaaggttagacacagcc 3481 cccatccccagatcaggactccatcttgctaagtggcatcaccgtcaccagcctcccctt 3541 atttaaaagcagcgactggtgttgccgcaggtacctggtctacgaagacgcaggcatccc 3601 tctcccaccgtccacctccccgggggccgctgacagcacagtcgcctgggtgcacgcttg 3661 tgggggcagcaggaacggggctgtcggctctcaggggatctggctgcagccagggcgagg 3721 gcctggcccttccttccagctccttccggctccttccagctgaagggcaggaagctctgg 3781 ccgcttagcttctagggttccatctccctagaaaggtgcccacgcccagggcatcagtca 3841 gtagcggcagcagcagcagactcggggctttcccagggtggcgcagccaccccagctgca 3901 tgtcacctcagctctccatcttattgccattttgtagatgaggaagctgagaccagaaag 3961 gctaagacccatgccccaggcaccacacccatctcttgggggctgggcacctgctacccg 4021 aggccacctcctgaagcccccactcttcccccatgttccacttcaggagccgcgggggcc 4081 catcctgacacccggggttcctcagcccagcgcagatgtgcttcagttccagagggcttg 4141 ttgatttgtttcttaggtacgttacctgtccaccctgagtccagtgaggctgtcccaaga 4201 gcccctgtagtgtgctcctgggaagggctgggggggctgggggggctgggagaggcccag 4261 gggcagctgtcactggaaccccagccagatgtccaaggaagccggccagaacacggagca 4321 gccagatggccccagctgcacctgtctagggagcccatgcagcctccttgcactggagaa 4381 gcagctgtgaaagtagacagagttgagacttcgccgtggtcaggagaaaatgcaaattcc 4441 caggaacaagaatcctttaagtgatatgtttttataaaactaaacaaatcaacaaataaa 4501 tcttgaaggcggatggttttcccagcagtgcaggggttggagggaggctgctggcactcc 4561 tggggccaagggggacaggcagtggtcctgagtctgctcagagaggcaaggcagaaggag 4621 ctcgccaggcaggtcagctcacatctgtccaagtcgctctggtcagaaacagcgactctc 4681 ccccattcccccagcgttcccaccaggcctgggctgctgggaagcccttgctgtacccag 4741 gagcccgacccgcagtatcctggcacagagccacttgtcactcagaacagtcagtgtctc 4801 caacgcacaaacatccactcctctgttaccagttaaagcactttaatgctttaaggtgaa 4861 aacgaaatcccatccgtgtttttcgtgtaagatcgtgcttctccgagcagtattaatgga 4921 cgccctccaatgacataacaactgtttttggtaatgtaatcttgggaaaatgtgttattt 4981 ttttagctgtgtttcagtggggatttttgtttttgtaacataataaagtgtatgttccaa 5041 tga SEQIDNO:119HumanTP73isoform9aminoacidsequence(NP_001191114.1) 1 maqstatspdggttfehlwsslepdstyfdlpqssrgnnevvggtdssmdvfhlegmtts 61 vmaqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntd 121 ypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampv 181 ykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpy 241 eppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgr 301 drkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvr 361 grenfeilmklkeslelmelvpqplvdsyrqqqqllqrpprdaqqpwprsasqrrdeqqp 421 qrpvhglgvplhsatpiprrpqprqffnrigvsklhrvfhlprvtehlppaepdh SEQIDNO:120HumanTP73transcriptvariant10cDNAsequence (NM_001204186.2;CDS:160-1371) 1 gccctgcctccccgcccgcgcacccgcccggaggctcgcgcgcccgcgaaggggacgcag 61 cgaaaccggggcccgcgccaggccagccgggacggacgccgatgcccggggctgcgacgg 121 ctgcagagcgagctgccctcggaggccggcgtggggaagatggcccagtccaccgccacc 181 tcccctgatgggggcaccacgtttgagcacctctggagctctctggaaccagacagcacc 241 tacttcgaccttccccagtcaagccgggggaataatgaggtggtgggcggaacggattcc 301 agcatggacgtcttccacctggagggcatgactacatctgtcatggcccagttcaatctg 361 ctgagcagcaccatggaccagatgagcagccgcgcggcctcggccagcccctacacccca 421 gagcacgccgccagcgtgcccacccactcgccctacgcacaacccagctccaccttcgac 481 accatgtcgccggcgcctgtcatcccctccaacaccgactaccccggaccccaccacttt 541 gaggtcactttccagcagtccagcacggccaagtcagccacctggacgtactccccgctc 601 ttgaagaaactctactgccagatcgccaagacatgccccatccagatcaaggtgtccacc 661 ccgccacccccaggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgtg 721 accgacgtcgtgaaacgctgccccaaccacgagctcgggagggacttcaacgaaggacag 781 tctgctccagccagccacctcatccgcgtggaaggcaataatctctcgcagtatgtggat 841 gaccctgtcaccggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggacg 901 gaattcaccaccatcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaac 961 cggcggcccatcctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccgc 1021 cggtcctttgagggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgaggac 1081 cactaccgggagcagcaggccctgaacgagagctccgccaagaacggggccgccagcaag 1141 cgtgccttcaagcagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcgg 1201 cggcatggagacgaggacacgtactaccttcaggtgcgaggccgggagaactttgagatc 1261 ctgatgaagctgaaagagagcctggagctgatggagttggtgccgcagccactggtggac 1321 tcctatcggcagcagcagcagctcctacagaggccgacctgggggccctgaagatccccg 1381 agcagtaccgcatgaccatctggcggggcctgcaggacctgaagcagggccacgactaca 1441 gcaccgcgcagcagctgctccgctctagcaacgcggccaccatctccatcggcggctcag 1501 gggaactgcagcgccagcgggtcatggaggccgtgcacttccgcgtgcgccacaccatca 1561 ccatccccaaccgcggcggcccaggcggcggccctgacgagtgggcggacttcggcttcg 1621 acctgcccgactgcaaggcccgcaagcagcccatcaaggaggagttcacggaggccgaga 1681 tccactgagggcctcgcctggctgcagcctgcgccaccgcccagagacccaagctgcctc 1741 ccctctccttcctgtgtgtccaaaactgcctcaggaggcaggaccttcgggctgtgcccg 1801 gggaaaggcaaggtccggcccatccccaggcacctcacaggccccaggaaaggcccagcc 1861 accgaagccgcctgtggacagcctgagtcacctgcagaaccttctggagctgccctagtg 1921 ctgggcttgtggggcgggggctggcccactctcagccctgccactgccccggcgtgctcc 1981 atggcaggcgtgggtggggaccgcagcgtcggctccgacttccaggcttcatcctagaga 2041 ctgtcatctcccaaccaggcgaggtccttccaaaggaaaggatcctctttgctgatggac 2101 tgccaaaaagtattttgcgacatcttttggttctggatagtagtgagcagccaagtgact 2161 gtgtctgaaacaccagtgtattttcagggaatgtccctaactgcgtcttgcccgcgccgg 2221 gggctggggactctctctgctggacttgggactggcctctgcccccagcacgctgtattc 2281 tgcaggaccgcctccttcctgcccctaacaacaaccacagtgttgctgaaattggagaaa 2341 actggggagggcgcaaccccccccaggcgcggggaagcatgtggtaccgcctcagccagt 2401 gcccctcagcctggccacagtcgcctctcctcggggacccctcagcagaaagggacagcc 2461 tgtccttagaggactggaaattgtcaatatttgataaaatgatacccttttctacatggt 2521 gggtcagcttttttttttttttttttaactttctttctcagcattctctttggagttcaa 2581 cctagcgcccatgagccaggctgaggaagctgagtgagaagccaggtgggcgggacttgt 2641 tcccaggaaggccgggtggggaggaagcctagagggaaccccaggaagggcaaatccagg 2701 caaatctgcaggaatgctctgccatgggagcagctcctcccttgccacggccaccttctc 2761 tagcactgcaaggtccacagggcattgctttcctttctaggcggtggcagtcagggaaca 2821 gactgaggtaggtgtaggggggtctaggccttcgtggagcaccccagggagttagtaggc 2881 cccggggagacagagtctgcacaggccctttctggggccacctccatccacgaggagcag 2941 cctgagccttggtggccgaaccttgaccgtcccggagcacagcttcagggcagggaaccg 3001 gagcccctggggggcctcacgggtgtgacgaggcccttcattgcaggcaggtgggccaat 3061 gggagccctcacccacgcaagccgagacaccacccagagtgcaggctgcctggccccttc 3121 tggcacggccagctccacaccccctgcctagggtatgtgtggtcctaagggctaggagct 3181 tcccctactaacatctcccagaaaaagcagttaagcccctcagggcacagcaaggttaga 3241 cacagcccccatccccagatcaggactccatcttgctaagtggcatcaccgtcaccagcc 3301 tccccttatttaaaagcagcgactggtgttgccgcaggtacctggtctacgaagacgcag 3361 gcatccctctcccaccgtccacctccccgggggccgctgacagcacagtcgcctgggtgc 3421 acgcttgtgggggcagcaggaacggggctgtcggctctcaggggatctggctgcagccag 3481 ggcgagggcctggcccttccttccagctccttccggctccttccagctgaagggcaggaa 3541 gctctggccgcttagcttctagggttccatctccctagaaaggtgcccacgcccagggca 3601 tcagtcagtagcggcagcagcagcagactcggggctttcccagggtggcgcagccacccc 3661 agctgcatgtcacctcagctctccatcttattgccattttgtagatgaggaagctgagac 3721 cagaaaggctaagacccatgccccaggcaccacacccatctcttgggggctgggcacctg 3781 ctacccgaggccacctcctgaagcccccactcttcccccatgttccacttcaggagccgc 3841 gggggcccatcctgacacccggggttcctcagcccagcgcagatgtgcttcagttccaga 3901 gggcttgttgatttgtttcttaggtacgttacctgtccaccctgagtccagtgaggctgt 3961 cccaagagcccctgtagtgtgctcctgggaagggctgggggggctgggggggctgggaga 4021 ggcccaggggcagctgtcactggaaccccagccagatgtccaaggaagccggccagaaca 4081 cggagcagccagatggccccagctgcacctgtctagggagcccatgcagcctccttgcac 4141 tggagaagcagctgtgaaagtagacagagttgagacttcgccgtggtcaggagaaaatgc 4201 aaattcccaggaacaagaatcctttaagtgatatgtttttataaaactaaacaaatcaac 4261 aaataaatcttgaaggcggatggttttcccagcagtgcaggggttggagggaggctgctg 4321 gcactcctggggccaagggggacaggcagtggtcctgagtctgctcagagaggcaaggca 4381 gaaggagctcgccaggcaggtcagctcacatctgtccaagtcgctctggtcagaaacagc 4441 gactctcccccattcccccagcgttcccaccaggcctgggctgctgggaagcccttgctg 4501 tacccaggagcccgacccgcagtatcctggcacagagccacttgtcactcagaacagtca 4561 gtgtctccaacgcacaaacatccactcctctgttaccagttaaagcactttaatgcttta 4621 aggtgaaaacgaaatcccatccgtgtttttcgtgtaagatcgtgcttctccgagcagtat 4681 taatggacgccctccaatgacataacaactgtttttggtaatgtaatcttgggaaaatgt 4741 gttatttttttagctgtgtttcagtggggatttttgtttttgtaacataataaagtgtat 4801 gttccaatga SEQIDNO:121HumanTP73isoform10aminoacidsequence(NP_001191115.1) 1 maqstatspdggttfehlwsslepdstyfdlpqssrgnnevvggtdssmdvfhlegmtts 61 vmaqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntd 121 ypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampv 181 ykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpy 241 eppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgr 301 drkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvr 361 grenfeilmklkeslelmelvpqplvdsyrqqqqllqrptwgp SEQIDNO:122HumanTP73transcriptvariant11cDNAsequence (NM_001204187.1;CDS:NP_001191116.1) 1 maqstatspdggttfehlwsslepdstyfdlpqssrgnnevvggtdssmdvfhlegmtts 61 vmaqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntd 121 ypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampv 181 ykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpy 241 eppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgr 301 drkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvr 361 grenfeilmklkeslelmelvpqplvdsyrqqqqllqrpprdaqqpwprsasqrrdeqqp 421 qrpvhglgvplhsatplprrpqprqdlgalkipeqyrmtiwrglqdlkqghdystaqqll 481 rssnaatisiggsgelqrqrvmeavhfrvrhtitipnrggpgggpdewadfgfdlpdcka 541 rkqpikeefteaeih SEQIDNO:123HumanTP73isoform11aminoacidsequence(NP_001191116.1) 1 maqstatspdggttfehlwsslepdstyfdlpqssrgnnevvggtdssmdvfhlegmtts 61 vmaqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntd 121 ypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampv 181 ykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpy 241 eppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgr 301 drkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvr 361 grenfeilmklkeslelmelvpqplvdsyrqqqqllqrpprdaqqpwprsasqrrdeqqp 421 qrpvhglgvplhsatplprrpqprqdlgalkipeqyrmtiwrglqdlkqghdystaqqll 481 rssnaatisiggsgelqrqrvmeavhfrvrhtitipnrggpgggpdewadfgfdlpdcka 541 rkqpikeefteaeih SEQIDNO:124HumanTP73transcriptvariant12cDNAsequence (NM_001204188.1;CDS:111-1733) 1 aggggacgcagcgaaaccggggcccgcgccaggccagccgggacggacgccgatgcccgg 61 ggctgcgacggctgcagagcgagctgccctcggaggccggcgtggggaagatggcccagt 121 ccaccgccacctcccctgatgggggcaccacgtttgagcacctctggagctctctggaac 181 cagacagcacctacttcgaccttccccagtcaagccgggggaataatgaggtggtgggcg 241 gaacggattccagcatggacgtcttccacctggagggcatgactacatctgtcatggccc 301 agttcaatctgctgagcagcaccatggaccagatgagcagccgcgcggcctcggccagcc 361 cctacaccccagagcacgccgccagcgtgcccacccactcgccctacgcacaacccagct 421 ccaccttcgacaccatgtcgccggcgcctgtcatcccctccaacaccgactaccccggac 481 cccaccactttgaggtcactttccagcagtccagcacggccaagtcagccacctggacgt 541 actccccgctcttgaagaaactctactgccagatcgccaagacatgccccatccagatca 601 aggtgtccaccccgccacccccaggcaccgccatccgggccatgcctgtttacaagaaag 661 cggagcacgtgaccgacgtcgtgaaacgctgccccaaccacgagctcgggagggacttca 721 acgaaggacagtctgctccagccagccacctcatccgcgtggaaggcaataatctctcgc 781 agtatgtggatgaccctgtcaccggcaggcagagcgtcgtggtgccctatgagccaccac 841 aggtggggacggaattcaccaccatcctgtacaacttcatgtgtaacagcagctgtgtag 901 ggggcatgaaccggcggcccatcctcatcatcatcaccctggagatgcgggatgggcagg 961 tgctgggccgccggtcctttgagggccgcatctgcgcctgtcctggccgcgaccgaaaag 1021 ctgatgaggaccactaccgggagcagcaggccctgaacgagagctccgccaagaacgggg 1081 ccgccagcaagcgtgccttcaagcagagcccccctgccgtccccgcccttggtgccggtg 1141 tgaagaagcggcggcatggagacgaggacacgtactaccttcaggtgcgaggccgggaga 1201 actttgagatcctgatgaagctgaaagagagcctggagctgatggagttggtgccgcagc 1261 cactggtggactcctatcggcagcagcagcagctcctacagaggccttttttaacaggat 1321 tggggtgtccaaactgcatcgagtatttcacctcccaagggttacagagcatttaccacc 1381 tgcagaacctgaccattgaggacctgggggccctgaagatccccgagcagtaccgcatga 1441 ccatctggcggggcctgcaggacctgaagcagggccacgactacagcaccgcgcagcagc 1501 tgctccgctctagcaacgcggccaccatctccatcggcggctcaggggaactgcagcgcc 1561 agcgggtcatggaggccgtgcacttccgcgtgcgccacaccatcaccatccccaaccgcg 1621 gcggcccaggcggcggccctgacgagtgggcggacttcggcttcgacctgcccgactgca 1681 aggcccgcaagcagcccatcaaggaggagttcacggaggccgagatccactgagggcctc 1741 gcctggctgcagcctgcgccaccgcccagagacccaagctgcctcccctctccttcctgt 1801 gtgtccaaaactgcctcaggaggcaggaccttcgggctgtgcccggggaaaggcaaggtc 1861 cggcccatccccaggcacctcacaggccccaggaaaggcccagccaccgaagccgcctgt 1921 ggacagcctgagtcacctgcagaaccttctggagctgccctagtgctgggcttgtggggc 1981 gggggctggcccactctcagccctgccactgccccggcgtgctccatggcaggcgtgggt 2041 ggggaccgcagcgtcggctccgacttccaggcttcatcctagagactgtcatctcccaac 2101 caggcgaggtccttccaaaggaaaggatcctctttgctgatggactgccaaaaagtattt 2161 tgcgacatcttttggttctggatagtagtgagcagccaagtgactgtgtctgaaacacca 2221 gtgtattttcagggaatgtccctaactgcgtcttgcccgcgccgggggctggggactctc 2281 tctgctggacttgggactggcctctgcccccagcacgctgtattctgcaggaccgcctcc 2341 ttcctgcccctaacaacaaccacagtgttgctgaaattggagaaaactggggagggcgca 2401 accccccccaggcgcggggaagcatgtggtaccgcctcagccagtgcccctcagcctggc 2461 cacagtcgcctctcctcggggacccctcagcagaaagggacagcctgtccttagaggact 2521 ggaaattgtcaatatttgataaaatgatacccttttctacatggtgggtcagcttttttt 2581 tttttttttttaactttctttctcagcattctctttggagttcaacctagcgcccatgag 2641 ccaggctgaggaagctgagtgagaagccaggtgggcgggacttgttcccaggaaggccgg 2701 gtggggaggaagcctagagggaaccccaggaagggcaaatccaggcaaatctgcaggaat 2761 gctctgccatgggagcagctcctcccttgccacggccaccttctctagcactgcaaggtc 2821 cacagggcattgctttcctttctaggcggtggcagtcagggaacagactgaggtaggtgt 2881 aggggggtctaggccttcgtggagcaccccagggagttagtaggccccggggagacagag 2941 tctgcacaggccctttctggggccacctccatccacgaggagcagcctgagccttggtgg 3001 ccgaaccttgaccgtcccggagcacagcttcagggcagggaaccggagcccctggggggc 3061 ctcacgggtgtgacgaggcccttcattgcaggcaggtgggccaatgggagccctcaccca 3121 cgcaagccgagacaccacccagagtgcaggctgcctggccccttctggcacggccagctc 3181 cacaccccctgcctagggtatgtgtggtcctaagggctaggagcttcccctactaacatc 3241 tcccagaaaaagcagttaagcccctcagggcacagcaaggttagacacagcccccatccc 3301 cagatcaggactccatcttgctaagtggcatcaccgtcaccagcctccccttatttaaaa 3361 gcagcgactggtgttgccgcaggtacctggtctacgaagacgcaggcatccctctcccac 3421 cgtccacctccccgggggccgctgacagcacagtcgcctgggtgcacgcttgtgggggca 3481 gcaggaacggggctgtcggctctcaggggatctggctgcagccagggcgagggcctggcc 3541 cttccttccagctccttccggctccttccagctgaagggcaggaagctctggccgcttag 3601 cttctagggttccatctccctagaaaggtgcccacgcccagggcatcagtcagtagcggc 3661 agcagcagcagactcggggctttcccagggtggcgcagccaccccagctgcatgtcacct 3721 cagctctccatcttattgccattttgtagatgaggaagctgagaccagaaaggctaagac 3781 ccatgccccaggcaccacacccatctcttgggggctgggcacctgctacccgaggccacc 3841 tcctgaagcccccactcttcccccatgttccacttcaggagccgcgggggcccatcctga 3901 cacccggggttcctcagcccagcgcagatgtgcttcagttccagagggcttgttgatttg 3961 tttcttaggtacgttacctgtccaccctgagtccagtgaggctgtcccaagagcccctgt 4021 agtgtgctcctgggaagggctgggggggctgggggggctgggagaggcccaggggcagct 4081 gtcactggaaccccagccagatgtccaaggaagccggccagaacacggagcagccagatg 4141 gccccagctgcacctgtctagggagcccatgcagcctccttgcactggagaagcagctgt 4201 gaaagtagacagagttgagacttcgccgtggtcaggagaaaatgcaaattcccaggaaca 4261 agaatcctttaagtgatatgtttttataaaactaaacaaatcaacaaataaatcttgaag 4321 gcggatggttttcccagcagtgcaggggttggagggaggctgctggcactcctggggcca 4381 agggggacaggcagtggtcctgagtctgctcagagaggcaaggcagaaggagctcgccag 4441 gcaggtcagctcacatctgtccaagtcgctctggtcagaaacagcgactctcccccattc 4501 ccccagcgttcccaccaggcctgggctgctgggaagcccttgctgtacccaggagcccga 4561 cccgcagtatcctggcacagagccacttgtcactcagaacagtcagtgtctccaacgcac 4621 aaacatccactcctctgttaccagttaaagcactttaatgctttaaggtgaaaacgaaat 4681 cccatccgtgtttttcgtgtaagatcgtgcttctccgagcagtattaatggacgccctcc 4741 aatgacataacaactgtttttggtaatgtaatcttgggaaaatgtgttatttttttagct 4801 gtgtttcagtggggatttttgtttttgtaacataataaagtgtatgttccaatgaaaaaa 4861 aaaaaa SEQIDNO:125HumanTP73isoform12aminoacidsequence(NP_001191117.1) 1 maqstatspdggttfehlwsslepdstyfdlpqssrgnnevvggtdssmdvfhlegmtts 61 vmaqfnllsstmdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntd 121 ypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampv 181 ykkaehvtdvvkrcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpy 241 eppqvgtefttilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgr 301 drkadedhyreqqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvr 361 grenfeilmklkeslelmelvpqplvdsyrqqqqllqrpfltglgcpncieyftsqglqs 421 iyhlqnltiedlgalkipeqyrmtiwrglqdlkqghdystaqqllrssnaatisiggsge 481 lqrqrvmeavhfrvrhtitipnrggpgggpdewadfgfdlpdckarkqpikeefteaeih SEQIDNO:126HumanTP73transcriptvariant13cDNAsequence (NM_001204192.2;CDS:134-1831) 1 aatgtgtgctggaaggtgtccaggaagccctgctaagcatctgtcagtgtctccagcaca 61 gcaggaggctgttacaggtggcgcctgattcacatctgcaggacaggcccagttcaatct 121 gctgagcagcaccatggaccagatgagcagccgcgcggcctcggccagcccctacacccc 181 agagcacgccgccagcgtgcccacccactcgccctacgcacaacccagctccaccttcga 241 caccatgtcgccggcgcctgtcatcccctccaacaccgactaccccggaccccaccactt 301 tgaggtcactttccagcagtccagcacggccaagtcagccacctggacgtactccccgct 361 cttgaagaaactctactgccagatcgccaagacatgccccatccagatcaaggtgtccac 421 cccgccacccccaggcaccgccatccgggccatgcctgtttacaagaaagcggagcacgt 481 gaccgacgtcgtgaaacgctgccccaaccacgagctcgggagggacttcaacgaaggaca 541 gtctgctccagccagccacctcatccgcgtggaaggcaataatctctcgcagtatgtgga 601 tgaccctgtcaccggcaggcagagcgtcgtggtgccctatgagccaccacaggtggggac 661 ggaattcaccaccatcctgtacaacttcatgtgtaacagcagctgtgtagggggcatgaa 721 ccggcggcccatcctcatcatcatcaccctggagatgcgggatgggcaggtgctgggccg 781 ccggtcctttgagggccgcatctgcgcctgtcctggccgcgaccgaaaagctgatgagga 841 ccactaccgggagcagcaggccctgaacgagagctccgccaagaacggggccgccagcaa 901 gcgtgccttcaagcagagcccccctgccgtccccgcccttggtgccggtgtgaagaagcg 961 gcggcatggagacgaggacacgtactaccttcaggtgcgaggccgggagaactttgagat 1021 cctgatgaagctgaaagagagcctggagctgatggagttggtgccgcagccactggtgga 1081 ctcctatcggcagcagcagcagctcctacagaggccgagtcacctacagcccccgtccta 1141 cgggccggtcctctcgcccatgaacaaggtgcacgggggcatgaacaagctgccctccgt 1201 caaccagctggtgggccagcctcccccgcacagttcggcagctacacccaacctggggcc 1261 cgtgggccccgggatgctcaacaaccatggccacgcagtgccagccaacggcgagatgag 1321 cagcagccacagcgcccagtccatggtctcggggtcccactgcactccgccaccccccta 1381 ccacgccgaccccagcctcgtcagttttttaacaggattggggtgtccaaactgcatcga 1441 gtatttcacctcccaagggttacagagcatttaccacctgcagaacctgaccattgagga 1501 cctgggggccctgaagatccccgagcagtaccgcatgaccatctggcggggcctgcagga 1561 cctgaagcagggccacgactacagcaccgcgcagcagctgctccgctctagcaacgcggc 1621 caccatctccatcggcggctcaggggaactgcagcgccagcgggtcatggaggccgtgca 1681 cttccgcgtgcgccacaccatcaccatccccaaccgcggcggcccaggcggcggccctga 1741 cgagtgggcggacttcggcttcgacctgcccgactgcaaggcccgcaagcagcccatcaa 1801 ggaggagttcacggaggccgagatccactgagggcctcgcctggctgcagcctgcgccac 1861 cgcccagagacccaagctgcctcccctctccttcctgtgtgtccaaaactgcctcaggag 1921 gcaggaccttcgggctgtgcccggggaaaggcaaggtccggcccatccccaggcacctca 1981 caggccccaggaaaggcccagccaccgaagccgcctgtggacagcctgagtcacctgcag 2041 aaccttctggagctgccctagtgctgggcttgtggggcgggggctggcccactctcagcc 2101 ctgccactgccccggcgtgctccatggcaggcgtgggtggggaccgcagcgtcggctccg 2161 acttccaggcttcatcctagagactgtcatctcccaaccaggcgaggtccttccaaagga 2221 aaggatcctctttgctgatggactgccaaaaagtattttgcgacatcttttggttctgga 2281 tagtagtgagcagccaagtgactgtgtctgaaacaccagtgtattttcagggaatgtccc 2341 taactgcgtcttgcccgcgccgggggctggggactctctctgctggacttgggactggcc 2401 tctgcccccagcacgctgtattctgcaggaccgcctccttcctgcccctaacaacaacca 2461 cagtgttgctgaaattggagaaaactggggagggcgcaaccccccccaggcgcggggaag 2521 catgtggtaccgcctcagccagtgcccctcagcctggccacagtcgcctctcctcgggga 2581 cccctcagcagaaagggacagcctgtccttagaggactggaaattgtcaatatttgataa 2641 aatgatacccttttctacatggtgggtcagcttttttttttttttttttaactttctttc 2701 tcagcattctctttggagttcaacctagcgcccatgagccaggctgaggaagctgagtga 2761 gaagccaggtgggcgggacttgttcccaggaaggccgggtggggaggaagcctagaggga 2821 accccaggaagggcaaatccaggcaaatctgcaggaatgctctgccatgggagcagctcc 2881 tcccttgccacggccaccttctctagcactgcaaggtccacagggcattgctttcctttc 2941 taggcggtggcagtcagggaacagactgaggtaggtgtaggggggtctaggccttcgtgg 3001 agcaccccagggagttagtaggccccggggagacagagtctgcacaggccctttctgggg 3061 ccacctccatccacgaggagcagcctgagccttggtggccgaaccttgaccgtcccggag 3121 cacagcttcagggcagggaaccggagcccctggggggcctcacgggtgtgacgaggccct 3181 tcattgcaggcaggtgggccaatgggagccctcacccacgcaagccgagacaccacccag 3241 agtgcaggctgcctggccccttctggcacggccagctccacaccccctgcctagggtatg 3301 tgtggtcctaagggctaggagcttcccctactaacatctcccagaaaaagcagttaagcc 3361 cctcagggcacagcaaggttagacacagcccccatccccagatcaggactccatcttgct 3421 aagtggcatcaccgtcaccagcctccccttatttaaaagcagcgactggtgttgccgcag 3481 gtacctggtctacgaagacgcaggcatccctctcccaccgtccacctccccgggggccgc 3541 tgacagcacagtcgcctgggtgcacgcttgtgggggcagcaggaacggggctgtcggctc 3601 tcaggggatctggctgcagccagggcgagggcctggcccttccttccagctccttccggc 3661 tccttccagctgaagggcaggaagctctggccgcttagcttctagggttccatctcccta 3721 gaaaggtgcccacgcccagggcatcagtcagtagaggcagcagcagcagactaggggctt 3781 tcccagggtggcgcagccaccccagctgcatgtcacctcagctctccatcttattgccat 3841 tttgtagatgaggaagctgagaccagaaaggctaagacccatgccccaggcaccacaccc 3901 atctcttgggggctgggcacctgctacccgaggccacctcctgaagcccccactcttccc 3961 ccatgttccacttcaggagccgcgggggcccatcctgacacccggggttcctcagcccag 4021 cgcagatgtgcttcagttccagagggcttgttgatttgtttcttaggtacgttacctgtc 4081 caccctgagtccagtgaggctgtcccaagagcccctgtagtgtgctcctgggaagggctg 4141 ggggggctgggggggctgggagaggcccaggggcagctgtcactggaaccccagccagat 4201 gtccaaggaagccggccagaacacggagcagccagatggccccagctgcacctgtctagg 4261 gagcccatgcagcctccttgcactggagaagcagctgtgaaagtagacagagttgagact 4321 tcgccgtggtcaggagaaaatgcaaattcccaggaacaagaatcctttaagtgatatgtt 4381 tttataaaactaaacaaatcaacaaataaatcttgaaggcggatggttttcccagcagtg 4441 caggggttggagggaggctgctggcactcctggggccaagggggacaggcagtggtcctg 4501 agtctgctcagagaggcaaggcagaaggagctcgccaggcaggtcagctcacatctgtcc 4561 aagtcgctctggtcagaaacagcgactctcccccattcccccagcgttcccaccaggcct 4621 gggctgctgggaagcccttgctgtacccaggagcccgacccgcagtatcctggcacagag 4681 ccacttgtcactcagaacagtcagtgtctccaacgcacaaacatccactcctctgttacc 4741 agttaaagcactttaatgctttaaggtgaaaacgaaatcccatccgtgtttttcgtgtaa 4801 gatcgtgcttctccgagcagtattaatggacgccctccaatgacataacaactgtttttg 4861 gtaatgtaatcttgggaaaatgtgttatttttttagctgtgtttcagtggggatttttgt 4921 ttttgtaacataataaagtgtatgttccaatga SEQIDNO:127HumanTP73isoform13aminoacidsequence(NP_001191121.1) 1 mdqmssraasaspytpehaasvpthspyaqpsstfdtmspapvipsntdypgphhfevtf 61 qqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampvykkaehvtdvv 121 krcpnhelgrdfnegqsapashlirvegnnlsqyvddpvtgrqsvvvpyeppqvgteftt 181 ilynfmcnsscvggmnrrpiliiitlemrdgqvlgrrsfegricacpgrdrkadedhyre 241 qqalnessakngaaskrafkqsppavpalgagvkkrrhgdedtyylqvrgrenfeilmkl 301 keslelmelvpqplvdsyrqqqqllqrpshlqppsygpvlspmnkvhggmnklpsvnqlv 361 gqppphssaatpnlgpvgpgmlnnhghavpangemssshsaqsmvsgshctppppyhadp 421 slvsfltglgcpncieyftsqglqsiyhlqnitiedlgalkipeqyrmtiwrglqdlkqg 481 hdystaqqllrssnaatisiggsgelqrqrvmeavhfrvrhtitipnrggpgggpdewad 541 fgfdlpdckarkqpikeefteaeih SEQIDNO:128MouseTP73transcriptvariant1cDNAsequence(NM_011642.4; CDS:76-1971) 1 gaggcaacgctgcagcccagccctcgccgacgccgacgcccggcccggagcagaatgagc 61 ggcagcgttggggagatggcccagacctcttcttcctcctcctccaccttcgagcacctg 121 tggagttctctagagccagacagcacctactttgacctcccccagcccagccaagggact 181 agcgaggcatcaggcagcgaggagtccaacatggatgtcttccacctgcaaggcatggcc 241 cagttcaatttgctcagcagtgccatggaccagatgggcagccgtgcggccccggcgagc 301 ccctacaccccggagcacgccgccagcgcgcccacccactcgccctacgcgcagcccagc 361 tccaccttcgacaccatgtctccggcgcctgtcatcccttccaataccgactaccccggc 421 ccccaccacttcgaggtcaccttccagcagtcgagcactgccaagtcggccacctggaca 481 tactccccactcttgaagaagttgtactgtcagattgctaagacatgccccatccagatc 541 aaagtgtccacaccaccacccccgggcacggccatccgggccatgcctgtctacaagaag 601 gcagagcatgtgaccgacattgttaagcgctgccccaaccacgagcttggaagggacttc 661 aatgaaggacagtctgccccggctagccacctcatccgtgtagaaggcaacaacctcgcc 721 cagtacgtggatgaccctgtcaccggaaggcagagtgtggttgtgccgtatgaaccccca 781 caggtgggaacagaatttaccaccatcctgtacaacttcatgtgtaacagcagctgtgtg 841 gggggcatgaataggaggcccatccttgtcatcatcaccctggagacccgggatggacag 901 gtcctgggccgccggtctttcgagggtcgcatctgtgcctgtcctggccgtgaccgcaaa 961 gctgatgaagaccattaccgggagcaacaggctctgaatgaaagtaccaccaaaaatgga 1021 gctgccagcaaacgtgcattcaagcagagcccccctgccatccctgccctgggtaccaac 1081 gtgaagaagagacgccacggggacgaggacatgttctacatgcacgtgcgaggccgggag 1141 aactttgagatcttgatgaaagtcaaggagagcctagaactgatggagcttgtgccccag 1201 cctttggttgactcctatcgacagcagcagcagcagcagctcctacagaggccgagtcac 1261 ctgcagcctccatcctatgggcccgtgctctccccaatgaacaaggtacacggtggtgtc 1321 aacaaactgccctccgtcaaccagctggtgggccagcctcccccgcacagctcagcagct 1381 gggcccaacctggggcccatgggctccgggatgctcaacagccacggccacagcatgccg 1441 gccaatggtgagatgaatggaggccacagctcccagaccatggtttcgggatcccactgc 1501 accccgccacccccctatcatgcagaccccagcctcgtcagttttttgacagggttgggg 1561 tgtccaaactgcatcgagtgcttcacttcccaagggttgcagagcatctaccacctgcag 1621 aaccttaccatcgaggaccttggggctctgaaggtccctgaccagtaccgtatgaccatc 1681 tggaggggcctacaggacctgaagcagagccatgactgcggccagcaactgctacgctcc 1741 agcagcaacgcggccaccatctccatcggcggctctggcgagctgcagcggcagcgggtc 1801 atggaagccgtgcatttccgtgtgcgccacaccatcacgatccccaaccgtggaggcgca 1861 ggtgcggtgacaggtcccgacgagtgggcggactttggctttgacctgcctgactgcaag 1921 tcccgtaagcagcccatcaaagaggagttcacagagacagagagccactgaggaacgtac 1981 cttcttctcctgtccttcctctgtgagaaactgctcttggaagtgggacctgttggctgt 2041 gcccacagaaaccagcaaggaccttctgccggatgccattcctgaagggaagtcgctcat 2101 gaactaactccctcttggaaacttctggaactgcccttagctacatatacacaagggcag 2161 gtggtgagccaagtgctgagacagggagctgtccctttgtgggtgggtatgcagcaccca 2221 tttgcttctcccgttctctattgaggactctgccacctccaggacagagcagcatccttc 2281 acttgctcaccctctgccacaaagtattccaacatcttctgttcctgctaaccatgcaca 2341 gcccagcctctgtgtcatcagcgcttacgtacaggtcgattccactgtgtcttgaaagtg 2401 aattcagggccagagacatcttctgcaggatgtgtggacagatctgtccctaatgtaggt 2461 cattctgccgttaccccttgtctcccgagtcttgattgctggggtcagggaagactgtgg 2521 cagagcaggggaagccgctggccctccgcctctagccagcaccctgaacatgctggctgt 2581 agcagcctctagggacctctctggtcagacaaagggacagaatgagtctcagactaccga 2641 aaattgaattgtcaatatttgataaaaggttactctttctacttggtggggtcagcttgc 2701 tttttcccccctctctgactctctcagcattcctttctgagatcagcctagtgtgtccac 2761 acgtacttctcaacaagtctaaaacgccgagcatcaatccaggaagggtccttacctgtt 2821 accaggatggttggaagggaaagagactcagagagagcatagccgtgggagtgcaggtca 2881 gacagaccccagctgtgaggaacatctgttctcactaagtgctcagagtctgggctctgt 2941 gcctgagtgctagcccatcctcgtggcctggaactggagtggctgctgggggccctggtc 3001 ttcatgattcatccccaaagagtcagtggctagagaaacagctcctgcatgcattcagcc 3061 aatggggccctgtacctgccagaagctttgtgaacttctgcaatgagagcccccagcagt 3121 ccctgccaggagtggagaagcacagaggagcccctgccaacagtaaagcccaacatctgc 3181 cgagtcactttggagccatcctctttaggcttggctttcattagcaaggcccaacagagg 3241 cagtgacgtccgtgggatagcctcagagtcagcactaccagggctggcgtcatatcaggg 3301 ctgcctcctcgaagcccagggacaatgttgccaatcttagcaatcttagcaagctctgca 3361 aacttaggtggttaccacccatgctatgcttcatgaatctctgaggggcaggatttgggt 3421 gcacttagggtaggtgcaggcatcacattgtcagagaccagtgctgaccatacaggcctt 3481 tccaacttgacagatgttgacagcttaggctctgggggggtggggggttcctgcacccag 3541 atgggccgttaacagctgcagcatcaggcttgcttcttgggtgtaggttgtggccctccc 3601 agtgagtggtaacacacttcacaaagcctgaggttgactacacacttcttgttgctgctc 3661 agatgaggaagctgaggctagacagactgagtgccctgcctcgggcatcagctcattgca 3721 gaagtgggtgttcactcctgaggtacatgctgccccatgctacctcagaaactaggcagc 3781 acattctcactcctaggcctgtgaaccccactgagatgcgcttgcgttctgggatctcac 3841 ataagtatgtctcaggcattgtccaggagggaccatcctaagcgccccaccacatgctcc 3901 tgggaaggaggagtggttaggaggagtggttgtcaccaggcatctgaggagggaagagcc 3961 cccctccagcaaggacccagggcttgtgtctccctagaccctgcctcaagtgccaaagct 4021 gtctcgtgagcttccaggatcctgacaggcctggagggaactgcaaagggccatctgcca 4081 ggaaataaacgtcacagaggcaatgcttgcagtgcctgagaagctctccaggaaccagcc 4141 tttgggtctgaaccaaactttgttctacaaaacacagaaagcaagagaaagcaaatcttc 4201 cagccaccaactttcccaggagcactggagtactagtttggaaacaagtttgggggtgcc 4261 ctggaagacatctgttgagcaagggcaggttgagcagggctgtaaaagcaggccactcca 4321 gcctcagtctgtatggtcccatccagctttgtgcatccaattaacagcagctcccatgtc 4381 ccttcctggccttgcttaccgtgcctgacagctctaccttgggctgctttgagcttgtga 4441 gttcgcagaaccagcacccctacgcaagaatcctgcaagggtcaaaagttgccacttagt 4501 tgcatttcagatgggagacaaaaaccaaaactaaattgtccatgtttcaatgtgatgaaa 4561 tgcttctccaagcagtattgatggatacagtctagtgactctattaactgttttgggtga 4621 tgtcattttagaaaaatgtgttattttttttagctgtgtttcggtgggaatttttgtttt 4681 tgtaatataataaaaatcacatgttcccat SEQIDNO:129MouseTP73isoform1aminoacidsequence(NP_035772.3) 1 maqtsssssstfehlwsslepdstyfdlpqpsqgtseasgseesnmdvfhlqgmaqfnll 61 ssamdqmgsraapaspytpehaasapthspyaqpsstfdtmspapvipsntdypgphhfe 121 vtfqqsstaksatwtyspllkklycqiaktcpiqikvstppppgtairampvykkaehvt 181 divkrcpnhelgrdfnegqsapashlirvegnnlaqyvddpvtgrqsvvvpyeppqvgte 241 fttilynfmcnsscvggmnrrpilviitletrdgqvlgrrsfegricacpgrdrkadedh 301 yreqqalnesttkngaaskrafkgsppaipalgtnvkkrrhgdedmfymhvrgrenfeil 361 mkvkeslelmelvpqplvdsyrqqqqqqllqrpshlqppsygpvlspmnkvhggvnklps 421 vnqlvgqppphssaagpnlgpmgsgmlnshghsmpangemngghssqtmvsgshctpppp 481 yhadpslvsfltglgcpnciecftsqglqsiyhlqnltiedlgalkvpdqyrmtiwrglq 541 dlkqshdcgqqllrsssnaatisiggsgelqrqrvmeavhfrvrhtitipnrggagavtg 601 pdewadfgfdlpdcksrkqpikeeftetesh SEQIDNO:130MouseTP73transcriptvariant2cDNAsequence (NM_001126330.1;CDS:242-2014) 1 gttgttggatgcagccagttgacagaaatgagggagatgggcagggtgagaatgccaact 61 ctcagtccgcacgcctctgagcatcctccgctcctgccttcctagccacagagcctcaac 121 ccctcagtccaccccaccgggcagccaccagtctacccctaccccacctagccacccaga 181 cccatgcctcgtcccgcggcacaccagctcctcagcgtgtgcagacccccacgagcctac 241 catgctttacgtcggtgaccccatgagacacctcgccacggcccagttcaatttgctcag 301 cagtgccatggaccagatgggcagccgtgcggccccggcgagcccctacaccccggagca 361 cgccgccagcgcgcccacccactcgccctacgcgcagcccagctccaccttcgacaccat 421 gtctccggcgcctgtcatcccttccaataccgactaccccggcccccaccacttcgaggt 481 caccttccagcagtcgagcactgccaagtcggccacctggacatactccccactcttgaa 541 gaagttgtactgtcagattgctaagacatgccccatccagatcaaagtgtccacaccacc 601 acccccgggcacggccatccgggccatgcctgtctacaagaaggcagagcatgtgaccga 661 cattgttaagcgctgccccaaccacgagcttggaagggacttcaatgaaggacagtctgc 721 cccggctagccacctcatccgtgtagaaggcaacaacctcgcccagtacgtggatgaccc 781 tgtcaccggaaggcagagtgtggttgtgccgtatgaacccccacaggtgggaacagaatt 841 taccaccatcctgtacaacttcatgtgtaacagcagctgtgtggggggcatgaatcggag 901 gcccatccttgtcatcatcaccctggagacccgggatggacaggtcctgggccgccggtc 961 tttcgagggtcgcatctgtgcctgtcctggccgtgaccgcaaagctgatgaagaccatta 1021 ccgggagcaacaggctctgaatgaaagtaccaccaaaaatggagctgccagcaaacgtgc 1081 attcaagcagagcccccctgccatccctgccctgggtaccaacgtgaagaagagacgcca 1141 cggggacgaggacatgttctacatgcacgtgcgaggccgggagaactttgagatcttgat 1201 gaaagtcaaggagagcctagaactgatggagcttgtgccccagcctttggttgactccta 1261 tcgacagcagcagcagcagcagctcctacagaggccgagtcacctgcagcctccatccta 1321 tgggcccgtgctctccccaatgaacaaggtacacggtggtgtcaacaaactgccctccgt 1381 caaccagctggtgggccagcctcccccgcacagctcagcagctgggcccaacctggggcc 1441 catgggctccgggatgctcaacagccacggccacagcatgccggccaatggtgagatgaa 1501 tggaggccacagctcccagaccatggtttcgggatcccactgcaccccgccaccccccta 1561 tcatgcagaccccagcctcgtcagttttttgacagggttggggtgtccaaactgcatcga 1621 gtgcttcacttcccaagggttgcagagcatctaccacctgcagaaccttaccatcgagga 1681 ccttggggctctgaaggtccctgaccagtaccgtatgaccatctggaggggcctacagga 1741 cctgaagcagagccatgactgcggccagcaactgctacgctccagcagcaacgcggccac 1801 catctccatcggcggctctggcgagctgcagcggcagcgggtcatggaagccgtgcattt 1861 ccgtgtgcgccacaccatcacgatccccaaccgtggaggcgcaggtgcggtgacaggtcc 1921 cgacgagtgggcggactttggctttgacctgcctgactgcaagtcccgtaagcagcccat 1981 caaagaggagttcacagagacagagagccactgaggaacgtaccttcttctcctgtcctt 2041 cctctgtgagaaactgctcttggaagtgggacctgttggctgtgcccacagaaaccagca 2101 aggaccttctgccggatgccattcctgaagggaagtcgctcatgaactaactccctcttg 2161 gaaacttctggaactgcccttagctacatatacacaagggcaggtggtgagccaagtgct 2221 gagacagggagctgtccctttgtgggtgggtatgcagcacccatttgcttctcccgttct 2281 ctattgaggactctgccacctccaggacagagcagcatccttcacttgctcaccctctgc 2341 cacaaagtattccaacatcttctgttcctgctaaccatgcacagcccagcctctgtgtca 2401 tcagcgcttacgtacaggtcgattccactgtgtcttgaaagtgaattcagggccagagac 2461 atcttctgcaggatgtgtggacagatctgtccctaatgtaggtcattctgccgttacccc 2521 ttgtctcccgagtcttgattgctggggtcagggaagactgtggcagagcaggggaagccg 2581 ctggccctccgcctctagccagcaccctgaacatgctggctgtagcagcctctagggacc 2641 tctctggtcagacaaagggacagaatgagtctcagactaccgaaaattgaattgtcaata 2701 tttgataaaaggttactctttctacttggtggggtcagcttgctttttcccccctctctg 2761 actctctcagcattcctttctgagatcagcctagtgtgtccacacgtacttctcaacaag 2821 tctaaaacgccgagcatcaatccaggaagggtccttacctgttaccaggatggttggaag 2881 ggaaagagactcagagagagcatagccgtgggagtgcaggtcagacagaccccagctgtg 2941 aggaacatctgttctcactaagtgctcagagtctgggctctgtgcctgagtgctagccca 3001 tcctcgtggcctggaactggagtggctgctgggggccctggtcttcatgattcatcccca 3061 aagagtcagtggctagagaaacagctcctgcatgcattcagccaatggggccctgtacct 3121 gccagaagctttgtgaacttctgcaatgagagcccccagcagtccctgccaggagtggag 3181 aagcacagaggagcccctgccaacagtaaagcccaacatctgccgagtcactttggagcc 3241 atcctctttaggcttggctttcattagcaaggcccaacagaggcagtgacgtccgtggga 3301 tagcctcagagtcagcactaccagggctggcgtcatatcagggctgcctcctcgaagccc 3361 agggacaatgttgccaatcttagcaatcttagcaagctctgcaaacttaggtggttacca 3421 cccatgctatgcttcatgaatctctgaggggcaggatttgggtgcacttagggtaggtgc 3481 aggcatcacattgtcagagaccagtgctgaccatacaggcctttccaacttgacagatgt 3541 tgacagcttaggctctgggggggtggggggttcctgcacccagatgggccgttaacagct 3601 gcagcatcaggcttgcttcttgggtgtaggttgtggccctcccagtgagtggtaacacac 3661 ttcacaaagcctgaggttgactacacacttcttgttgctgctcagatgaggaagctgagg 3721 ctagacagactgagtgccctgcctcgggcatcagctcattgcagaagtgggtgttcactc 3781 ctgaggtacatgctgccccatgctacctcagaaactaggcagcacattctcactcctagg 3841 cctgtgaaccccactgagatgcgcttgcgttctgggatctcacataagtatgtctcaggc 3901 attgtccaggagggaccatcctaagcgccccaccacatgctcctgggaaggaggagtggt 3961 taggaggagtggttgtcaccaggcatctgaggagggaagagcccccctccagcaaggacc 4021 cagggcttgtgtctccctagaccctgcctcaagtgccaaagctgtctcgtgagcttccag 4081 gatcctgacaggcctggagggaactgcaaagggccatctgccaggaaataaacgtcacag 4141 aggcaatgcttgcagtgcctgagaagctctccaggaaccagcctttgggtctgaaccaaa 4201 ctttgttctacaaaacacagaaagcaagagaaagcaaatcttccagccaccaactttccc 4261 aggagcactggagtactagtttggaaacaagtttgggggtgccctggaagacatctgttg 4321 agcaagggcaggttgagcagggctgtaaaagcaggccactccagcctcagtctgtatggt 4381 cccatccagctttgtgcatccaattaacagcagctcccatgtcccttcctggccttgctt 4441 accgtgcctgacagctctaccttgggctgctttgagcttgtgagttcgcagaaccagcac 4501 ccctacgcaagaatcctgcaagggtcaaaagttgccacttagttgcatttcagatgggag 4561 acaaaaaccaaaactaaattgtccatgtttcaatgtgatgaaatgcttctccaagcagta 4621 ttgatggatacagtctagtgactctattaactgttttgggtgatgtcattttagaaaaat 4681 gtgttattttttttagctgtgtttcggtgggaatttttgtttttgtaatataataaaaat 4741 cacatgttcccatggt SEQIDNO:131MouseTP73isoform2aminoacidsequence(NP_001119802.1) 1 mlyvgdpmrhlataqfnllssamdqmgsraapaspytpehaasapthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdivkrcpnhelgrdfnegqsapashlirvegnnlaqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpilviitletrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnesttkngaaskrafkqsppaipalgtnvkkrrh 301 gdedmfymhvrgrenfeilmkvkeslelmelvpqplvdsyrqqqqqqllqrpshlqppsy 361 gpvlspmnkvhggvnklpsvnqlvgqppphssaagpnlgpmgsgmlnshghsmpangemn 421 gghssqtmvsgshctppppyhadpslvsfltglgcpnciecftsqglqsiyhlqnltied 481 lgalkvpdqyrmtiwrglqdlkqshdcgqqllrsssnaatisiggsgelqrqrvmeavhf 541 rvrhtitipnrggagavtgpdewadfgfdlpdcksrkqpikeeftetesh SEQIDNO:132MouseTP73transcriptvariant3cDNAsequence (NM_001126331.1;CDS:242-1726) 1 gttgttggatgcagccagttgacagaaatgagggagatgggcagggtgagaatgccaact 61 ctcagtccgcacgcctctgagcatcctccgctcctgccttcctagccacagagcctcaac 121 ccctcagtccaccccaccgggcagccaccagtctacccctaccccacctagccacccaga 181 cccatgcctcgtcccgcggcacaccagctcctcagcgtgtgcagacccccacgagcctac 241 catgctttacgtcggtgaccccatgagacacctcgccacggcccagttcaatttgctcag 301 cagtgccatggaccagatgggcagccgtgcggccccggcgagcccctacaccccggagca 361 cgccgccagcgcgcccacccactcgccctacgcgcagcccagctccaccttcgacaccat 421 gtctccggcgcctgtcatcccttccaataccgactaccccggcccccaccacttcgaggt 481 caccttccagcagtcgagcactgccaagtcggccacctggacatactccccactcttgaa 541 gaagttgtactgtcagattgctaagacatgccccatccagatcaaagtgtccacaccacc 601 acccccgggcacggccatccgggccatgcctgtctacaagaaggcagagcatgtgaccga 661 cattgttaagcgctgccccaaccacgagcttggaagggacttcaatgaaggacagtctgc 721 cccggctagccacctcatccgtgtagaaggcaacaacctcgcccagtacgtggatgaccc 781 tgtcaccggaaggcagagtgtggttgtgccgtatgaacccccacaggtgggaacagaatt 841 taccaccatcctgtacaacttcatgtgtaacagcagctgtgtggggggcatgaatcggag 901 gcccatccttgtcatcatcaccctggagacccgggatggacaggtcctgggccgccggtc 961 tttcgagggtcgcatctgtgcctgtcctggccgtgaccgcaaagctgatgaagaccatta 1021 ccgggagcaacaggctctgaatgaaagtaccaccaaaaatggagctgccagcaaacgtgc 1081 attcaagcagagcccccctgccatccctgccctgggtaccaacgtgaagaagagacgcca 1141 cggggacgaggacatgttctacatgcacgtgcgaggccgggagaactttgagatcttgat 1201 gaaagtcaaggagagcctagaactgatggagcttgtgccccagcctttggttgactccta 1261 tcgacagcagcagcagcagcagctcctacagaggccttttttgacagggttggggtgtcc 1321 aaactgcatcgagtgcttcacttcccaagggttgcagagcatctaccacctgcagaacct 1381 taccatcgaggaccttggggctctgaaggtccctgaccagtaccgtatgaccatctggag 1441 gggcctacaggacctgaagcagagccatgactgcggccagcaactgctacgctccagcag 1501 caacgcggccaccatctccatcggcggctctggcgagctgcagcggcagcgggtcatgga 1561 agccgtgcatttccgtgtgcgccacaccatcacgatccccaaccgtggaggcgcaggtgc 1621 ggtgacaggtcccgacgagtgggcggactttggctttgacctgcctgactgcaagtcccg 1681 taagcagcccatcaaagaggagttcacagagacagagagccactgaggaacgtaccttct 1741 tctcctgtccttcctctgtgagaaactgctcttggaagtgggacctgttggctgtgccca 1801 cagaaaccagcaaggaccttctgccggatgccattcctgaagggaagtcgctcatgaact 1861 aactccctcttggaaacttctggaactgcccttagctacatatacacaagggcaggtggt 1921 gagccaagtgctgagacagggagctgtccctttgtgggtgggtatgcagcacccatttgc 1981 ttctcccgttctctattgaggactctgccacctccaggacagagcagcatccttcacttg 2041 ctcaccctctgccacaaagtattccaacatcttctgttcctgctaaccatgcacagccca 2101 gcctctgtgtcatcagcgcttacgtacaggtcgattccactgtgtcttgaaagtgaattc 2161 agggccagagacatcttctgcaggatgtgtggacagatctgtccctaatgtaggtcattc 2221 tgccgttaccccttgtctcccgagtcttgattgctggggtcagggaagactgtggcagag 2281 caggggaagccgctggccctccgcctctagccagcaccctgaacatgctggctgtagcag 2341 cctctagggacctctctggtcagacaaagggacagaatgagtctcagactaccgaaaatt 2401 gaattgtcaatatttgataaaaggttactctttctacttggtggggtcagcttgcttttt 2461 cccccctctctgactctctcagcattcctttctgagatcagcctagtgtgtccacacgta 2521 cttctcaacaagtctaaaacgccgagcatcaatccaggaagggtccttacctgttaccag 2581 gatggttggaagggaaagagactcagagagagcatagccgtgggagtgcaggtcagacag 2641 accccagctgtgaggaacatctgttctcactaagtgctcagagtctgggctctgtgcctg 2701 agtgctagcccatcctcgtggcctggaactggagtggctgctgggggccctggtcttcat 2761 gattcatccccaaagagtcagtggctagagaaacagctcctgcatgcattcagccaatgg 2821 ggccctgtacctgccagaagctttgtgaacttctgcaatgagagcccccagcagtccctg 2881 ccaggagtggagaagcacagaggagcccctgccaacagtaaagcccaacatctgccgagt 2941 cactttggagccatcctctttaggcttggctttcattagcaaggcccaacagaggcagtg 3001 acgtccgtgggatagcctcagagtcagcactaccagggctggcgtcatatcagggctgcc 3061 tcctcgaagcccagggacaatgttgccaatcttagcaatcttagcaagctctgcaaactt 3121 aggtggttaccacccatgctatgcttcatgaatctctgaggggcaggatttgggtgcact 3181 tagggtaggtgcaggcatcacattgtcagagaccagtgctgaccatacaggcctttccaa 3241 cttgacagatgttgacagcttaggctctgggggggtggggggttcctgcacccagatggg 3301 ccgttaacagctgcagcatcaggcttgcttcttgggtgtaggttgtggccctcccagtga 3361 gtggtaacacacttcacaaagcctgaggttgactacacacttcttgttgctgctcagatg 3421 aggaagctgaggctagacagactgagtgccctgcctcgggcatcagctcattgcagaagt 3481 gggtgttcactcctgaggtacatgctgccccatgctacctcagaaactaggcagcacatt 3541 ctcactcctaggcctgtgaaccccactgagatgcgcttgcgttctgggatctcacataag 3601 tatgtctcaggcattgtccaggagggaccatcctaagcgccccaccacatgctcctggga 3661 aggaggagtggttaggaggagtggttgtcaccaggcatctgaggagggaagagcccccct 3721 ccagcaaggacccagggcttgtgtctccctagaccctgcctcaagtgccaaagctgtctc 3781 gtgagcttccaggatcctgacaggcctggagggaactgcaaagggccatctgccaggaaa 3841 taaacgtcacagaggcaatgcttgcagtgcctgagaagctctccaggaaccagcctttgg 3901 gtctgaaccaaactttgttctacaaaacacagaaagcaagagaaagcaaatcttccagcc 3961 accaactttcccaggagcactggagtactagtttggaaacaagtttgggggtgccctgga 4021 agacatctgttgagcaagggcaggttgagcagggctgtaaaagcaggccactccagcctc 4081 agtctgtatggtcccatccagctttgtgcatccaattaacagcagctcccatgtcccttc 4141 ctggccttgcttaccgtgcctgacagctctaccttgggctgctttgagcttgtgagttcg 4201 cagaaccagcacccctacgcaagaatcctgcaagggtcaaaagttgccacttagttgcat 4261 ttcagatgggagacaaaaaccaaaactaaattgtccatgtttcaatgtgatgaaatgctt 4321 ctccaagcagtattgatggatacagtctagtgactctattaactgttttgggtgatgtca 4381 ttttagaaaaatgtgttattttttttagctgtgtttcggtgggaatttttgtttttgtaa 4441 tataataaaaatcacatgttcccatggt SEQIDNO:133MouseTP73isoform3aminoacidsequence(NP_001119803.1) 1 mlyvgdpmrhlataqfnllssamdqmgsraapaspytpehaasapthspyaqpsstfdtm 61 spapvipsntdypgphhfevtfqqsstaksatwtyspllkklycqiaktcpiqikvstpp 121 ppgtairampvykkaehvtdivkrcpnhelgrdfnegqsapashlirvegnnlaqyvddp 181 vtgrqsvvvpyeppqvgtefttilynfmcnsscvggmnrrpilviitletrdgqvlgrrs 241 fegricacpgrdrkadedhyreqqalnesttkngaaskrafkqsppaipalgtnvkkrrh 301 gdedmfymhvrgrenfeilmkvkeslelmelvpqplvdsyrqqqqqqllqrpfltglgcp 361 nciecftsqglqsiyhlqnltiedlgalkvpdqyrmtiwrglqdlkqshdcgqqllrsss 421 naatisiggsgelqrqrvmeavhfrvrhtitipnrggagavtgpdewadfgfdlpdcksr 481 kqpikeeftetesh SEQIDNO:134HumanSMAD1transcriptvariant1cDNAsequence (NM_001003688.1;CDS:241-1638) 1 cactgcatgtgtattcgtgagttcgcggttgaacaactgttcctttactctgctccctgt 61 ctttgtgctgactgggttacttttttaaacactaggaatggtaatttctactcttctgga 121 cttcaaactaagaagttaaagagacttctctgtaaataaacaaatctcttctgctgtcct 181 tttgcatttggagacagctttatttcaccatatccaaggagtataactagtgctgtcatt 241 atgaatgtgacaagtttattttcctttacaagtccagctgtgaagagacttcttgggtgg 301 aaacagggcgatgaagaagaaaaatgggcagagaaagctgttgatgctttggtgaaaaaa 361 ctgaagaaaaagaaaggtgccatggaggaactggaaaaggccttgagctgcccagggcaa 421 ccgagtaactgtgtcaccattccccgctctctggatggcaggctgcaagtctcccaccgg 481 aagggactgcctcatgtcatttactgccgtgtgtggcgctggcccgatcttcagagccac 541 catgaactaaaaccactggaatgctgtgagtttccttttggttccaagcagaaggaggtc 601 tgcatcaatccctaccactataagagagtagaaagccctgtacttcctcctgtgctggtt 661 ccaagacacagcgaatataatcctcagcacagcctcttagctcagttccgtaacttagga 721 caaaatgagcctcacatgccactcaacgccacttttccagattctttccagcaacccaac 781 agccacccgtttcctcactctcccaatagcagttacccaaactctcctgggagcagcagc 841 agcacctaccctcactctcccaccagctcagacccaggaagccctttccagatgccagct 901 gatacgcccccacctgcttacctgcctcctgaagaccccatgacccaggatggctctcag 961 ccgatggacacaaacatgatggcgcctcccctgccctcagaaatcaacagaggagatgtt 1021 caggcggttgcttatgaggaaccaaaacactggtgctctattgtctactatgagctcaac 1081 aatcgtgtgggtgaagcgttccatgcctcctccacaagtgtgttggtggatggtttcact 1141 gatccttccaacaataagaaccgtttctgccttgggctgctctccaatgttaaccggaat 1201 tccactattgaaaacaccaggcggcatattggaaaaggagttcatctttattatgttgga 1261 ggggaggtgtatgccgaatgccttagtgacagtagcatctttgtgcaaagtcggaactgc 1321 aactaccatcatggatttcatcctactactgtttgcaagatccctagtgggtgtagtctg 1381 aaaatttttaacaaccaagaatttgctcagttattggcacagtctgtgaaccatggattt 1441 gagacagtctatgagcttacaaaaatgtgtactatacgtatgagctttgtgaagggctgg 1501 ggagcagaataccaccgccaggatgttactagcaccccctgctggattgagatacatctg 1561 cacggccccctccagtggctggataaagttcttactcaaatgggttcacctcataatcct 1621 atttcatctgtatcttaaatggccccaggcatctgcctctggaaaactattgagccttgc 1681 atgtacttgaaggatggatgagtcagacacgattgagaactgacaaaggagccttgataa 1741 tacttgacctctgtgaccaactgttggattcagaaatttaaacaaaaaaaaaaaaaaaca 1801 cacacaccttggtaacatactgttgatatcaagaacctgtttagtttacattgtaacatt 1861 ctattgtaaaatcaactaaaattcagacttttagcaggactttgtgtacagttaaaggag 1921 agatggccaagccagggacaaattgtctattagaaaacggtcctaagagattctttggtg 1981 tttggcactttaaggtcatcgttgggcagaagtttagcattaatagttgttctgaaacgt 2041 gttttatcaggtttagagcccatgttgagtcttcttttcatgggttttcataatatttta 2101 aaactatttgtttagcgatggttttgttcgtttaagtaaaggttaatcttgatgatatac 2161 ataataatctttctaaaattgtatgctgaccatacttgctgtcagaataatgctaggcat 2221 atgctttttgctaaatatgtatgtacagagtatttggaagttaagaattgattagactag 2281 tgaatttaggagtatttgaggtgggtggggggaagagggaaatgacaactgcaaatgtag 2341 actatactgtaaaaattcagtttgttgctttaaagaaacaaactgatacctgaattttgc 2401 tgtgtttccattttttagagatttttatcatttttttctctctcggcattcttttttctc 2461 atactcttcaaaaagcagttctgcagctggttaattcatgtaactgtgagagcaaatgaa 2521 taattcctgctattctgaaattgcctacatgtttcaataccagttatatggagtgcttga 2581 atttaataagcagtttttacggagtttacagtacagaaataggctttaattttcaagtga 2641 attttttgccaaacttagtaactctgttaaatatttggaggatttaaagaacatcccagt 2701 ttgaattcatttcaaactttttaaatttttttgtactatgtttggttttattttccttct 2761 gttaatcttttgtattcacttatgctctcgtacattgagtacttttattccaaaactagt 2821 gggttttctctactggaaattttcaataaacctgtcattattgcttactttgattaaaaa SEQIDNO:135HumanSMAD1transcriptvariant2cDNAsequence (NM_001354811.1;CDS:664-2061) 1 gctgtgggaagcccagttcccgggcccccgagcctcggctcccgggcctgaccgcgctgg 61 gatctccccggccgcgctccccttccgcgcgctcctcacatctctcccgtgctgccgccg 121 ggccgaggcccgttcgcgtggcccgcggacccattgtgtcccccgcgccggcggggcgac 181 ccctgcgggagctggaggacgaccgctggcgctgctctccaaggcgcctggtggagcggg 241 tctcgcgggcgggggaccccggcgccccgggcccctccacatcccgcacgggttttcttc 301 tcggccccagcaagcctctttggggtcgaggtcaaggaaagttcgcaccgagatcccctc 361 taatttattcaaaggtttggcggcggcgcgtaattttttccccctcttccgcctacaccc 421 gctgcgtctcctggtgtctcgttcctttccctttaccggagtcgattgcctcactgcatg 481 tgtattcgtgctgactgggttacttttttaaacactaggaatggtaatttctactcttct 541 ggacttcaaactaagaagttaaagagacttctctgtaaataaacaaatctcttctgctgt 601 ccttttgcatttggagacagctttatttcaccatatccaaggagtataactagtgctgtc 661 attatgaatgtgacaagtttattttcctttacaagtccagctgtgaagagacttcttggg 721 tggaaacagggcgatgaagaagaaaaatgggcagagaaagctgttgatgctttggtgaaa 781 aaactgaagaaaaagaaaggtgccatggaggaactggaaaaggccttgagctgcccaggg 841 caaccgagtaactgtgtcaccattccccgctctctggatggcaggctgcaagtctcccac 901 cggaagggactgcctcatgtcatttactgccgtgtgtggcgctggcccgatcttcagagc 961 caccatgaactaaaaccactggaatgctgtgagtttccttttggttccaagcagaaggag 1021 gtctgcatcaatccctaccactataagagagtagaaagccctgtacttcctcctgtgctg 1081 gttccaagacacagcgaatataatcctcagcacagcctcttagctcagttccgtaactta 1141 ggacaaaatgagcctcacatgccactcaacgccacttttccagattctttccagcaaccc 1201 aacagccacccgtttcctcactctcccaatagcagttacccaaactctcctgggagcagc 1261 agcagcacctaccctcactctcccaccagctcagacccaggaagccctttccagatgcca 1321 gctgatacgcccccacctgcttacctgcctcctgaagaccccatgacccaggatggctct 1381 cagccgatggacacaaacatgatggcgcctcccctgccctcagaaatcaacagaggagat 1441 gttcaggcggttgcttatgaggaaccaaaacactggtgctctattgtctactatgagctc 1501 aacaatcgtgtgggtgaagcgttccatgcctcctccacaagtgtgttggtggatggtttc 1561 actgatccttccaacaataagaaccgtttctgccttgggctgctctccaatgttaaccgg 1621 aattccactattgaaaacaccaggcggcatattggaaaaggagttcatctttattatgtt 1681 ggaggggaggtgtatgccgaatgccttagtgacagtagcatctttgtgcaaagtcggaac 1741 tgcaactaccatcatggatttcatcctactactgtttgcaagatccctagtgggtgtagt 1801 ctgaaaatttttaacaaccaagaatttgctcagttattggcacagtctgtgaaccatgga 1861 tttgagacagtctatgagcttacaaaaatgtgtactatacgtatgagctttgtgaagggc 1921 tggggagcagaataccaccgccaggatgttactagcaccccctgctggattgagatacat 1981 ctgcacggccccctccagtggctggataaagttcttactcaaatgggttcacctcataat 2041 cctatttcatctgtatcttaaatggccccaggcatctgcctctggaaaactattgagcct 2101 tgcatgtacttgaaggatggatgagtcagacacgattgagaactgacaaaggagccttga 2161 taatacttgacctctgtgaccaactgttggattcagaaatttaaacaaaaaaaaaaaaaa 2221 acacacacaccttggtaacatactgttgatatcaagaacctgtttagtttacattgtaac 2281 attctattgtaaaatcaactaaaattcagacttttagcaggactttgtgtacagttaaag 2341 gagagatggccaagccagggacaaattgtctattagaaaacggtcctaagagattctttg 2401 gtgtttggcactttaaggtcatcgttgggcagaagtttagcattaatagttgttctgaaa 2461 cgtgttttatcaggtttagagcccatgttgagtcttcttttcatgggttttcataatatt 2521 ttaaaactatttgtttagcgatggttttgttcgtttaagtaaaggttaatcttgatgata 2581 tacataataatctttctaaaattgtatgctgaccatacttgctgtcagaataatgctagg 2641 catatgctttttgctaaatatgtatgtacagagtatttggaagttaagaattgattagac 2701 tagtgaatttaggagtatttgaggtgggtggggggaagagggaaatgacaactgcaaatg 2761 tagactatactgtaaaaattcagtttgttgctttaaagaaacaaactgatacctgaattt 2821 tgctgtgtttccattttttagagatttttatcatttttttctctctcggcattctttttt 2881 ctcatactcttcaaaaagcagttctgcagctggttaattcatgtaactgtgagagcaaat 2941 gaataattcctgctattctgaaattgcctacatgtttcaataccagttatatggagtgct 3001 tgaatttaataagcagtttttacggagtttacagtacagaaataggctttaattttcaag 3061 tgaattttttgccaaacttagtaactctgttaaatatttggaggatttaaagaacatccc 3121 agtttgaattcatttcaaactttttaaatttttttgtactatgtttggttttattttcct 3181 tctgttaatcttttgtattcacttatgctctcgtacattgagtacttttattccaaaact 3241 agtgggttttctctactggaaattttcaataaacctgtcattattgcttactttgattaa 3301 aaa SEQIDNO:136HumanSMAD1transcriptvariant3cDNAsequence (NM_001354812.1;CDS:272-1669) 1 caattctgggtacgtacaacttctggggcctgcaaattattggagagtgagtgaggggca 61 acgaaagatagacataaaagggcgcgtctcgaaaggtgctgactgggttacttttttaaa 121 cactaggaatggtaatttctactcttctggacttcaaactaagaagttaaagagacttct 181 ctgtaaataaacaaatctcttctgctgtccttttgcatttggagacagctttatttcacc 241 atatccaaggagtataactagtgctgtcattatgaatgtgacaagtttattttcctttac 301 aagtccagctgtgaagagacttcttgggtggaaacagggcgatgaagaagaaaaatgggc 361 agagaaagctgttgatgctttggtgaaaaaactgaagaaaaagaaaggtgccatggagga 421 actggaaaaggccttgagctgcccagggcaaccgagtaactgtgtcaccattccccgctc 481 tctggatggcaggctgcaagtctcccaccggaagggactgcctcatgtcatttactgccg 541 tgtgtggcgctggcccgatcttcagagccaccatgaactaaaaccactggaatgctgtga 601 gtttccttttggttccaagcagaaggaggtctgcatcaatccctaccactataagagagt 661 agaaagccctgtacttcctcctgtgctggttccaagacacagcgaatataatcctcagca 721 cagcctcttagctcagttccgtaacttaggacaaaatgagcctcacatgccactcaacgc 781 cacttttccagattctttccagcaacccaacagccacccgtttcctcactctcccaatag 841 cagttacccaaactctcctgggagcagcagcagcacctaccctcactctcccaccagctc 901 agacccaggaagccctttccagatgccagctgatacgcccccacctgcttacctgcctcc 961 tgaagaccccatgacccaggatggctctcagccgatggacacaaacatgatggcgcctcc 1021 cctgccctcagaaatcaacagaggagatgttcaggcggttgcttatgaggaaccaaaaca 1081 ctggtgctctattgtctactatgagctcaacaatcgtgtgggtgaagcgttccatgcctc 1141 ctccacaagtgtgttggtggatggtttcactgatccttccaacaataagaaccgtttctg 1201 ccttgggctgctctccaatgttaaccggaattccactattgaaaacaccaggcggcatat 1261 tggaaaaggagttcatctttattatgttggaggggaggtgtatgccgaatgccttagtga 1321 cagtagcatctttgtgcaaagtcggaactgcaactaccatcatggatttcatcctactac 1381 tgtttgcaagatccctagtgggtgtagtctgaaaatttttaacaaccaagaatttgctca 1441 gttattggcacagtctgtgaaccatggatttgagacagtctatgagcttacaaaaatgtg 1501 tactatacgtatgagctttgtgaagggctggggagcagaataccaccgccaggatgttac 1561 tagcaccccctgctggattgagatacatctgcacggccccctccagtggctggataaagt 1621 tcttactcaaatgggttcacctcataatcctatttcatctgtatcttaaatggccccagg 1681 catctgcctctggaaaactattgagccttgcatgtacttgaaggatggatgagtcagaca 1741 cgattgagaactgacaaaggagccttgataatacttgacctctgtgaccaactgttggat 1801 tcagaaatttaaacaaaaaaaaaaaaaaacacacacaccttggtaacatactgttgatat 1861 caagaacctgtttagtttacattgtaacattctattgtaaaatcaactaaaattcagact 1921 tttagcaggactttgtgtacagttaaaggagagatggccaagccagggacaaattgtcta 1981 ttagaaaacggtcctaagagattctttggtgtttggcactttaaggtcatcgttgggcag 2041 aagtttagcattaatagttgttctgaaacgtgttttatcaggtttagagcccatgttgag 2101 tcttcttttcatgggttttcataatattttaaaactatttgtttagcgatggttttgttc 2161 gtttaagtaaaggttaatcttgatgatatacataataatctttctaaaattgtatgctga 2221 ccatacttgctgtcagaataatgctaggcatatgctttttgctaaatatgtatgtacaga 2281 gtatttggaagttaagaattgattagactagtgaatttaggagtatttgaggtgggtggg 2341 gggaagagggaaatgacaactgcaaatgtagactatactgtaaaaattcagtttgttgct 2401 ttaaagaaacaaactgatacctgaattttgctgtgtttccattttttagagatttttatc 2461 atttttttctctctcggcattcttttttctcatactcttcaaaaagcagttctgcagctg 2521 gttaattcatgtaactgtgagagcaaatgaataattcctgctattctgaaattgcctaca 2581 tgtttcaataccagttatatggagtgcttgaatttaataagcagtttttacggagtttac 2641 agtacagaaataggctttaattttcaagtgaattttttgccaaacttagtaactctgtta 2701 aatatttggaggatttaaagaacatcccagtttgaattcatttcaaactttttaaatttt 2761 tttgtactatgtttggttttattttccttctgttaatcttttgtattcacttatgctctc 2821 gtacattgagtacttttattccaaaactagtgggttttctctactggaaattttcaataa 2881 acctgtcattattgcttactttgattaaaaa SEQIDNO:137HumanSMAD1transcriptvariant4cDNAsequence (NM_001354813.1;CDS:280-1677) 1 gccgtcctccggccccggccgcgctgcgctcacgccggccgggccgggaatttggagagg 61 atccctggtcgcgcggcagcggcggcggcgcgcgggtgagcgggtgctgactgggttact 121 tttttaaacactaggaatggtaatttctactcttctggacttcaaactaagaagttaaag 181 agacttctctgtaaataaacaaatctcttctgctgtccttttgcatttggagacagcttt 241 atttcaccatatccaaggagtataactagtgctgtcattatgaatgtgacaagtttattt 301 tcctttacaagtccagctgtgaagagacttcttgggtggaaacagggcgatgaagaagaa 361 aaatgggcagagaaagctgttgatgctttggtgaaaaaactgaagaaaaagaaaggtgcc 421 atggaggaactggaaaaggccttgagctgcccagggcaaccgagtaactgtgtcaccatt 481 ccccgctctctggatggcaggctgcaagtctcccaccggaagggactgcctcatgtcatt 541 tactgccgtgtgtggcgctggcccgatcttcagagccaccatgaactaaaaccactggaa 601 tgctgtgagtttccttttggttccaagcagaaggaggtctgcatcaatccctaccactat 661 aagagagtagaaagccctgtacttcctcctgtgctggttccaagacacagcgaatataat 721 cctcagcacagcctcttagctcagttccgtaacttaggacaaaatgagcctcacatgcca 781 ctcaacgccacttttccagattctttccagcaacccaacagccacccgtttcctcactct 841 cccaatagcagttacccaaactctcctgggagcagcagcagcacctaccctcactctccc 901 accagctcagacccaggaagccctttccagatgccagctgatacgcccccacctgcttac 961 ctgcctcctgaagaccccatgacccaggatggctctcagccgatggacacaaacatgatg 1021 gcgcctcccctgccctcagaaatcaacagaggagatgttcaggcggttgcttatgaggaa 1081 ccaaaacactggtgctctattgtctactatgagctcaacaatcgtgtgggtgaagcgttc 1141 catgcctcctccacaagtgtgttggtggatggtttcactgatccttccaacaataagaac 1201 cgtttctgccttgggctgctctccaatgttaaccggaattccactattgaaaacaccagg 1261 cggcatattggaaaaggagttcatctttattatgttggaggggaggtgtatgccgaatgc 1321 cttagtgacagtagcatctttgtgcaaagtcggaactgcaactaccatcatggatttcat 1381 cctactactgtttgcaagatccctagtgggtgtagtctgaaaatttttaacaaccaagaa 1441 tttgctcagttattggcacagtctgtgaaccatggatttgagacagtctatgagcttaca 1501 aaaatgtgtactatacgtatgagctttgtgaagggctggggagcagaataccaccgccag 1561 gatgttactagcaccccctgctggattgagatacatctgcacggccccctccagtggctg 1621 gataaagttcttactcaaatgggttcacctcataatcctatttcatctgtatcttaaatg 1681 gccccaggcatctgcctctggaaaactattgagccttgcatgtacttgaaggatggatga 1741 gtcagacacgattgagaactgacaaaggagccttgataatacttgacctctgtgaccaac 1801 tgttggattcagaaatttaaacaaaaaaaaaaaaaaacacacacaccttggtaacatact 1861 gttgatatcaagaacctgtttagtttacattgtaacattctattgtaaaatcaactaaaa 1921 ttcagacttttagcaggactttgtgtacagttaaaggagagatggccaagccagggacaa 1981 attgtctattagaaaacggtcctaagagattctttggtgtttggcactttaaggtcatcg 2041 ttgggcagaagtttagcattaatagttgttctgaaacgtgttttatcaggtttagagccc 2101 atgttgagtcttcttttcatgggttttcataatattttaaaactatttgtttagcgatgg 2161 ttttgttcgtttaagtaaaggttaatcttgatgatatacataataatctttctaaaattg 2221 tatgctgaccatacttgctgtcagaataatgctaggcatatgctttttgctaaatatgta 2281 tgtacagagtatttggaagttaagaattgattagactagtgaatttaggagtatttgagg 2341 tgggtggggggaagagggaaatgacaactgcaaatgtagactatactgtaaaaattcagt 2401 ttgttgctttaaagaaacaaactgatacctgaattttgctgtgtttccattttttagaga 2461 tttttatcatttttttctctctcggcattcttttttctcatactcttcaaaaagcagttc 2521 tgcagctggttaattcatgtaactgtgagagcaaatgaataattcctgctattctgaaat 2581 tgcctacatgtttcaataccagttatatggagtgcttgaatttaataagcagtttttacg 2641 gagtttacagtacagaaataggctttaattttcaagtgaattttttgccaaacttagtaa 2701 ctctgttaaatatttggaggatttaaagaacatcccagtttgaattcatttcaaactttt 2761 taaatttttttgtactatgtttggttttattttccttctgttaatcttttgtattcactt 2821 atgctctcgtacattgagtacttttattccaaaactagtgggttttctctactggaaatt 2881 ttcaataaacctgtcattattgcttactttgattaaaaa SEQIDNO:138HumanSMAD1transcriptvariant5cDNAsequence (NM_001354814.1;CDS:272-1669) 1 gccgtcctccggccccggccgcgctgcgctcacgccggccgggccgggaatttggagagg 61 atccctggtcgcgcggcagcggcggcggcgcgcgggtgctgactgggttacttttttaaa 121 cactaggaatggtaatttctactcttctggacttcaaactaagaagttaaagagacttct 181 ctgtaaataaacaaatctcttctgctgtccttttgcatttggagacagctttatttcacc 241 atatccaaggagtataactagtgctgtcattatgaatgtgacaagtttattttcctttac 301 aagtccagctgtgaagagacttcttgggtggaaacagggcgatgaagaagaaaaatgggc 361 agagaaagctgttgatgctttggtgaaaaaactgaagaaaaagaaaggtgccatggagga 421 actggaaaaggccttgagctgcccagggcaaccgagtaactgtgtcaccattccccgctc 481 tctggatggcaggctgcaagtctcccaccggaagggactgcctcatgtcatttactgccg 541 tgtgtggcgctggcccgatcttcagagccaccatgaactaaaaccactggaatgctgtga 601 gtttccttttggttccaagcagaaggaggtctgcatcaatccctaccactataagagagt 661 agaaagccctgtacttcctcctgtgctggttccaagacacagcgaatataatcctcagca 721 cagcctcttagctcagttccgtaacttaggacaaaatgagcctcacatgccactcaacgc 781 cacttttccagattctttccagcaacccaacagccacccgtttcctcactctcccaatag 841 cagttacccaaactctcctgggagcagcagcagcacctaccctcactctcccaccagctc 901 agacccaggaagccctttccagatgccagctgatacgcccccacctgcttacctgcctcc 961 tgaagaccccatgacccaggatggctctcagccgatggacacaaacatgatggcgcctcc 1021 cctgccctcagaaatcaacagaggagatgttcaggcggttgcttatgaggaaccaaaaca 1081 ctggtgctctattgtctactatgagctcaacaatcgtgtgggtgaagcgttccatgcctc 1141 ctccacaagtgtgttggtggatggtttcactgatccttccaacaataagaaccgtttctg 1201 ccttgggctgctctccaatgttaaccggaattccactattgaaaacaccaggcggcatat 1261 tggaaaaggagttcatctttattatgttggaggggaggtgtatgccgaatgccttagtga 1321 cagtagcatctttgtgcaaagtcggaactgcaactaccatcatggatttcatcctactac 1381 tgtttgcaagatccctagtgggtgtagtctgaaaatttttaacaaccaagaatttgctca 1441 gttattggcacagtctgtgaaccatggatttgagacagtctatgagcttacaaaaatgtg 1501 tactatacgtatgagctttgtgaagggctggggagcagaataccaccgccaggatgttac 1561 tagcaccccctgctggattgagatacatctgcacggccccctccagtggctggataaagt 1621 tcttactcaaatgggttcacctcataatcctatttcatctgtatcttaaatggccccagg 1681 catctgcctctggaaaactattgagccttgcatgtacttgaaggatggatgagtcagaca 1741 cgattgagaactgacaaaggagccttgataatacttgacctctgtgaccaactgttggat 1801 tcagaaatttaaacaaaaaaaaaaaaaaacacacacaccttggtaacatactgttgatat 1861 caagaacctgtttagtttacattgtaacattctattgtaaaatcaactaaaattcagact 1921 tttagcaggactttgtgtacagttaaaggagagatggccaagccagggacaaattgtcta 1981 ttagaaaacggtcctaagagattctttggtgtttggcactttaaggtcatcgttgggcag 2041 aagtttagcattaatagttgttctgaaacgtgttttatcaggtttagagcccatgttgag 2101 tcttcttttcatgggttttcataatattttaaaactatttgtttagcgatggttttgttc 2161 gtttaagtaaaggttaatcttgatgatatacataataatctttctaaaattgtatgctga 2221 ccatacttgctgtcagaataatgctaggcatatgctttttgctaaatatgtatgtacaga 2281 gtatttggaagttaagaattgattagactagtgaatttaggagtatttgaggtgggtggg 2341 gggaagagggaaatgacaactgcaaatgtagactatactgtaaaaattcagtttgttgct 2401 ttaaagaaacaaactgatacctgaattttgctgtgtttccattttttagagatttttatc 2461 atttttttctctctcggcattcttttttctcatactcttcaaaaagcagttctgcagctg 2521 gttaattcatgtaactgtgagagcaaatgaataattcctgctattctgaaattgcctaca 2581 tgtttcaataccagttatatggagtgcttgaatttaataagcagtttttacggagtttac 2641 agtacagaaataggctttaattttcaagtgaattttttgccaaacttagtaactctgtta 2701 aatatttggaggatttaaagaacatcccagtttgaattcatttcaaactttttaaatttt 2761 tttgtactatgtttggttttattttccttctgttaatcttttgtattcacttatgctctc 2821 gtacattgagtacttttattccaaaactagtgggttttctctactggaaattttcaataa 2881 acctgtcattattgcttactttgattaaaaa SEQIDNO:139HumanSMAD1transcriptvariant6cDNAsequence (NM_001354816.1;CDS:551-1948) 1 gctgtgggaagcccagttcccgggcccccgagcctcggctcccgggcctgaccgcgctgg 61 gatctccccggccgcgctccccttccgcgcgctcctcacatctctcccgtgctgccgccg 121 ggccgaggcccgttcgcgtggcccgcggacccattgtgtcccccgcgccggcggggcgac 181 ccctgcgggagctggaggacgaccgctggcgctgctctccaaggcgcctggtggagcggg 241 tctcgcgggcgggggaccccggcgccccgggcccctccacatcccgcacgggttttcttc 301 tcggccccagcaagcctctttggggtcgaggtcaaggaaagttcgcaccgagatcccctc 361 taatttattcaaaggtgctgactgggttacttttttaaacactaggaatggtaatttcta 421 ctcttctggacttcaaactaagaagttaaagagacttctctgtaaataaacaaatctctt 481 ctgctgtccttttgcatttggagacagctttatttcaccatatccaaggagtataactag 541 tgctgtcattatgaatgtgacaagtttattttcctttacaagtccagctgtgaagagact 601 tcttgggtggaaacagggcgatgaagaagaaaaatgggcagagaaagctgttgatgcttt 661 ggtgaaaaaactgaagaaaaagaaaggtgccatggaggaactggaaaaggccttgagctg 721 cccagggcaaccgagtaactgtgtcaccattccccgctctctggatggcaggctgcaagt 781 ctcccaccggaagggactgcctcatgtcatttactgccgtgtgtggcgctggcccgatct 841 tcagagccaccatgaactaaaaccactggaatgctgtgagtttccttttggttccaagca 901 gaaggaggtctgcatcaatccctaccactataagagagtagaaagccctgtacttcctcc 961 tgtgctggttccaagacacagcgaatataatcctcagcacagcctcttagctcagttccg 1021 taacttaggacaaaatgagcctcacatgccactcaacgccacttttccagattctttcca 1081 gcaacccaacagccacccgtttcctcactctcccaatagcagttacccaaactctcctgg 1141 gagcagcagcagcacctaccctcactctcccaccagctcagacccaggaagccctttcca 1201 gatgccagctgatacgcccccacctgcttacctgcctcctgaagaccccatgacccagga 1261 tggctctcagccgatggacacaaacatgatggcgcctcccctgccctcagaaatcaacag 1321 aggagatgttcaggcggttgcttatgaggaaccaaaacactggtgctctattgtctacta 1381 tgagctcaacaatcgtgtgggtgaagcgttccatgcctcctccacaagtgtgttggtgga 1441 tggtttcactgatccttccaacaataagaaccgtttctgccttgggctgctctccaatgt 1501 taaccggaattccactattgaaaacaccaggcggcatattggaaaaggagttcatcttta 1561 ttatgttggaggggaggtgtatgccgaatgccttagtgacagtagcatctttgtgcaaag 1621 tcggaactgcaactaccatcatggatttcatcctactactgtttgcaagatccctagtgg 1681 gtgtagtctgaaaatttttaacaaccaagaatttgctcagttattggcacagtctgtgaa 1741 ccatggatttgagacagtctatgagcttacaaaaatgtgtactatacgtatgagctttgt 1801 gaagggctggggagcagaataccaccgccaggatgttactagcaccccctgctggattga 1861 gatacatctgcacggccccctccagtggctggataaagttcttactcaaatgggttcacc 1921 tcataatcctatttcatctgtatcttaaatggccccaggcatctgcctctggaaaactat 1981 tgagccttgcatgtacttgaaggatggatgagtcagacacgattgagaactgacaaagga 2041 gccttgataatacttgacctctgtgaccaactgttggattcagaaatttaaacaaaaaaa 2101 aaaaaaaacacacacaccttggtaacatactgttgatatcaagaacctgtttagtttaca 2161 ttgtaacattctattgtaaaatcaactaaaattcagacttttagcaggactttgtgtaca 2221 gttaaaggagagatggccaagccagggacaaattgtctattagaaaacggtcctaagaga 2281 ttctttggtgtttggcactttaaggtcatcgttgggcagaagtttagcattaatagttgt 2341 tctgaaacgtgttttatcaggtttagagcccatgttgagtcttcttttcatgggttttca 2401 taatattttaaaactatttgtttagcgatggttttgttcgtttaagtaaaggttaatctt 2461 gatgatatacataataatctttctaaaattgtatgctgaccatacttgctgtcagaataa 2521 tgctaggcatatgctttttgctaaatatgtatgtacagagtatttggaagttaagaattg 2581 attagactagtgaatttaggagtatttgaggtgggtggggggaagagggaaatgacaact 2641 gcaaatgtagactatactgtaaaaattcagtttgttgctttaaagaaacaaactgatacc 2701 tgaattttgctgtgtttccattttttagagatttttatcatttttttctctctcggcatt 2761 cttttttctcatactcttcaaaaagcagttctgcagctggttaattcatgtaactgtgag 2821 agcaaatgaataattcctgctattctgaaattgcctacatgtttcaataccagttatatg 2881 gagtgcttgaatttaataagcagtttttacggagtttacagtacagaaataggctttaat 2941 tttcaagtgaattttttgccaaacttagtaactctgttaaatatttggaggatttaaaga 3001 acatcccagtttgaattcatttcaaactttttaaatttttttgtactatgtttggtttta 3061 ttttccttctgttaatcttttgtattcacttatgctctcgtacattgagtacttttattc 3121 caaaactagtgggttttctctactggaaattttcaataaacctgtcattattgcttactt 3181 tgattaaaaa SEQIDNO:140HumanSMAD1transcriptvariant7cDNAsequence (NM_001354817.1;CDS:549-1946) 1 cactgcatgtgtattcgtgagttcgcggttgaacaactgttcctttactctgctccctgt 61 ctttgttagtgtttctcggggttgtttctgtaggaaggtgggggtggtgggcgtgagaga 121 cagatgtgggcttgtttttctagttgctgaaactgtatgaaggctttaaagggagaacgt 181 tttcttgatgtgctttaggaggggaggaggaacaaatgcctgccagatctcacagctaca 241 gtagctgagcttttgtttattttgaagagcatgcaatttttaaatacacggtgcaagata 301 accagtaaaggcgcgttccttctgaaaattgaggccggtctcagaaccatctcctgagaa 361 agcatccttttcgtgctgactgggttacttttttaaacactaggaatggtaatttctact 421 cttctggacttcaaactaagaagttaaagagacttctctgtaaataaacaaatctcttct 481 gctgtccttttgcatttggagacagctttatttcaccatatccaaggagtataactagtg 541 ctgtcattatgaatgtgacaagtttattttcctttacaagtccagctgtgaagagacttc 601 ttgggtggaaacagggcgatgaagaagaaaaatgggcagagaaagctgttgatgctttgg 661 tgaaaaaactgaagaaaaagaaaggtgccatggaggaactggaaaaggccttgagctgcc 721 cagggcaaccgagtaactgtgtcaccattccccgctctctggatggcaggctgcaagtct 781 cccaccggaagggactgcctcatgtcatttactgccgtgtgtggcgctggcccgatcttc 841 agagccaccatgaactaaaaccactggaatgctgtgagtttccttttggttccaagcaga 901 aggaggtctgcatcaatccctaccactataagagagtagaaagccctgtacttcctcctg 961 tgctggttccaagacacagcgaatataatcctcagcacagcctcttagctcagttccgta 1021 acttaggacaaaatgagcctcacatgccactcaacgccacttttccagattctttccagc 1081 aacccaacagccacccgtttcctcactctcccaatagcagttacccaaactctcctggga 1141 gcagcagcagcacctaccctcactctcccaccagctcagacccaggaagccctttccaga 1201 tgccagctgatacgcccccacctgcttacctgcctcctgaagaccccatgacccaggatg 1261 gctctcagccgatggacacaaacatgatggcgcctcccctgccctcagaaatcaacagag 1321 gagatgttcaggcggttgcttatgaggaaccaaaacactggtgctctattgtctactatg 1381 agctcaacaatcgtgtgggtgaagcgttccatgcctcctccacaagtgtgttggtggatg 1441 gtttcactgatccttccaacaataagaaccgtttctgccttgggctgctctccaatgtta 1501 accggaattccactattgaaaacaccaggcggcatattggaaaaggagttcatctttatt 1561 atgttggaggggaggtgtatgccgaatgccttagtgacagtagcatctttgtgcaaagtc 1621 ggaactgcaactaccatcatggatttcatcctactactgtttgcaagatccctagtgggt 1681 gtagtctgaaaatttttaacaaccaagaatttgctcagttattggcacagtctgtgaacc 1741 atggatttgagacagtctatgagcttacaaaaatgtgtactatacgtatgagctttgtga 1801 agggctggggagcagaataccaccgccaggatgttactagcaccccctgctggattgaga 1861 tacatctgcacggccccctccagtggctggataaagttcttactcaaatgggttcacctc 1921 ataatcctatttcatctgtatcttaaatggccccaggcatctgcctctggaaaactattg 1981 agccttgcatgtacttgaaggatggatgagtcagacacgattgagaactgacaaaggagc 2041 cttgataatacttgacctctgtgaccaactgttggattcagaaatttaaacaaaaaaaaa 2101 aaaaaacacacacaccttggtaacatactgttgatatcaagaacctgtttagtttacatt 2161 gtaacattctattgtaaaatcaactaaaattcagacttttagcaggactttgtgtacagt 2221 taaaggagagatggccaagccagggacaaattgtctattagaaaacggtcctaagagatt 2281 ctttggtgtttggcactttaaggtcatcgttgggcagaagtttagcattaatagttgttc 2341 tgaaacgtgttttatcaggtttagagcccatgttgagtcttcttttcatgggttttcata 2401 atattttaaaactatttgtttagcgatggttttgttcgtttaagtaaaggttaatcttga 2461 tgatatacataataatctttctaaaattgtatgctgaccatacttgctgtcagaataatg 2521 ctaggcatatgctttttgctaaatatgtatgtacagagtatttggaagttaagaattgat 2581 tagactagtgaatttaggagtatttgaggtgggtggggggaagagggaaatgacaactgc 2641 aaatgtagactatactgtaaaaattcagtttgttgctttaaagaaacaaactgatacctg 2701 aattttgctgtgtttccattttttagagatttttatcatttttttctctctcggcattct 2761 tttttctcatactcttcaaaaagcagttctgcagctggttaattcatgtaactgtgagag 2821 caaatgaataattcctgctattctgaaattgcctacatgtttcaataccagttatatgga 2881 gtgcttgaatttaataagcagtttttacggagtttacagtacagaaataggctttaattt 2941 tcaagtgaattttttgccaaacttagtaactctgttaaatatttggaggatttaaagaac 3001 atcccagtttgaattcatttcaaactttttaaatttttttgtactatgtttggttttatt 3061 ttccttctgttaatcttttgtattcacttatgctctcgtacattgagtacttttattcca 3121 aaactagtgggttttctctactggaaattttcaataaacctgtcattattgcttactttg 3181 attaaaaa SEQIDNO:141HumanSMAD1transcriptvariant8cDNAsequence(NM_005900.3; CDS:363-1760) 1 agatcaatccaggctccaggagaaagcaggcgggcgggcggagaaaggagaggccgagcg 61 gctcaacccgggccgaggctcggggagcggagagtggcgcagcgcccggccgtccggacc 121 cgggccgcgagaccccgctcgcccggccactcgtgctcccacacggacgggcgcgccgcc 181 aacccggtgctgactgggttacttttttaaacactaggaatggtaatttctactcttctg 241 gacttcaaactaagaagttaaagagacttctctgtaaataaacaaatctcttctgctgtc 301 cttttgcatttggagacagctttatttcaccatatccaaggagtataactagtgctgtca 361 ttatgaatgtgacaagtttattttcctttacaagtccagctgtgaagagacttcttgggt 421 ggaaacagggcgatgaagaagaaaaatgggcagagaaagctgttgatgctttggtgaaaa 481 aactgaagaaaaagaaaggtgccatggaggaactggaaaaggccttgagctgcccagggc 541 aaccgagtaactgtgtcaccattccccgctctctggatggcaggctgcaagtctcccacc 601 ggaagggactgcctcatgtcatttactgccgtgtgtggcgctggcccgatcttcagagcc 661 accatgaactaaaaccactggaatgctgtgagtttccttttggttccaagcagaaggagg 721 tctgcatcaatccctaccactataagagagtagaaagccctgtacttcctcctgtgctgg 781 ttccaagacacagcgaatataatcctcagcacagcctcttagctcagttccgtaacttag 841 gacaaaatgagcctcacatgccactcaacgccacttttccagattctttccagcaaccca 901 acagccacccgtttcctcactctcccaatagcagttacccaaactctcctgggagcagca 961 gcagcacctaccctcactctcccaccagctcagacccaggaagccctttccagatgccag 1021 ctgatacgcccccacctgcttacctgcctcctgaagaccccatgacccaggatggctctc 1081 agccgatggacacaaacatgatggcgcctcccctgccctcagaaatcaacagaggagatg 1141 ttcaggcggttgcttatgaggaaccaaaacactggtgctctattgtctactatgagctca 1201 acaatcgtgtgggtgaagcgttccatgcctcctccacaagtgtgttggtggatggtttca 1261 ctgatccttccaacaataagaaccgtttctgccttgggctgctctccaatgttaaccgga 1321 attccactattgaaaacaccaggcggcatattggaaaaggagttcatctttattatgttg 1381 gaggggaggtgtatgccgaatgccttagtgacagtagcatctttgtgcaaagtcggaact 1441 gcaactaccatcatggatttcatcctactactgtttgcaagatccctagtgggtgtagtc 1501 tgaaaatttttaacaaccaagaatttgctcagttattggcacagtctgtgaaccatggat 1561 ttgagacagtctatgagcttacaaaaatgtgtactatacgtatgagctttgtgaagggct 1621 ggggagcagaataccaccgccaggatgttactagcaccccctgctggattgagatacatc 1681 tgcacggccccctccagtggctggataaagttcttactcaaatgggttcacctcataatc 1741 ctatttcatctgtatcttaaatggccccaggcatctgcctctggaaaactattgagcctt 1801 gcatgtacttgaaggatggatgagtcagacacgattgagaactgacaaaggagccttgat 1861 aatacttgacctctgtgaccaactgttggattcagaaatttaaacaaaaaaaaaaaaaaa 1921 cacacacaccttggtaacatactgttgatatcaagaacctgtttagtttacattgtaaca 1981 ttctattgtaaaatcaactaaaattcagacttttagcaggactttgtgtacagttaaagg 2041 agagatggccaagccagggacaaattgtctattagaaaacggtcctaagagattctttgg 2101 tgtttggcactttaaggtcatcgttgggcagaagtttagcattaatagttgttctgaaac 2161 gtgttttatcaggtttagagcccatgttgagtcttcttttcatgggttttcataatattt 2221 taaaactatttgtttagcgatggttttgttcgtttaagtaaaggttaatcttgatgatat 2281 acataataatctttctaaaattgtatgctgaccatacttgctgtcagaataatgctaggc 2341 atatgctttttgctaaatatgtatgtacagagtatttggaagttaagaattgattagact 2401 agtgaatttaggagtatttgaggtgggtggggggaagagggaaatgacaactgcaaatgt 2461 agactatactgtaaaaattcagtttgttgctttaaagaaacaaactgatacctgaatttt 2521 gctgtgtttccattttttagagatttttatcatttttttctctctcggcattcttttttc 2581 tcatactcttcaaaaagcagttctgcagctggttaattcatgtaactgtgagagcaaatg 2641 aataattcctgctattctgaaattgcctacatgtttcaataccagttatatggagtgctt 2701 gaatttaataagcagtttttacggagtttacagtacagaaataggctttaattttcaagt 2761 gaattttttgccaaacttagtaactctgttaaatatttggaggatttaaagaacatccca 2821 gtttgaattcatttcaaactttttaaatttttttgtactatgtttggttttattttcctt 2881 ctgttaatcttttgtattcacttatgctctcgtacattgagtacttttattccaaaacta 2941 gtgggttttctctactggaaattttcaataaacctgtcattattgcttactttgattaaa 3001 aa SEQIDNO:142HumanSMAD1aminoacidsequence (NP_005891.1.NP_001341746.1,NP_001341745.1,NP_001341743.1,NP_001341742.1, NP_001341741.1,NP_001341740.1,NP_001003688.1) 1 mnvtslfsftspavkrllgwkqgdeeekwaekavdalvkklkkkkgameelekalscpgq 61 psncvtiprsldgrlqvshrkglphviycrvwrwpdlqshhelkpleccefpfgskqkev 121 cinpyhykrvespvlppvlvprhseynpqhsllaqfrnlgqnephmplnatfpdsfqqpn 181 shpfphspnssypnspgsssstyphsptssdpgspfqmpadtpppaylppedpmtqdgsq 241 pmdtnmmapplpseinrgdvqavayeepkhwcsivyyelnnrvgeafhasstsvlvdgft 301 dpsnnknrfclgllsnvnrnstientrrhigkgvhlyyvggevyaeclsdssifvqsrnc 361 nyhhgfhpttvckipsgcslkifnnqefaqllaqsvnhgfetvyeltkmctirmsfvkgw 421 gaeyhrqdvtstpcwieihlhgplqwldkvltqmgsphnpissvs SEQIDNO:143MouseSMAD1cDNAsequence(NM_008539.4;CDS:358-1755) 1 agatcaatccaggctcggggagcgagcgggcgcaccaaggcgaggccggggccgaggcgc 61 ggggacggcggcccggagctaagcagagcgcggggacggcggccgggagcggatcggagc 121 acgggacccggcgccgggtctcgtgcgtccctgcggatgggcgcgccgccgagccggcgc 181 taactgggatcctcgctggaacaggagggacagtattttctacctttccaaaccgcagac 241 caagaagctaaggagaatctatgtaaatatactgaaatctctgttggctctgcgcccaac 301 accccggagctggcacctcaccctgtctgaggagcgtgtagaactagaccagccgctatg 361 aatgtgaccagcttgttttcattcacaagtccagctgtgaagagactccttgggtggaaa 421 cagggcgatgaagaagagaaatgggcagagaaagctgtggacgctttggtgaagaaactg 481 aagaagaagaaaggggccatggaagagctggagaaggccctgagctgccctggacagccg 541 agtaactgcgtcaccattcctcgctccctggatggcaggttgcaggtgtcccaccggaag 601 ggactacctcatgtcatttattgccgtgtgtggcgctggcccgacctccagagccaccat 661 gaactgaagcctctggaatgctgtgagttcccatttggttccaagcagaaggaggtctgc 721 atcaacccctaccactataagcgagtggagagcccggttctcccgccggtgctggttccg 781 aggcacagcgagtacaatcctcagcacagccttctggctcagttccgcaacctgggacaa 841 aatgagcctcacatgccactgaacgccacgttcccagactctttccagcagcccaacagc 901 cacccgttcccccactcccccaacagcagctaccccaactctcctggcggcagcagcagc 961 acctaccctcactccccaaccagctcagacccgggcagcccttttcagatgccagctgac 1021 acacccccacctgcttacctgcctcctgaagaccccatggcccaggatggctctcagccc 1081 atggacacgaacatgatggcgcctccactgcccgctgaaatcagcagaggagatgttcag 1141 gcagttgcttacgaggaaccaaaacactggtgctctattgtgtactatgagctcaacaac 1201 cgtgtgggtgaagcgttccacgcctcgtccaccagcgtgctggtggatggtttcacagat 1261 ccgtccaacaataagaaccgcttctgccttggcttgctctccaacgttaaccggaattcc 1321 actattgaaaacaccaggcgacatattgggaaaggagtccacctttattacgttggagga 1381 gaggtgtatgcggaatgcctcagtgacagcagcatcttcgtgcagagccggaactgcaac 1441 taccaccacggctttcaccccaccaccgtctgcaagatccccagcgggtgcagcttgaaa 1501 atcttcaacaaccaagagtttgctcagctactggcgcagtctgtgaaccacgggttcgag 1561 accgtgtatgaactcaccaaaatgtgcactattcggatgagcttcgtgaagggttgggga 1621 gccgaataccaccggcaggatgttaccagcaccccctgctggattgagatccatctgcat 1681 ggccctctccagtggctggataaggttctgacccagatgggctcaccccacaatcctatt 1741 tcatccgtgtcttaaaagacctgtggcttccgtctcttgcaaactatcgagccttgcatg 1801 tacttgaaggatggacaagtcagacaggatggagacctgacgaaggagccacgataatac 1861 ttgacctctgtgaccaactattggattgagaaactgacaagccttggttgatagcaagaa 1921 ccctttcagtttacattgtgacattctgttgtaaaaatcaactaaaatgctgactttcag 1981 caggacttttgtgtatagttaaaaaaaaaagagatggccaagccagggacaaattatcta 2041 ttaggaaaaaagaaaaaaatgattgtaatcaatccttttgtgtggggtgttggcagaagg 2101 ttggcgctgatagtctttctgaagtgggctttcatcaggctcagagcccacgttgaatca 2161 tcttctcatgggttttcttaatattttaaaactacttgtttagaaatgaatgggtttttt 2221 gtttgtttttaaagtacaggttaatcgttatgacatgcatagtaatctttctgaaactgt 2281 atgctggctgtattactgtcagaatgatggcaggcatatgctctttgctaaatatgtata 2341 tacagaatatttggaggttatgaatagtctaaatggctagtgggtttacagagtatctga 2401 ggggcggggtcgggaagaaaacgacggctgcaaatgtagactataccgtaaagctcagct 2461 tgctgccttaaacagacaagctggtgtctgaatttgctgtgtttcagtttttgtagagtt 2521 ttatctgacttcttttcttctgtcttatccgctccacggcacagttaagcagctggttaa 2581 ttcctctaactgtgagagcagatgagtaattccttctgttcgcaaatcaactggcttcgt 2641 gtttcagtacccagtatatgaaaagcttgaattgaatgagcagtttttatggagtttaca 2701 gtacagacataggctttgatttccaaataaattgtttgccaaacctggtaactctgttca 2761 ttattcgcaggattaaagatctctctattggaatccatttcaaaggttgttttttttgtt 2821 tttgtttttgttttttgttttattttgatttgtttttttttgtactatttggtttctttt 2881 cttctgttaatttttttattctcctttgctcttatacagcgagtacttttattccaacac 2941 tagcagggtttttctctactggaaatttttaaataaaacctgtcattattgcttactttg 3001 attaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa SEQIDNO:144MouseSMAD1isoformaminoacidsequence(NP_0325652) 1 mnvtslfsftspavkrllgwkqgdeeekwaekavdalvkklkkkkgameelekalscpgq 61 psncvtiprsldgrlqvshrkglphviycrvwrwpdlqshhelkpleccefpfgskqkev 121 cinpyhykrvespvlppvlvprhseynpqhsllaqfrnlgqnephmpinatfpdsfqqpn 181 shpfphspnssypnspggssstyphsptssdpgspfqmpadtpppaylppedpmaqdgsq 241 pmdtnmmapplpaeisrgdvqavayeepkhwcsivyyelnnrvgeafhasstsvlvdgft 301 dpsnnknrfclgllsnvnrnstientrrhigkgvhlyyvggevyaeclsdssifvqsrnc 361 nyhhgfhpttvckipsgcslkifnnqefaqllaqsvnhgfetvyeltkmctirmsfvkgw 421 gaeyhrqdvtstpcwieihlhgplqwldkvltqmgsphnpissvs SEQIDNO:145SMAD3transcriptvariant1cDNAsequence(NM_005902.4; CDS:554-1831) 1 gaaacacagactgggagcgggcgggagcgggagcgcggcgcacgccccgggccggcccag 61 ccagcgagcgagcgagcggcgagccgggaggaggagggtggcggggcggtgaggccgcag 121 aggcggagggatctgcgcatcaaagctagcgaggcgagcgaagtttggccgggggttgga 181 ctttccttcccggaggcggcacccaaacagctaccccgtgcggaaacccaaacttctgct 241 gccacttggagtctcgcggccgccgcctccgccccgcgttcggggccttcccgaccctgc 301 actgctgccgtccgcccgcccggccgctcttctcttcgccgtgggagccgctccgggcgc 361 agggccgcgcgccgagccccgcaggctgcagcgccgcggcccggcccggcgccccggcaa 421 cttcgccgagagttgaggcgaagtttgggcgaccgcggcaggccccggccgagctcccct 481 ctgcgcccccggcgtcccgtcgagcccagccccgccgggggcgctcctcgccgcccgcgc 541 gccctccccagccatgtcgtccatcctgcctttcactcccccgatcgtgaagcgcctgct 601 gggctggaagaagggcgagcagaacgggcaggaggagaaatggtgcgagaaggcggtcaa 661 gagcctggtcaagaaactcaagaagacggggcagctggacgagctggagaaggccatcac 721 cacgcagaacgtcaacaccaagtgcatcaccatccccaggtccctggatggccggttgca 781 ggtgtcccatcggaaggggctccctcatgtcatctactgccgcctgtggcgatggccaga 841 cctgcacagccaccacgagctacgggccatggagctgtgtgagttcgccttcaatatgaa 901 gaaggacgaggtctgcgtgaatccctaccactaccagagagtagagacaccagttctacc 961 tcctgtgttggtgccacgccacacagagatcccggccgagttccccccactggacgacta 1021 cagccattccatccccgaaaacactaacttccccgcaggcatcgagccccagagcaatat 1081 tccagagaccccaccccctggctacctgagtgaagatggagaaaccagtgaccaccagat 1141 gaaccacagcatggacgcaggttctccaaacctatccccgaatccgatgtccccagcaca 1201 taataacttggacctgcagccagttacctactgcgagccggccttctggtgctccatctc 1261 ctactacgagctgaaccagcgcgtcggggagacattccacgcctcgcagccatccatgac 1321 tgtggatggcttcaccgacccctccaattcggagcgcttctgcctagggctgctctccaa 1381 tgtcaacaggaatgcagcagtggagctgacacggagacacatcggaagaggcgtgcggct 1441 ctactacatcggaggggaggtcttcgcagagtgcctcagtgacagcgctatttttgtcca 1501 gtctcccaactgtaaccagcgctatggctggcacccggccaccgtctgcaagatcccacc 1561 aggatgcaacctgaagatcttcaacaaccaggagttcgctgccctcctggcccagtcggt 1621 caaccagggctttgaggctgtctaccagttgacccgaatgtgcaccatccgcatgagctt 1681 cgtcaaaggctggggagcggagtacaggagacagactgtgaccagtaccccctgctggat 1741 tgagctgcacctgaatgggcctttgcagtggcttgacaaggtcctcacccagatgggctc 1801 cccaagcatccgctgttccagtgtgtcttagagacatcaagtatggtaggggagggcagg 1861 cttggggaaaatggccatgcaggaggtggagaaaattggaactctactcaacccattgtt 1921 gtcaaggaagaagaaatctttctccctcaactgaaggggtgcacccacctgttttctgaa 1981 acacacgagcaaacccagaggtggatgttatgaacagctgtgtctgccaaacacatttac 2041 cctttggccccactttgaagggcaagaaatggcgtctgctctggtggcttaagtgagcag 2101 aacaggtagtattacaccaccggccccctccccccagactctttttttgagtgacagctt 2161 tctgggatgtcacagtccaaccagaaacacccctctgtctaggactgcagtgtggagttc 2221 accttggaagggcgttctaggtaggaagagcccgcagggccatgcagacctcatgcccag 2281 ctctctgacgcttgtgacagtgcctcttccagtgaacattcccagcccagccccgccccg 2341 ccccgccccaccactccagcagaccttgccccttgtgagctggatagacttgggatgggg 2401 agggagggagttttgtctgtctccctcccctctcagaacatactgattgggaggtgcgtg 2461 ttcagcagaacctgcacacaggacagcgggaaaaatcgatgagcgccacctctttaaaaa 2521 ctcacttacgtttgtcctttttcactttgaaaagttggaaggatctgctgaggcccagtg 2581 catatgcaatgtatagtgtctattatcacattaatctcaaagagattcgaatgacggtaa 2641 gtgttctcatgaagcaggaggcccttgtcgtgggatggcatttggtctcaggcagcacca 2701 cactgggtgcgtctccagtcatctgtaagagcttgctccagattctgatgcatacggcta 2761 tattggtttatgtagtcagttgcattcattaaatcaactttatcatatgctcttttaaat 2821 gtttggtttatatattttctttaaaaatcctgggctggcacattgactgggaaacctgag 2881 tgagacccagcaactgcttctctcccttctctctcctgaggtgaagcttttccaggtttt 2941 gttgaagagatacctgccagcacttctgcaagctgaaatttacagaagcaaattcaccag 3001 aagggaaacatctcaggccaacataggcaaatgaaaagggctattaaaatatttttacac 3061 ctttgaaaattgcaggcttggtacaaagaggtctgtcatcttccccctgggatataagat 3121 gatctagctcccggtagaggatcaccggtgacaactatagcagttgtattgtgtaacaag 3181 tactgctcccagcagcaattagggagaaaactagtctaaattatttcaactggaaaaaag 3241 aaaaaagagtcctcttcttttcccagccttttgcagaacacagtagacagaactgccacc 3301 ttcaattggtactttattctttgctgctgtttttgtataaaatgacctatcccacgtttt 3361 tgcatgaatttatagcaggaaaaatcaagggatttcctatggaagtcctgctttattcca 3421 ggtgaagggaaggaagtgtatatacttttggcaagtcatacagctcaaatgtgatgagat 3481 ttctgatgttagagggagatggagaggcttcctgatgcctcatctgcagggtcctgtgcc 3541 tctgaagttctagccatgaggtttccaggtaggacagctgctccccaagcctcctgagga 3601 cacaggaagagacggaaggagcaccttgacagacttgtgtgagtcttctcgaaggagggt 3661 tgactcagaacccagagacaatacaaaacccctcacttcctctgagagggccaaatgctg 3721 tgagtctgaagtatgtgcctggtgtgaaatgatctatggcctgtttcttacacaggaagc 3781 cccctgaacctcctgtacatgtgttcatgttcccagccagctctgagacccaggaaccaa 3841 atattccattttggcttctgctagagcagtcatggttcctctcctaaaagccatgggcag 3901 cagtttccgagggcctgcatgatccacctgctgcacgatcctatgagggcttcctgtggc 3961 acacagccctctgggtgcttgggaactagcttcaggcacagcctgattctggtgatccag 4021 tgatctatggaagtcgtgtcttactccaggtgaagggggaaaaaaaaagcctatactttg 4081 gcaggttatgaactttgaatgtgatgaaatgacacgtttggctgcatttggatggtgtct 4141 tagaaccctcattgctcagacctgaaggctacttctaggagcatgaagtttgagttttgt 4201 gtttttccaaaggatacttccttggccctttttctttattgactagaccaccagaggagg 4261 atgtgtgggattgtaggcaaacccacctgtggcatcactgaaaataaatttgatcatacc 4321 taagaggttaggaaatggtgccattcccaccttagagtgctacataggtgctttgggcgt 4381 atgtaacattagtgtccttccttgaagccacaagctagttttcttagttttaaaatcctg 4441 ttgtatgaatggcatttgtatattaaaacacttttttaaaggacagttgaaaagggcaag 4501 aggaaaccagggcagttctagaggagtgctggtgactggatagcagttttaagtggcgtt 4561 cacctagtcaacacgaccgcgtgtgttgcccctgccctgggctccccgccatgacatctt 4621 caccttgcagcttgtgctgagactgacccaagtgcagctagcactgggacacagatcctt 4681 gtcttcagcaccttccaaggagccaacttttattccctttcctctctcccctccccacct 4741 cgcttcttcccaatttagtaacttagatgcttccagcacatacgtaggtagctaccccag 4801 ccggtttggattacaggcctgtgctggaacatcatctcagttggccaccttcctggcagg 4861 ctgtagacctgacattttgagacaagcctagaggagtcaggagcagggactttgactctt 4921 aggaagagcacacatgagggcaaggctgctggcagacgtctccattgtccttatgttgtc 4981 tgtgttgtatttttttttttttattgaccatggtgattatttttttaaaccatcgttaat 5041 atactgaagtgagctatagcacatatcatgtgcttagtttgtttatttttctccatctcc 5101 ccttggcttcctagagtttggacatattccaggctaaatgcttttactcaagactacaga 5161 aaggtttgaagtagtgtgtgcatggcatgcacgtatgtaagtaatctggggaagaagcaa 5221 agatctgtttcattcttagcctcaggcctcatgagggtctccacagggccggagctcagg 5281 ttacaccactccttcgtccttacaggagatgtagggagaagaatctgcaggctgcttgta 5341 ggactgttcaccaagggggataccagcagcaagagagtgcacccgtttagccctggaccc 5401 tgtttcttactgtgtgacttggctagagttgggagttcccccaaaataaacgtgtcccca 5461 ttttaccagaaccaaacctcaacacagcgaagctgtactgtctttgtgtggcaaagatgt 5521 tcccttgtaggcccctttcaggtaaccgtcttcacaatgtattttcatcacagtttaagg 5581 agcatcagccgcttctcaagtgggtagggaaagcagaaaaacgtacgcaagaggacatgg 5641 atccaaaatgatgatgaagcatctcccatggggaggtgatggtggggagatgatgggcta 5701 aacaggcaacttttcaaaaacacagctatcatagaaaagaaacttgcctcatgtaaactg 5761 gattgagaaattctcagtgattctgcaatggatttttttttaatgcagaagtaatgtata 5821 ctctagtattctggtgtttttatatttatgtaataatttcttaaaaccattcagacagat 5881 aactatttaattttttttaagaaagttggaaaggtctctcctcccaaggacagtggctgg 5941 aagagttggggcacagccagttctgaatgttggtggagggtgtagtggctttttggctca 6001 gcatccagaaacaccaaaccaggctggctaaacaagtggccgcgtgtaaaaacagacagc 6061 tctgagtcaaatctgggcccttccacaagggtcctctgaaccaagccccactcccttgct 6121 aggggtgaaagcattacagagagatggagccatctatccaagaagccttcactcaccttc 6181 actgctgctgttgcaactcggctgttctggactctgatgtgtgtggagggatggggaata 6241 gaacattgactgtgttgattaccttcactattcggccagcctgaccttttaataactttg 6301 taaaaagcatgtatgtatttatagtgttttagatttttctaacttttatatcttaaaagc 6361 agagcacctgtttaagcattgtacccctattgttaaagatttgtgtcctctcattccctc 6421 tcttcctcttgtaagtgcccttctaataaacttttcatggaaaa SEQIDNO:146HumanSMAD3isoform1aminoacidsequence(NP_005893.1) 1 mssilpftppivkrllgwkkgeqngqeekwcekavkslvkklkktgqldelekaittqnv 61 ntkcitiprsldgrlqvshrkglphviycrlwrwpdlhshhelramelcefafnmkkdev 121 cvnpyhyqrvetpvlppvlvprhteipaefpplddyshsipentnfpagiepqsnipetp 181 ppgylsedgetsdhqmnhsmdagspnlspnpmspahnnldlqpvtycepafwcsisyyel 241 nqrvgetfhasqpsmtvdgftdpsnserfclgllsnvnrnaaveltrrhigrgvrlyyig 301 gevfaeclsdsaifvqspncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgf 361 eavyqltrmctirmsfvkgwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsir 421 cssvs SEQIDNO:147HumanSMAD3transcriptvariant2cDNAsequence (NM_001145102.1;CDS:379-1341) 1 aaatatgagcttgtgcttgctggaggaggatgacagaggagcctgctgctgagttcactg 61 gtgctggggttaggtcactgctgggctgaagcgcactgaccataagagcaacatgtgggc 121 aagagccgcggcactggggtaatttattgccgccgctcgcttcaccaggaaccccacacg 181 ctgggttcccacaggatgcgacattcccacaggatgggacaactgcatggaaacccacac 241 tcgggcctgtgttgagcaaccacgtttgagtccctggatggccggttgcaggtgtcccat 301 cggaaggggctccctcatgtcatctactgccgcctgtggcgatggccagacctgcacagc 361 caccacgagctacgggccatggagctgtgtgagttcgccttcaatatgaagaaggacgag 421 gtctgcgtgaatccctaccactaccagagagtagagacaccagttctacctcctgtgttg 481 gtgccacgccacacagagatcccggccgagttccccccactggacgactacagccattcc 541 atccccgaaaacactaacttccccgcaggcatcgagccccagagcaatattccagagacc 601 ccaccccctggctacctgagtgaagatggagaaaccagtgaccaccagatgaaccacagc 661 atggacgcaggttctccaaacctatccccgaatccgatgtccccagcacataataacttg 721 gacctgcagccagttacctactgcgagccggccttctggtgctccatctcctactacgag 781 ctgaaccagcgcgtcggggagacattccacgcctcgcagccatccatgactgtggatggc 841 ttcaccgacccctccaattcggagcgcttctgcctagggctgctctccaatgtcaacagg 901 aatgcagcagtggagctgacacggagacacatcggaagaggcgtgcggctctactacatc 961 ggaggggaggtcttcgcagagtgcctcagtgacagcgctatttttgtccagtctcccaac 1021 tgtaaccagcgctatggctggcacccggccaccgtctgcaagatcccaccaggatgcaac 1081 ctgaagatcttcaacaaccaggagttcgctgccctcctggcccagtcggtcaaccagggc 1141 tttgaggctgtctaccagttgacccgaatgtgcaccatccgcatgagcttcgtcaaaggc 1201 tggggagcggagtacaggagacagactgtgaccagtaccccctgctggattgagctgcac 1261 ctgaatgggcctttgcagtggcttgacaaggtcctcacccagatgggctccccaagcatc 1321 cgctgttccagtgtgtcttagagacatcaagtatggtaggggagggcaggcttggggaaa 1381 atggccatgcaggaggtggagaaaattggaactctactcaacccattgttgtcaaggaag 1441 aagaaatctttctccctcaactgaaggggtgcacccacctgttttctgaaacacacgagc 1501 aaacccagaggtggatgttatgaacagctgtgtctgccaaacacatttaccctttggccc 1561 cactttgaagggcaagaaatggcgtctgctctggtggcttaagtgagcagaacaggtagt 1621 attacaccaccggccccctccccccagactctttttttgagtgacagctttctgggatgt 1681 cacagtccaaccagaaacacccctctgtctaggactgcagtgtggagttcaccttggaag 1741 ggcgttctaggtaggaagagcccgcagggccatgcagacctcatgcccagctctctgacg 1801 cttgtgacagtgcctcttccagtgaacattcccagcccagccccgccccgccccgcccca 1861 ccactccagcagaccttgccccttgtgagctggatagacttgggatggggagggagggag 1921 ttttgtctgtctccctcccctctcagaacatactgattgggaggtgcgtgttcagcagaa 1981 cctgcacacaggacagcgggaaaaatcgatgagcgccacctctttaaaaactcacttacg 2041 tttgtcctttttcactttgaaaagttggaaggatctgctgaggcccagtgcatatgcaat 2101 gtatagtgtctattatcacattaatctcaaagagattcgaatgacggtaagtgttctcat 2161 gaagcaggaggcccttgtcgtgggatggcatttggtctcaggcagcaccacactgggtgc 2221 gtctccagtcatctgtaagagcttgctccagattctgatgcatacggctatattggttta 2281 tgtagtcagttgcattcattaaatcaactttatcatatgctcttttaaatgtttggttta 2341 tatattttctttaaaaatcctgggctggcacattgactgggaaacctgagtgagacccag 2401 caactgcttctctcccttctctctcctgaggtgaagcttttccaggttttgttgaagaga 2461 tacctgccagcacttctgcaagctgaaatttacagaagcaaattcaccagaagggaaaca 2521 tctcaggccaacataggcaaatgaaaagggctattaaaatatttttacacctttgaaaat 2581 tgcaggcttggtacaaagaggtctgtcatcttccccctgggatataagatgatctagctc 2641 ccggtagaggatcaccggtgacaactatagcagttgtattgtgtaacaagtactgctccc 2701 agcagcaattagggagaaaactagtctaaattatttcaactggaaaaaagaaaaaagagt 2761 cctcttcttttcccagccttttgcagaacacagtagacagaactgccaccttcaattggt 2821 actttattctttgctgctgtttttgtataaaatgacctatcccacgtttttgcatgaatt 2881 tatagcaggaaaaatcaagggatttcctatggaagtcctgctttattccaggtgaaggga 2941 aggaagtgtatatacttttggcaagtcatacagctcaaatgtgatgagatttctgatgtt 3001 agagggagatggagaggcttcctgatgcctcatctgcagggtcctgtgcctctgaagttc 3061 tagccatgaggtttccaggtaggacagctgctccccaagcctcctgaggacacaggaaga 3121 gacggaaggagcaccttgacagacttgtgtgagtcttctcgaaggagggttgactcagaa 3181 cccagagacaatacaaaacccctcacttcctctgagagggccaaatgctgtgagtctgaa 3241 gtatgtgcctggtgtgaaatgatctatggcctgtttcttacacaggaagccccctgaacc 3301 tcctgtacatgtgttcatgttcccagccagctctgagacccaggaaccaaatattccatt 3361 ttggcttctgctagagcagtcatggttcctctcctaaaagccatgggcagcagtttccga 3421 gggcctgcatgatccacctgctgcacgatcctatgagggcttcctgtggcacacagccct 3481 ctgggtgcttgggaactagcttcaggcacagcctgattctggtgatccagtgatctatgg 3541 aagtcgtgtcttactccaggtgaagggggaaaaaaaaagcctatactttggcaggttatg 3601 aactttgaatgtgatgaaatgacacgtttggctgcatttggatggtgtcttagaaccctc 3661 attgctcagacctgaaggctacttctaggagcatgaagtttgagttttgtgtttttccaa 3721 aggatacttccttggccctttttctttattgactagaccaccagaggaggatgtgtggga 3781 ttgtaggcaaacccacctgtggcatcactgaaaataaatttgatcatacctaagaggtta 3841 ggaaatggtgccattcccaccttagagtgctacataggtgctttgggcgtatgtaacatt 3901 agtgtccttccttgaagccacaagctagttttcttagttttaaaatcctgttgtatgaat 3961 ggcatttgtatattaaaacacttttttaaaggacagttgaaaagggcaagaggaaaccag 4021 ggcagttctagaggagtgctggtgactggatagcagttttaagtggcgttcacctagtca 4081 acacgaccgcgtgtgttgcccctgccctgggctccccgccatgacatcttcaccttgcag 4141 cttgtgctgagactgacccaagtgcagctagcactgggacacagatccttgtcttcagca 4201 ccttccaaggagccaacttttattccctttcctctctcccctccccacctcgcttcttcc 4261 caatttagtaacttagatgcttccagcacatacgtaggtagctaccccagccggtttgga 4321 ttacaggcctgtgctggaacatcatctcagttggccaccttcctggcaggctgtagacct 4381 gacattttgagacaagcctagagtcaggagcagggactttgactcttaggaagagcacac 4441 atgagggcaaggctgctggcagacgtctccattgtccttatgttgtctgtgttgtatttt 4501 tttttttttattgaccatggtgattatttttttaaaccatcgttaatatactgaagtgag 4561 ctatagcacatatcatgtgcttagtttgtttatttttctccatctccccttggcttccta 4621 gagtttggacatattccaggctaaatgcttttactcaagactacagaaaggtttgaagta 4681 gtgtgtgcatggcatgcacgtatgtaagtaatctggggaagaagcaaagatctgtttcat 4741 tcttagcctcaggcctcatgagggtctccacagggccggagctcaggttacaccactcct 4801 tcgtccttacaggagatgtagggagaagaatctgcaggctgcttgtaggactgttcacca 4861 agggggataccagcagcaagagagtgcacccgtttagccctggaccctgtttcttactgt 4921 gtgacttggctagagttgggagttcccccaaaataaacgtgtccccattttaccagaacc 4981 aaacctcaacacagcgaagctgtactgtctttgtgtggcaaagatgttcccttgtaggcc 5041 cctttcaggtaaccgtcttcacaatgtattttcatcacagtttaaggagcatcagccgct 5101 tctcaagtgggtagggaaagcagaaaaacgtacgcaagaggacatggatccaaaatgatg 5161 atgaagcatctcccatggggaggtgatggtggggagatgatgggctaaacaggcaacttt 5221 tcaaaaacacagctatcatagaaaagaaacttgcctcatgtaaactggattgagaaattc 5281 tcagtgattctgcaatggatttttttttaatgcagaagtaatgtatactctagtattctg 5341 gtgtttttatatttatgtaataatttcttaaaaccattcagacagataactatttaattt 5401 tttttaagaaagttggaaaggtctctcctcccaaggacagtggctggaagagttggggca 5461 cagccagttctgaatgttggtggagggtgtagtggctttttggctcagcatccagaaaca 5521 ccaaaccaggctggctaaacaagtggccgcgtgtaaaaacagacagctctgagtcaaatc 5581 tgggcccttccacaagggtcctctgaaccaagccccactcccttgctaggggtgaaagca 5641 ttacagagagatggagccatctatccaagaagccttcactcaccttcactgctgctgttg 5701 caactcggctgttctggactctgatgtgtgtggagggatggggaatagaacattgactgt 5761 gttgattaccttcactattcggccagcctgaccttttaataactttgtaaaaagcatgta 5821 tgtatttatagtgttttagatttttctaacttttatatcttaaaagcagagcacctgttt 5881 aagcattgtacccctattgttaaagatttgtgtcctctcattccctctcttcctcttgta 5941 agtgcccttctaataaacttttcatggaaaagctcctgtgccaggagctcagtctga SEQIDNO:148HumanSMAD3isoform2aminoacidsequence(NP_001138574.1) 1 melcefafnmkkdevcvnpyhyqrvetpvlppvlvprhteipaefpplddyshsipentn 61 fpagiepqsnipetpppgylsedgetsdhqmnhsmdagspnlspnpmspahnnldlqpvt 121 ycepafwcsisyyelnqrvgetfhasqpsmtvdgftdpsnserfclgllsnvnrnaavel 181 trrhigrgvrlyyiggevfaeclsdsaifvqspncnqrygwhpatvckippgcnlkifnn 241 qefaallaqsvnqgfeavyqltrmctirmsfvkgwgaeyrrqtvtstpcwielhlngplq 301 wldkvltqmgspsircssvs SEQIDNO:149HumanSMAD3transcriptvariant3cDNAsequence (NM_001145103.1;CDS:7-1152) 1 acaaacatgtcttgcctgcaccctaggcaaacgtggaaaggcgcagctctggtacaccgg 61 aaagcatggtggatggggaggtccctggatggccggttgcaggtgtcccatcggaagggg 121 ctccctcatgtcatctactgccgcctgtggcgatggccagacctgcacagccaccacgag 181 ctacgggccatggagctgtgtgagttcgccttcaatatgaagaaggacgaggtctgcgtg 241 aatccctaccactaccagagagtagagacaccagttctacctcctgtgttggtgccacgc 301 cacacagagatcccggccgagttccccccactggacgactacagccattccatccccgaa 361 aacactaacttccccgcaggcatcgagccccagagcaatattccagagaccccaccccct 421 ggctacctgagtgaagatggagaaaccagtgaccaccagatgaaccacagcatggacgca 481 ggttctccaaacctatccccgaatccgatgtccccagcacataataacttggacctgcag 541 ccagttacctactgcgagccggccttctggtgctccatctcctactacgagctgaaccag 601 cgcgtcggggagacattccacgcctcgcagccatccatgactgtggatggcttcaccgac 661 ccctccaattcggagcgcttctgcctagggctgctctccaatgtcaacaggaatgcagca 721 gtggagctgacacggagacacatcggaagaggcgtgcggctctactacatcggaggggag 781 gtcttcgcagagtgcctcagtgacagcgctatttttgtccagtctcccaactgtaaccag 841 cgctatggctggcaccaggccaccgtctgcaagatcccaccaggatgcaacctgaagatc 901 ttcaacaaccaggagttcgctgccctcctggcccagtcggtcaaccagggctttgaggct 961 gtctaccagttgacccgaatgtgcaccatccgcatgagcttcgtcaaaggctggggagcg 1021 gagtacaggagacagactgtgaccagtaccccctgctggattgagctgcacctgaatggg 1081 cctttgcagtggcttgacaaggtcctcacccagatgggctccccaagcatccgctgttcc 1141 agtgtgtcttagagacatcaagtatggtaggggagggcaggcttggggaaaatggccatg 1201 caggaggtggagaaaattggaactctactcaacccattgttgtcaaggaagaagaaatct 1261 ttctccctcaactgaaggggtgcacccacctgttttctgaaacacacgagcaaacccaga 1321 ggtggatgttatgaacagctgtgtctgccaaacacatttaccctttggccccactttgaa 1381 gggcaagaaatggcgtctgctctggtggcttaagtgagcagaacaggtagtattacacca 1441 ccggccccctccccccagactctttttttgagtgacagctttctgggatgtcacagtcca 1501 accagaaacacccctctgtctaggactgcagtgtggagttcaccttggaagggcgttcta 1561 ggtaggaagagcccgcagggccatgcagacctcatgcccagctctctgacgcttgtgaca 1621 gtgcctcttccagtgaacattcccagcccagccccgccccgccccgccccaccactccag 1681 cagaccttgccccttgtgagctggatagacttgggatggggagggagggagttttgtctg 1741 tctccctcccctctcagaacatactgattgggaggtgcgtgttcagcagaacctgcacac 1801 aggacagcgggaaaaatcgatgagcgccacctctttaaaaactcacttacgtttgtcctt 1861 tttcactttgaaaagttggaaggatctgctgaggcccagtgcatatgcaatgtatagtgt 1921 ctattatcacattaatctcaaagagattcgaatgacggtaagtgttctcatgaagcagga 1981 ggcccttgtcgtgggatggcatttggtctcaggcagcaccacactgggtgcgtctccagt 2041 catctgtaagagcttgctccagattctgatgcatacggctatattggtttatgtagtcag 2101 ttgcattcattaaatcaactttatcatatgctcttttaaatgtttggtttatatattttc 2161 tttaaaaatcctgggctggcacattgactgggaaacctgagtgagacccagcaactgctt 2221 ctctcccttctctctcctgaggtgaagcttttccaggttttgttgaagagatacctgcca 2281 gcacttctgcaagctgaaatttacagaagcaaattcaccagaagggaaacatctcaggcc 2341 aacataggcaaatgaaaagggctattaaaatatttttacacctttgaaaattgcaggctt 2401 ggtacaaagaggtctgtcatcttccccctgggatataagatgatctagctcccggtagag 2461 gatcaccggtgacaactatagcagttgtattgtgtaacaagtactgctcccagcagcaat 2521 tagggagaaaactagtctaaattatttcaactggaaaaaagaaaaaagagtcctcttctt 2581 ttcccagccttttgcagaacacagtagacagaactgccaccttcaattggtactttattc 2641 tttgctgctgtttttgtataaaatgacctatcccacgtttttgcatgaatttatagcagg 2701 aaaaatcaagggatttcctatggaagtcctgctttattccaggtgaagggaaggaagtgt 2761 atatacttttggcaagtcatacagctcaaatgtgatgagatttctgatgttagagggaga 2821 tggagaggcttcctgatgcctcatctgcagggtcctgtgcctctgaagttctagccatga 2881 ggtttccaggtaggacagctgctccccaagcctcctgaggacacaggaagagacggaagg 2941 agcaccttgacagacttgtgtgagtcttctcgaaggagggttgactcagaacccagagac 3001 aatacaaaacccctcacttcctctgagagggccaaatgctgtgagtctgaagtatgtgcc 3061 tggtgtgaaatgatctatggcctgtttcttacacaggaagccccctgaacctcctgtaca 3121 tgtgttcatgttcccagccagctctgagacccaggaaccaaatattccattttggcttct 3181 gctagagcagtcatggttcctctcctaaaagccatgggcagcagtttccgagggcctgca 3241 tgatccacctgctgcacgatcctatgagggcttcctgtggcacacagccctctgggtgct 3301 tgggaactagcttcaggcacagcctgattctggtgatccagtgatctatggaagtcgtgt 3361 cttactccaggtgaagggggaaaaaaaaagcctatactttggcaggttatgaactttgaa 3421 tgtgatgaaatgacacgtttggctgcatttggatggtgtcttagaaccctcattgctcag 3481 acctgaaggctacttctaggagcatgaagtttgagttttgtgtttttccaaaggatactt 3541 ccttggccctttttctttattgactagaccaccagaggaggatgtgtgggattgtaggca 3601 aacccacctgtggcatcactgaaaataaatttgatcatacctaagaggttaggaaatggt 3661 gccattcccaccttagagtgctacataggtgctttgggcgtatgtaacattagtgtcctt 3721 ccttgaagccacaagctagttttcttagttttaaaatcctgttgtatgaatggcatttgt 3781 atattaaaacacttttttaaaggacagttgaaaagggcaagaggaaaccagggcagttct 3841 agaggagtgctggtgactggatagcagttttaagtggcgttcacctagtcaacacgaccg 3901 cgtgtgttgcccctgccctgggctccccgccatgacatcttcaccttgcagcttgtgctg 3961 agactgacccaagtgcagctagcactgggacacagatccttgtcttcagcaccttccaag 4021 gagccaacttttattccctttcctctctcccctccccacctcgcttcttcccaatttagt 4081 aacttagatgcttccagcacatacgtaggtagctaccccagccggtttggattacaggcc 4141 tgtgctggaacatcatctcagttggccaccttcctggcaggctgtagacctgacattttg 4201 agacaagcctagagtcaggagcagggactttgactcttaggaagagcacacatgagggca 4261 aggctgctggcagacgtctccattgtccttatgttgtctgtgttgtattttttttttttt 4321 attgaccatggtgattatttttttaaaccatcgttaatatactgaagtgagctatagcac 4381 atatcatgtgcttagtttgtttatttttctccatctccccttggcttcctagagtttgga 4441 catattccaggctaaatgcttttactcaagactacagaaaggtttgaagtagtgtgtgca 4501 tggcatgcacgtatgtaagtaatctggggaagaagcaaagatctgtttcattcttagcct 4561 caggcctcatgagggtctccacagggccggagctcaggttacaccactccttcgtcctta 4621 caggagatgtagggagaagaatctgcaggctgcttgtaggactgttcaccaagggggata 4681 ccagcagcaagagagtgcacccgtttagccctggaccctgtttcttactgtgtgacttgg 4741 ctagagttgggagttcccccaaaataaacgtgtccccattttaccagaaccaaacctcaa 4801 cacagcgaagctgtactgtctttgtgtggcaaagatgttcccttgtaggcccctttcagg 4861 taaccgtcttcacaatgtattttcatcacagtttaaggagcatcagccgcttctcaagtg 4921 ggtagggaaagcagaaaaacgtacgcaagaggacatggatccaaaatgatgatgaagcat 4981 ctcccatggggaggtgatggtggggagatgatgggctaaacaggcaacttttcaaaaaca 5041 cagctatcatagaaaagaaacttgcctcatgtaaactggattgagaaattctcagtgatt 5101 ctgcaatggatttttttttaatgcagaagtaatgtatactctagtattctggtgttttta 5161 tatttatgtaataatttcttaaaaccattcagacagataactatttaattttttttaaga 5221 aagttggaaaggtctctcctcccaaggacagtggctggaagagttggggcacagccagtt 5281 ctgaatgttggtggagggtgtagtggctttttggctcagcatccagaaacaccaaaccag 5341 gctggctaaacaagtggccgcgtgtaaaaacagacagctctgagtcaaatctgggccctt 5401 ccacaagggtcctctgaaccaagccccactcccttgctaggggtgaaagcattacagaga 5461 gatggagccatctatccaagaagccttcactcaccttcactgctgctgttgcaactcggc 5521 tgttctggactctgatgtgtgtggagggatggggaatagaacattgactgtgttgattac 5581 cttcactattcggccagcctgaccttttaataactttgtaaaaagcatgtatgtatttat 5641 agtgttttagatttttctaacttttatatcttaaaagcagagcacctgtttaagcattgt 5701 acccctattgttaaagatttgtgtcctctcattccctctcttcctcttgtaagtgccctt 5761 ctaataaacttttcatggaaaagctcctgtgccaggagctcagtctga SEQIDNO:150HumanSMAD3isoform3aminoacidsequence(NP_001138575.1) 1 msclhprqtwkgaalvhrkawwmgrsldgrlqvshrkglphviycrlwrwpdlhshhelr 61 amelcefafnmkkdevcvnpyhyqrvetpvlppvlvprhteipaefpplddyshsipent 121 nfpagiepqsnipetpppgylsedgetsdhqmnhsmdagspnlspnpmspahnnldlqpv 181 tycepafwcsisyyelnqrvgetfhasqpsmtvdgftdpsnserfclgllsnvnrnaave 241 ltrrhigrgvrlyyiggevfaeclsdsaifvqspncnqrygwhpatvckippgcnlkifn 301 nqefaallaqsvnqgfeavyqltrmctirmsfvkgwgaeyrrqtvtstpcwielhlngpl 361 qwldkvltqmgspsircssvs SEQIDNO:151HumanSMAD3transcriptvariant4cDNAsequence (NM_001145104.1;CDS:93-785) 1 cttctcagatcctttgcgggtagccctggcgtcccgcggagaccccaccccctggctacc 61 tgagtgaagatggagaaaccagtgaccaccagatgaaccacagcatggacgcaggttctc 121 caaacctatccccgaatccgatgtccccagcacataataacttggacctgcagccagtta 181 cctactgcgagccggccttctggtgctccatctcctactacgagctgaaccagcgcgtcg 241 gggagacattccacgcctcgcagccatccatgactgtggatggcttcaccgacccctcca 301 attcggagcgcttctgcctagggctgctctccaatgtcaacaggaatgcagcagtggagc 361 tgacacggagacacatcggaagaggcgtgcggctctactacatcggaggggaggtcttcg 421 cagagtgcctcagtgacagcgctatttttgtccagtctcccaactgtaaccagcgctatg 481 gctggcacccggccaccgtctgcaagatcccaccaggatgcaacctgaagatcttcaaca 541 accaggagttcgctgccctcctggcccagtcggtcaaccagggctttgaggctgtctacc 601 agttgacccgaatgtgcaccatccgcatgagcttcgtcaaaggctggggagcggagtaca 661 ggagacagactgtgaccagtaccccctgctggattgagctgcacctgaatgggcctttgc 721 agtggcttgacaaggtcctcacccagatgggctccccaagcatccgctgttccagtgtgt 781 cttagagacatcaagtatggtaggggagggcaggcttggggaaaatggccatgcaggagg 841 tggagaaaattggaactctactcaacccattgttgtcaaggaagaagaaatctttctccc 901 tcaactgaaggggtgcacccacctgttttctgaaacacacgagcaaacccagaggtggat 961 gttatgaacagctgtgtctgccaaacacatttaccctttggccccactttgaagggcaag 1021 aaatggcgtctgctctggtggcttaagtgagcagaacaggtagtattacaccaccggccc 1081 cctccccccagactctttttttgagtgacagctttctgggatgtcacagtccaaccagaa 1141 acacccctctgtctaggactgcagtgtggagttcaccttggaagggcgttctaggtagga 1201 agagcccgcagggccatgcagacctcatgcccagctctctgacgcttgtgacagtgcctc 1261 ttccagtgaacattcccagcccagccccgccccgccccgccccaccactccagcagacct 1321 tgccccttgtgagctggatagacttgggatggggagggagggagttttgtctgtctccct 1381 cccctctcagaacatactgattgggaggtgcgtgttcagcagaacctgcacacaggacag 1441 cgggaaaaatcgatgagcgccacctctttaaaaactcacttacgtttgtcctttttcact 1501 ttgaaaagttggaaggatctgctgaggcccagtgcatatgcaatgtatagtgtctattat 1561 cacattaatctcaaagagattcgaatgacggtaagtgttctcatgaagcaggaggccctt 1621 gtcgtgggatggcatttggtctcaggcagcaccacactgggtgcgtctccagtcatctgt 1681 aagagcttgctccagattctgatgcatacggctatattggtttatgtagtcagttgcatt 1741 cattaaatcaactttatcatatgctcttttaaatgtttggtttatatattttctttaaaa 1801 atcctgggctggcacattgactgggaaacctgagtgagacccagcaactgcttctctccc 1861 ttctctctcctgaggtgaagcttttccaggttttgttgaagagatacctgccagcacttc 1921 tgcaagctgaaatttacagaagcaaattcaccagaagggaaacatctcaggccaacatag 1981 gcaaatgaaaagggctattaaaatatttttacacctttgaaaattgcaggcttggtacaa 2041 agaggtctgtcatcttccccctgggatataagatgatctagctcccggtagaggatcacc 2101 ggtgacaactatagcagttgtattgtgtaacaagtactgctcccagcagcaattagggag 2161 aaaactagtctaaattatttcaactggaaaaaagaaaaaagagtcctcttcttttcccag 2221 ccttttgcagaacacagtagacagaactgccaccttcaattggtactttattctttgctg 2281 ctgtttttgtataaaatgacctatcccacgtttttgcatgaatttatagcaggaaaaatc 2341 aagggatttcctatggaagtcctgctttattccaggtgaagggaaggaagtgtatatact 2401 tttggcaagtcatacagctcaaatgtgatgagatttctgatgttagagggagatggagag 2461 gcttcctgatgcctcatctgcagggtcctgtgcctctgaagttctagccatgaggtttcc 2521 aggtaggacagctgctccccaagcctcctgaggacacaggaagagacggaaggagcacct 2581 tgacagacttgtgtgagtcttctcgaaggagggttgactcagaacccagagacaatacaa 2641 aacccctcacttcctctgagagggccaaatgctgtgagtctgaagtatgtgcctggtgtg 2701 aaatgatctatggcctgtttcttacacaggaagccccctgaacctcctgtacatgtgttc 2761 atgttcccagccagctctgagacccaggaaccaaatattccattttggcttctgctagag 2821 cagtcatggttcctctcctaaaagccatgggcagcagtttccgagggcctgcatgatcca 2881 cctgctgcacgatcctatgagggcttcctgtggcacacagccctctgggtgcttgggaac 2941 tagcttcaggcacagcctgattctggtgatccagtgatctatggaagtcgtgtcttactc 3001 caggtgaagggggaaaaaaaaagcctatactttggcaggttatgaactttgaatgtgatg 3061 aaatgacacgtttggctgcatttggatggtgtcttagaaccctcattgctcagacctgaa 3121 ggctacttctaggagcatgaagtttgagttttgtgtttttccaaaggatacttccttggc 3181 cctttttctttattgactagaccaccagaggaggatgtgtgggattgtaggcaaacccac 3241 ctgtggcatcactgaaaataaatttgatcatacctaagaggttaggaaatggtgccattc 3301 ccaccttagagtgctacataggtgctttgggcgtatgtaacattagtgtccttccttgaa 3361 gccacaagctagttttcttagttttaaaatcctgttgtatgaatggcatttgtatattaa 3421 aacacttttttaaaggacagttgaaaagggcaagaggaaaccagggcagttctagaggag 3481 tgctggtgactggatagcagttttaagtggcgttcacctagtcaacacgaccgcgtgtgt 3541 tgcccctgccctgggctccccgccatgacatcttcaccttgcagcttgtgctgagactga 3601 cccaagtgcagctagcactgggacacagatccttgtcttcagcaccttccaaggagccaa 3661 cttttattccctttcctctctcccctccccacctcgcttcttcccaatttagtaacttag 3721 atgcttccagcacatacgtaggtagctaccccagccggtttggattacaggcctgtgctg 3781 gaacatcatctcagttggccaccttcctggcaggctgtagacctgacattttgagacaag 3841 cctagagtcaggagcagggactttgactcttaggaagagcacacatgagggcaaggctgc 3901 tggcagacgtctccattgtccttatgttgtctgtgttgtatttttttttttttattgacc 3961 atggtgattatttttttaaaccatcgttaatatactgaagtgagctatagcacatatcat 4021 gtgcttagtttgtttatttttctccatctccccttggcttcctagagtttggacatattc 4081 caggctaaatgcttttactcaagactacagaaaggtttgaagtagtgtgtgcatggcatg 4141 cacgtatgtaagtaatctggggaagaagcaaagatctgtttcattcttagcctcaggcct 4201 catgagggtctccacagggccggagctcaggttacaccactccttcgtccttacaggaga 4261 tgtagggagaagaatctgcaggctgcttgtaggactgttcaccaagggggataccagcag 4321 caagagagtgcacccgtttagccctggaccctgtttcttactgtgtgacttggctagagt 4381 tgggagttcccccaaaataaacgtgtccccattttaccagaaccaaacctcaacacagcg 4441 aagctgtactgtctttgtgtggcaaagatgttcccttgtaggcccctttcaggtaaccgt 4501 cttcacaatgtattttcatcacagtttaaggagcatcagccgcttctcaagtgggtaggg 4561 aaagcagaaaaacgtacgcaagaggacatggatccaaaatgatgatgaagcatctcccat 4621 ggggaggtgatggtggggagatgatgggctaaacaggcaacttttcaaaaacacagctat 4681 catagaaaagaaacttgcctcatgtaaactggattgagaaattctcagtgattctgcaat 4741 ggatttttttttaatgcagaagtaatgtatactctagtattctggtgtttttatatttat 4801 gtaataatttcttaaaaccattcagacagataactatttaattttttttaagaaagttgg 4861 aaaggtctctcctcccaaggacagtggctggaagagttggggcacagccagttctgaatg 4921 ttggtggagggtgtagtggctttttggctcagcatccagaaacaccaaaccaggctggct 4981 aaacaagtggccgcgtgtaaaaacagacagctctgagtcaaatctgggcccttccacaag 5041 ggtcctctgaaccaagccccactcccttgctaggggtgaaagcattacagagagatggag 5101 ccatctatccaagaagccttcactcaccttcactgctgctgttgcaactcggctgttctg 5161 gactctgatgtgtgtggagggatggggaatagaacattgactgtgttgattaccttcact 5221 attcggccagcctgaccttttaataactttgtaaaaagcatgtatgtatttatagtgttt 5281 tagatttttctaacttttatatcttaaaagcagagcacctgtttaagcattgtaccccta 5341 ttgttaaagatttgtgtcctctcattccctctcttcctcttgtaagtgcccttctaataa 5401 acttttcatggaaaagctcctgtgccaggagctcagtctga SEQIDNO:152HumanSMAD3isoform4aminoacidsequence(NP_001138576.1) 1 mnhsmdagspnlspnpmspahnnldlqpvtycepafwcsisyyelnqrvgetfhasqpsm 61 tvdgftdpsnserfclgllsnvnrnaaveltrrhigrgvrlyyiggevfaeclsdsaifv 121 qspncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgfeavyqltrmctirms 181 fvkgwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsircssvs SEQIDNO:153MouseSMAD3cDNAsequence(NM_016769.4;CDS:318-1595) 1 ggcggcacccaaacagctaccccgtgcggaaacccaaactttctactgccacttggagtc 61 tcgcggccgccgcctccgccccgcgcgtccggggcctgcccgtcagtccgtcggtccgcg 121 tggagcagctcgggcgccgccgtgctcccgatccccgcagctgcagcgccgcagtcctgg 181 cccggacgcccgggcaagttctccagagttaaaagcgaagttcgggcgaggcgcgggccg 241 agctgcctctgagcgcccccggcgtccccagtgcgcccagccccgccgggggcgccggtg 301 acccttcggtgccagccatgtcgtccatcctgcccttcacccccccgatcgtgaagcgcc 361 tgctgggttggaagaagggcgagcagaacgggcaggaggagaagtggtgcgagaaggcgg 421 tcaagagcttggtgaagaagctcaagaagacggggcagttggacgagctggagaaggcca 481 tcaccacgcagaacgtgaacaccaagtgcattaccatccccaggtcactggatggtcggc 541 tgcaggtgtcccatcggaaggggctccctcacgttatctactgccgcctgtggcgatggc 601 ccgacctgcacagccaccatgaattacgggccatggagctctgtgagtttgccttcaaca 661 tgaagaaggatgaagtgtgtgtaaatccttaccactatcagagagtagagacgccagttc 721 tacctccagtgttggtgccacgccacaccgagatcccggccgagttccccccactggatg 781 actacagccattccattcccgagaacactaacttccctgctggcattgagccccagagca 841 atattccagaaaccccacctcctggctacctgagtgaagatggagaaaccagtgaccacc 901 agatgaaccacagcatggacgcaggttctccaaacctctccccgaatccgatgtccccag 961 cacacaataacttggacctacagccagtcacctactgtgagccggccttctggtgctcca 1021 tctcctactacgagctgaaccagcgagttggggagacattccacgcctcacagccatcca 1081 tgacagtagatggcttcactgacccctccaactcggagcgcttctgcctgggcctactgt 1141 ccaatgtcaaccggaatgcagccgtggaacttacaaggcgacacattgggagaggtgtgc 1201 ggctctactacatcggaggggaggtctttgcggagtgcctcagtgacagtgctattttcg 1261 tccagtctcccaactgcaaccagcgctatggctggcacccggccactgtctgcaagatcc 1321 caccaggctgcaacctgaagatcttcaacaaccaggaatttgctgccctcctagctcagt 1381 ctgtcaaccagggctttgaggctgtctaccagctgacgcgcatgtgcaccatccgtatga 1441 gcttcgtcaaaggctggggagcagagtacaggagacagacagtgaccagcaccccctgct 1501 ggattgagctacacctgaatggacccttgcagtggcttgacaaggtcctcacccagatgg 1561 gttccccgagcatccgctgttccagtgtgtcttagagacactaggagtaaagggagcggg 1621 ttggggagggcgggcttggggaaaatgaccttggaagagaactccatccaacttggtctt 1681 gtcaaagaacaccgattccactcaactaaggcaccagcctgtttctgagaccacagaaga 1741 aaaccccagggatggatttatgaacagctgtgtctgctacatacacgtgcccctgtctga 1801 aggccaagtgatggcttctgttctggtggcttgaactaacaggtggtgtatcgccacctg 1861 actccttgtttaatgacagaggtctgggatgtcacagtccaaaaggaaagtgcctttctc 1921 catggctggagtatggagtttacctttggagaagttgtaatggagcatgccctgtcccac 1981 cactctcagagagggtgtacctgtcaaactggatggcctacataggtactcccccctacc 2041 cctaggatgcagagagacgggaacacgccggagggtagagctggggagaacccattcttc 2101 cttggaaggatccgctgaaggtcagcgtataggtgatgtacagttcctaatatcacatca 2161 gtctcagagtgttcacaggaagcagcaagggcactcgtggagtatgtgtcctgggtgagg 2221 tggcaccacaccgaatgaatgcatctctgggagctggcaccacaaccctgatgtataggc 2281 tgtgttggtttatggagacaagttgcatcaatgaattcacctagcataggctctttgaaa 2341 tgtcctctgtttgataaaaaacaatcctgggtacgtatgttggctggaaaaccacaatgg 2401 accctgccactgcttcttgccctgaggtttggaagctgagagttatagaagccaattcac 2461 caggaggtaagacatcccaggctgacatgggcaaatgaaaagggctattaaaattttttt 2521 acaccttggaaaattgcaggcttggtgcagagcgctctgtcatcttcaccctgggatgta 2581 ggattacctagctatggtaaaggattgccacagcaaactgtgacactgtgtaatgagcac 2641 tgttcccagcggcaattacagagaaaacgagtgtaaattatttcaactggaaaaaagtcc 2701 ctttcttggctgttttagaacagggtacacaggatcgccacctgcaactggtactcgctt 2761 cttggctgctgcttctgttgtgaaaagacgagcccatgtttctgcatggatttcccatgg 2821 aagtcctgtcctgctacagaggggaagaaagtgtaccctccaatgtgataaatcttctga 2881 tgcccccagactcttggagcacatcctggtgcccctcctgcaggagcctgtggcatattt 2941 ccagctgggcatgctgatcctccttgagacacagatgcctgtgtgagtctccgttgatac 3001 aattctgaacccctcaggttctctgaaagggcacagaccatgggcgtgaacattgtgccg 3061 tacctgagatggtctgtggactgctgcttcagacacacgagtcctcggaactgcctggct 3121 gcctgtcacgcatgctctgagtcagaacacaccaacgctctgctgtggctcctagggaag 3181 cattcatggtcctctgttatcagcaggggtttatgtcacttgctgtccggtttcctaggg 3241 gcttcctgtgccccttccccagctatcctccaggtggctagggacagtctattctgctgc 3301 aactggaaagtagagggaaccggcactgctcagagcagatggcggcttctggaggcacac 3361 agtgggagtacaccccttcatgttattggccagttgctggagaatgctgtaggagaaaat 3421 tctaggcaggtctactcttggcatccctgagagtcaaaggcttggagtctaggaaaggtc 3481 acaccatgatggagaacacaggtcatttgggtacgtgtaatcaaagtgccctcccaaatc 3541 agttctccttttcgtatgaacagcatctctacttttaaagaggagttgaggatcgagaag 3601 atgacagtgcagcagtgggtgtggcctgactacatgtgctgttccagccctgggtgccca 3661 ctgacaccgacccccaggcagaggcctttgtcttcagcactcctgagaagttggctcttt 3721 accccttctcctctgctgcccctccttcctgctggttcaggtagccccagccacgtgggt 3781 tagagtcctgtgctggcctgccatggcagctggctaccttccagaccaactgtagagata 3841 cctggcattttgaagaaagcctagactggagagcagggcctctcttgggaaggacacaag 3901 gcgggcaaggctgctggcagacttctccactgacctgagtgtgctttttttttcccctaa 3961 atgtattgcatcaagcctcagtgcttatggagtgcagtggtcttcatcttccccaacttg 4021 cttctcagagctgggatgtattccagagcctgatgtttttattcaaaccacagaaaagtt 4081 ttctttaagtagcctgtgcagtcatgcatgtgcctgagttgtctggagcagaggcaaaca 4141 tctgacttcattcttagccccaagctgccatttctgagtccttgagaggctgagaaggct 4201 ctagctttgtactgtattcttactgtgtgactagatgcgtgagcgctttacattagaagg 4261 aacctggttagagctcgctcctcctgtctttgtgtggcatttgtgttccattaccggccc 4321 ctttaagtaacggccttcacagcaccttcccagtgggtagaaagccacacaccaggatgt 4381 gggtcaaccatgaagatgtggcattgcagacgggggaacatgtggatgcatggctatcgc 4441 cctgaacagtccctgcagctacttgtgttaacacagaactgatgtttagcattctgccgc 4501 tttcgtatttatgtaacaattccttaaagccattcaaatggctaactatttaatttcttt 4561 aggacagttgtaaaggtctctctcctgaggacaatgacttggaagaactggggcacagcc 4621 agtcccagacactggtggaggctgcagtgactttttttggctcaagatccacaagcatta 4681 gagtagactgggccaacaagtcaacaagtggtggcgtgtgcaaacgggctgccctagtca 4741 agcccagtcccttcaacagtatgtctgatgcaccacaggccctccctactggaagtggga 4801 acttcaaatggaaattggagccatcttttatcccagaagcctttgctgctgccagggcaa 4861 gtgggctggtgtggactcttgtttaggaggctgaggttcttgtcactccttagccagcca 4921 ggcctttagtgtctttgtaaaaagcatgtatttatagtgttttagatttttctaactttt 4981 gtatcttacagcattgtaccccattgttaaagagccgtgtcccctcttcttataaacgcc 5041 cttctaataaacttttcaccgtaaagctcctgagacaggagcacagtctg SEQIDNO:154MouseSMAD3aminoacidsequence(NP_032565.2) 1 mssilpftppivkrllgwkkgeqngqeekwcekavkslvkklkktgqldelekaittqnv 61 ntkcitiprsldgrlqvshrkglphviycrlwrwpdlhshhelramelcefafnmkkdev 121 cvnpyhyqrvetpvlppvlvprhteipaefpplddyshsipentnfpagiepqsnipetp 181 ppgylsedgetsdhqmnhsmdagspnlspnpmspahnnldlqpvtycepafwcsisyyel 241 nqrvgetfhasqpsmtvdgftdpsnserfclgllsnvnrnaaveltrrhigrgvrlyyig 301 gevfaeclsdsaifvqspncnqrygwhpatvckippgcnlkifnnqefaallaqsvnqgf 361 eavyqltrmctirmsfvkgwgaeyrrqtvtstpcwielhlngplqwldkvltqmgspsir 421 cssvs SEQIDNO:155HumanSMAD4cDNAsequence(NM_005359.5;CDS:539-2197) 1 atgctcagtggcttctcgacaagttggcagcaacaacacggccctggtcgtcgtcgccgc 61 tgcggtaacggagcggtttgggtggcggagcctgcgttcgcgccttcccgctctcctcgg 121 gaggcccttcctgctctcccctaggctccgcggccgcccagggggtgggagcgggtgagg 181 ggagccaggcgcccagcgagagaggccccccgccgcagggcggcccgggagctcgaggcg 241 gtccggcccgcgcgggcagcggcgcggcgctgaggaggggcggcctggccgggacgcctc 301 ggggcgggggccgaggagctctccgggccgccggggaaagctacgggcccggtgcgtccg 361 cggaccagcagcgcgggagagcggactcccctcgccaccgcccgagcccaggttatcctg 421 aatacatgtctaacaattttccttgcaacgttagctgttgtttttcactgtttccaaagg 481 atcaaaattgcttcagaaattggagacatatttgatttaaaaggaaaaacttgaacaaat 541 ggacaatatgtctattacgaatacaccaacaagtaatgatgcctgtctgagcattgtgca 601 tagtttgatgtgccatagacaaggtggagagagtgaaacatttgcaaaaagagcaattga 661 aagtttggtaaagaagctgaaggagaaaaaagatgaattggattctttaataacagctat 721 aactacaaatggagctcatcctagtaaatgtgttaccatacagagaacattggatgggag 781 gcttcaggtggctggtcggaaaggatttcctcatgtgatctatgcccgtctctggaggtg 841 gcctgatcttcacaaaaatgaactaaaacatgttaaatattgtcagtatgcgtttgactt 901 aaaatgtgatagtgtctgtgtgaatccatatcactacgaacgagttgtatcacctggaat 961 tgatctctcaggattaacactgcagagtaatgctccatcaagtatgatggtgaaggatga 1021 atatgtgcatgactttgagggacagccatcgttgtccactgaaggacattcaattcaaac 1081 catccagcatccaccaagtaatcgtgcatcgacagagacatacagcaccccagctctgtt 1141 agccccatctgagtctaatgctaccagcactgccaactttcccaacattcctgtggcttc 1201 cacaagtcagcctgccagtatactggggggcagccatagtgaaggactgttgcagatagc 1261 atcagggcctcagccaggacagcagcagaatggatttactggtcagccagctacttacca 1321 tcataacagcactaccacctggactggaagtaggactgcaccatacacacctaatttgcc 1381 tcaccaccaaaacggccatcttcagcaccacccgcctatgccgccccatcccggacatta 1441 ctggcctgttcacaatgagcttgcattccagcctcccatttccaatcatcctgctcctga 1501 gtattggtgttccattgcttactttgaaatggatgttcaggtaggagagacatttaaggt 1561 tccttcaagctgccctattgttactgttgatggatacgtggacccttctggaggagatcg 1621 cttttgtttgggtcaactctccaatgtccacaggacagaagccattgagagagcaaggtt 1681 gcacataggcaaaggtgtgcagttggaatgtaaaggtgaaggtgatgtttgggtcaggtg 1741 ccttagtgaccacgcggtctttgtacagagttactacttagacagagaagctgggcgtgc 1801 acctggagatgctgttcataagatctacccaagtgcatatataaaggtctttgatttgcg 1861 tcagtgtcatcgacagatgcagcagcaggcggctactgcacaagctgcagcagctgccca 1921 ggcagcagccgtggcaggaaacatccctggcccaggatcagtaggtggaatagctccagc 1981 tatcagtctgtcagctgctgctggaattggtgttgatgaccttcgtcgcttatgcatact 2041 caggatgagttttgtgaaaggctggggaccggattacccaagacagagcatcaaagaaac 2101 accttgctggattgaaattcacttacaccgggccctccagctcctagacgaagtacttca 2161 taccatgccgattgcagacccacaacctttagactgaggtcttttaccgttggggccctt 2221 aaccttatcaggatggtggactacaaaatacaatcctgtttataatctgaagatatattt 2281 cacttttgttctgctttatcttttcataaagggttgaaaatgtgtttgctgccttgctcc 2341 tagcagacagaaactggattaaaacaattttttttttcctcttcagaacttgtcaggcat 2401 ggctcagagcttgaagattaggagaaacacattcttattaattcttcacctgttatgtat 2461 gaaggaatcattccagtgctagaaaatttagccctttaaaacgtcttagagccttttatc 2521 tgcagaacatcgatatgtatatcattctacagaataatccagtattgctgattttaaagg 2581 cagagaagttctcaaagttaattcacctatgttattttgtgtacaagttgttattgttga 2641 acatacttcaaaaataatgtgccatgtgggtgagttaattttaccaagagtaactttact 2701 ctgtgtttaaaaagtaagttaataatgtattgtaatctttcatccaaaatattttttgca 2761 agttatattagtgaagatggtttcaattcagattgtcttgcaacttcagttttatttttg 2821 ccaaggcaaaaaactcttaatctgtgtgtatattgagaatcccttaaaattaccagacaa 2881 aaaaatttaaaattacgtttgttattcctagtggatgactgttgatgaagtatacttttc 2941 ccctgttaaacagtagttgtattcttctgtatttctaggcacaaggttggttgctaagaa 3001 gcctataagaggaatttcttttccttcattcatagggaaaggttttgtattttttaaaac 3061 actaaaagcagcgtcactctacctaatgtctcactgttctgcaaaggtggcaatgcttaa 3121 actaaataatgaataaactgaatattttggaaactgctaaattctatgttaaatactgtg 3181 cagaataatggaaacattacagttcataataggtagtttggatatttttgtacttgattt 3241 gatgtgactttttttggtataatgtttaaatcatgtatgttatgatattgtttaaaattc 3301 agtttttgtatcttggggcaagactgcaaacttttttatatcttttggttattctaagcc 3361 ctttgccatcaatgatcatatcaattggcagtgactttgtatagagaatttaagtagaaa 3421 agttgcagatgtattgactgtaccacagacacaatatgtatgctttttacctagctggta 3481 gcataaataaaactgaatctcaacatacaaagttgaattctaggtttgatttttaagatt 3541 ttttttttcttttgcacttttgagtccaatctcagtgatgaggtaccttctactaaatga 3601 caggcaacagccagttctattgggcagctttgtttttttccctcacactctaccgggact 3661 tccccatggacattgtgtatcatgtgtagagttggttttttttttttttaatttttattt 3721 tactatagcagaaatagacctgattatctacaagatgataaatagattgtctacaggata 3781 aatagtatgaaataaaatcaaggattatctttcagatgtgtttacttttgcctggagaac 3841 ttttagctatagaaacacttgtgtgatgatagtcctccttatatcacctggaatgaacac 3901 agcttctactgccttgctcagaaggtcttttaaatagaccatcctagaaaccactgagtt 3961 tgcttatttctgtgatttaaacatagatcttgatccaagctacatgacttttgtctttaa 4021 ataacttatctaccacctcatttgtactcttgattacttacaaattctttcagtaaacac 4081 ctaattttcttctgtaaaagtttggtgatttaagttttattggcagttttataaaaagac 4141 atcttctctagaaattgctaactttaggtccattttactgtgaatgaggaataggagtga 4201 gttttagaataacagatttttaaaaatccagatgatttgattaaaaccttaatcatacat 4261 tgacataattcattgcttcttttttttgagatatggagtcttgctgtgttgcccaggcag 4321 gagtgcagtggtatgatctcagctcactgcaacctctgcctcccgggttcaactgattct 4381 cctgcctcagcctccctggtagctaggattacaggtgcccgccaccatgcctggctaact 4441 tttgtagttttagtagagacggggttttgcctgttggccaggctggtcttgaactcctga 4501 cctcaagtgatccatccaccttggcctcccaaagtgctgggattacgggcgtgagccact 4561 gtccctggcctcattgttcccttttctactttaaggaaagttttcatgtttaatcatctg 4621 gggaaagtatgtgaaaaatatttgttaagaagtatctctttggagccaagccacctgtct 4681 tggtttctttctactaagagccataaagtatagaaatacttctagttgttaagtgcttat 4741 atttgtacctagatttagtcacacgcttttgagaaaacatctagtatgttatgatcagct 4801 attcctgagagcttggttgttaatctatatttctatttcttagtggtagtcatctttgat 4861 gaataagactaaagattctcacaggtttaaaattttatgtctactttaagggtaaaatta 4921 tgaggttatggttctgggtgggttttctctagctaattcatatctcaaagagtctcaaaa 4981 tgttgaatttcagtgcaagctgaatgagagatgagccatgtacacccaccgtaagacctc 5041 attccatgtttgtccagtgcctttcagtgcattatcaaagggaatccttcatggtgttgc 5101 ctttattttccggggagtagatcgtgggatatagtctatctcatttttaatagtttaccg 5161 cccctggtatacaaagataatgacaataaatcactgccatataaccttgctttttccaga 5221 aacatggctgttttgtattgctgtaaccactaaataggttgcctataccattcctcctgt 5281 gaacagtgcagatttacaggttgcatggtctggcttaaggagagccatacttgagacatg 5341 tgagtaaactgaactcatattagctgtgctgcatttcagacttaaaatccatttttgtgg 5401 ggcagggtgtggtgtgtaaaggggggtgtttgtaatacaagttgaaggcaaaataaaatg 5461 tcctgtctcccagatgatatacatcttattatttttaaagtttattgctaattgtaggaa 5521 ggtgagttgcaggtatctttgactatggtcatctggggaaggaaaattttacattttact 5581 attaatgctccttaagtgtctatggaggttaaagaataaaatggtaaatgtttctgtgcc 5641 tggtttgatggtaactggttaatagttactcaccattttatgcagagtcacattagttca 5701 caccctttctgagagccttttgggagaagcagttttattctctgagtggaacagagttct 5761 ttttgttgataatttctagtttgctcccttcgttattgccaactttactggcattttatt 5821 taatgatagcagattgggaaaatggcaaatttaggttacggaggtaaatgagtatatgaa 5881 agcaattacctctaaagccagttaacaattattttgtaggtggggtacactcagcttaaa 5941 gtaatgcatttttttttcccgtaaaggcagaatccatcttgttgcagatagctatctaaa 6001 taatctcatatcctcttttgcaaagactacagagaataggctatgacaatcttgttcaag 6061 cctttccatttttttccctgataactaagtaatttctttgaacataccaagaagtatgta 6121 aaaagtccatggccttattcatccacaaagtggcatcctaggcccagccttatccctagc 6181 agttgtcccagtgctgctaggttgcttatcttgtttatctggaatcactgtggagtgaaa 6241 ttttccacatcatccagaattgccttatttaagaagtaaaacgttttaatttttagcctt 6301 tttttggtggagttatttaatatgtatatcagaggatatactagatggtaacatttcttt 6361 ctgtgcttggctatctttgtggacttcaggggcttctaaaacagacaggactgtgttgcc 6421 tttactaaatggtctgagacagctatggttttgaatttttagttttttttttttaaccca 6481 cttcccctcctggtctcttccctctctgataattaccattcatatgtgagtgttagtgtg 6541 cctccttttagcattttcttcttctctttctgattcttcatttctgactgcctaggcaag 6601 gaaaccagataaccaaacttactagaacgttctttaaaacacaagtacaaactctgggac 6661 aggacccaagacactttcctgtgaagtgctgaaaaagacctcattgtattggcatttgat 6721 atcagtttgatgtagcttagagtgcttcctgattcttgctgagtttcaggtagttgagat 6781 agagagaagtgagtcatattcatattttcccccttagaataatattttgaaaggtttcat 6841 tgcttccacttgaatgctgctcttacaaaaactggggttacaagggttactaaattagca 6901 tcagtagccagaggcaataccgttgtctggaggacaccagcaaacaacacacaacaaagc 6961 aaaacaaaccttgggaaactaaggccatttgttttgttttggtgtcccctttgaagccct 7021 gccttctggccttactcctgtacagatatttttgacctataggtgcctttatgagaattg 7081 agggtctgacatcctgccccaaggagtagctaaagtaattgctagtgttttcagggattt 7141 taacatcagactggaatgaatgaatgaaactttttgtcctttttttttctgttttttttt 7201 ttctaatgtagtaaggactaaggaaaacctttggtgaagacaatcatttctctctgttga 7261 tgtggatacttttcacaccgtttatttaaatgctttctcaataggtccagagccagtgtt 7321 cttgttcaacctgaaagtaatggctctgggttgggccagacagttgcactctctagtttg 7381 ccctctgccacaaatttgatgtgtgacctttgggcaagtcatttatcttctctgggcctt 7441 agttgcctcatctgtaaaatgagggagttggagtagattaattattccagctctgaaatt 7501 ctaagtgaccttggctaccttgcagcagttttggatttcttccttatctttgttctgctg 7561 tttgagggggctttttacttatttccatgttattcaaaggagactaggcttgatatttta 7621 ttactgttcttttatggacaaaaggttacatagtatgcccttaagacttaattttaacca 7681 aaggcctagcaccaccttaggggctgcaataaacacttaacgcgcgtgcgcacgcgcgcg 7741 cgcacacacacacacacacacacacacacacacaggtcagagtttaaggctttcgagtca 7801 tgacattctagcttttgaattgcgtgcacacacacacgcacgcacacactctggtcagag 7861 tttattaaggctttcgagtcatgacattatagcttttgagttggtgtgtgtgacaccacc 7921 ctcctaagtggtgtgtgcttgtaattttttttttcagtgaaaatggattgaaaacctgtt 7981 gttaatgcttagtgatattatgctcaaaacaaggaaattcccttgaaccgtgtcaattaa 8041 actggtttatatgactcaagaaaacaataccagtagatgattattaactttattcttggc 8101 tctttttaggtccattttgattaagtgacttttggctggatcattcagagctctcttcta 8161 gcctacccttggatgagtacaattaatgaaattcatattttcaaggacctgggagccttc 8221 cttggggctgggttgagggtggggggttggggagtcctggtagaggccagctttgtggta 8281 gctggagaggaagggatgaaaccagctgctgttgcaaaggctgcttgtcattgatagaag 8341 gactcacgggcttggattgattaagactaaacatggagttggcaaactttcttcaagtat 8401 tgagttctgttcaatgcattggacatgtgatttaagggaaaagtgtgaatgcttatagat 8461 gatgaaaacctggtgggctgcagagcccagtttagaagaagtgagttgggggttggggac 8521 agatttggtggtggtatttcccaactgtttcctcccctaaattcagaggaatgcagctat 8581 gccagaagccagagaagagccactcgtagcttctgctttggggacaactggtcagttgaa 8641 agtcccaggagttcctttgtggctttctgtatacttttgcctggttaaagtctgtggcta 8701 aaaaatagtcgaacctttcttgagaactctgtaacaaagtatgtttttgattaaaagaga 8761 aagccaactaaaaaaaaaaaaaaaaaaaa SEQIDNO:156HumanSMAD4aminoacidsequence(NP_005350.1) 1 mdnmsitntptsndaclsivhslmchrqggesetfakraieslvkklkekkdeldslita 61 ittngahpskcvtiqrtldgrlqvagrkgfphviyarlwrwpdlhknelkhvkycqyafd 121 lkcdsvcvnpyhyervvspgidlsgltlqsnapssmmvkdeyvhdfegqpslsteghsiq 181 tiqhppsnrastetystpallapsesnatstanfpnipvastsqpasilggshsegllqi 241 asgpqpgqqqngftgqpatyhhnstttwtgsrtapytpnlphhqnghlqhhppmpphpgh 301 ywpvhnelafqppisnhpapeywcsiayfemdvqvgetfkvpsscpivtvdgyvdpsggd 361 rfclgqlsnvhrteaierarlhigkgvqleckgegdvwvrclsdhavfvqsyyldreagr 421 apgdavhkiypsayikvfdlrqchrqmqqqaataqaaaaaqaaavagnipgpgsvggiap 481 aislsaaagigvddlrrlcilrmsfvkgwgpdyprqsiketpcwieihlhralqlldevl 541 htmpiadpqpld SEQIDNO:157MouseSMAD4transcriptvariant1cDNAsequence (NM_001364967.1;CDS:491-1699) 1 agtgtccttccgacaagttggcagcaacaacacggccctggtcgtcgtcgccgctgcggt 61 aacggagcggctcgggtggcggagcccgtgttcgcgtccgtccgcccgcccgcccgccgt 121 cctccggaggcccttcccgcgccgcgctccgctccgcggccgtccccggggcgggagcgc 181 gtgaccggagccggcgcccgcgagcgaggccccccgcagcggggcggctccggagctcca 241 gcggcccggccggccggcgcggtccgcggcgcggcggggagagggggccgcctgggccgg 301 acgccgcgggcggggcccgggaagcgacagcgaggcgaggcgcggtgcggcgaggagccc 361 aggtcatcctgctcaccagatgtcttgacagtttttcttgcaacattggccattggtttt 421 cactgccttcaaaagatcaaaattactccagaaattggagagttggatttaaaagaaaaa 481 acttgaacaaatggacaatatgtctataacaaatacaccaacaagtaacgatgcctgtct 541 gagcattgtacatagtttgatgtgtcatagacaaggtggggaaagtgaaacctttgcaaa 601 aagagcaattgagagtttggtaaagaagctgaaagagaaaaaagatgaattggattcttt 661 aataacagctataactacaaatggagctcatcctagcaagtgtgtcaccatacagagaac 721 attggatggacgacttcaggtggctggtcggaaaggatttcctcatgtgatctatgcccg 781 tctgtggaggtggcctgatctacacaagaatgaactaaagcatgttaaatattgtcagta 841 tgcgtttgacttaaaatgtgacagtgtctgtgtgaatccatatcactatgagcgggttgt 901 ctcacctggaattgatctctcaggattaacactgcagagtaatgctccaagtatgttagt 961 gaaggatgagtacgttcacgactttgaaggacagccgtccttacccactgaaggacattc 1021 gattcaaaccatccaacacccgccaagtaatcgcgcatcaacggagacgtacagcgcccc 1081 ggctctgttagccccggcagagtctaacgccaccagcaccaccaacttccccaacattcc 1141 tgtggcttccacaaggccagttcacaatgagcttgcattccagcctcccatttccaatca 1201 tcctgctcctgagtactggtgctccattgcttactttgaaatggacgttcaggtaggaga 1261 gacgtttaaggtcccttcaagctgccctgttgtgactgtggatggctatgtggatccttc 1321 gggaggagatcgcttttgcttgggtcaactctccaatgtccacaggacagaagcgattga 1381 gagagcgaggttgcacataggcaaaggagtgcagttggaatgtaaaggtgaaggtgacgt 1441 ttgggtcaggtgccttagtgaccacgcggtctttgtacagagttactacctggacagaga 1501 agctggccgagcacctggcgacgctgttcataagatctacccaagcgcgtatataaaggt 1561 cagtgtttatatgtctttgatctgcggcagtgtcaccggcagatgcagcaacaggcggcc 1621 actgcgcaagctgcagctgctgctcaggcggcggccgtggcagggaacatccctggccct 1681 gggtccgtgggtggaatagctccagccatcagtctgtctgctgctgctggcatcggtgtg 1741 gatgacctccggcgattgtgcattctcaggatgagctttgtgaagggctggggcccagac 1801 taccccaggcagagcatcaaggaaaccccgtgctggattgagattcaccttcaccgagct 1861 ctgcagctcttggatgaagtcctgcacaccatgcccattgcggacccacagcctttagac 1921 tgagatctcacaccacggacgccctaaccatttccaggatggtggactatgaaatatact 1981 cgtgtttataatctgaagatctattgcattttgttctgctctgtcttttcctaaagggtt 2041 gagagatgtgtttgctgccttgctcttagcagacagaaactgaattaaaacttcttttct 2101 attttagaactttcaggtgtggctcagtgcttgaagatcagaaagatgcagttcttgctg 2161 agtcttccctgctggttctgtatggaggagtcggccagtgctgggcgctcagccctttag 2221 tgtgtgcgagcgccttgcatgccgaggagagtcagagctgctgattgtaaggctgagaag 2281 ttctcacagttaagccacctgccccttagtgggcgagttattaaacgcactgtgctcacg 2341 tggcgctgggccagccagctctaccaagagcaactttactctcctttaaaaaccttttag 2401 caacctttgattcacaatggtttttgcaagttaaacagtgaaggtgaattaaattcatac 2461 tgtcttgcagacttcagggtttcttccccaagacaaaacactaatctgtgtgcatattga 2521 caattccttacaattatcagtcaaagaaatgccatttaaaattacaatttttttaatccc 2581 taatggatgaccactatcaagatgtatactttgccctgttaaacagtaaatgaattcttc 2641 tatatttctaggcacaaggttagttatttaaaaaaaaaaaaaaaagcctaggggagggat 2701 ttttcccttaattcctagggagaaggttttgtataaaacactaaaagcagtgtcactctg 2761 cctgctgcttcactgttctgcaaggtggcagtacttcaactgaaataatgaatattttgg 2821 aaactgctaaattctatgttaaatactgtgcagaataatggaaacagtgcagttggtaac 2881 aggtggtttggatatttttgtacttgatttgatgtgtgacttcttttcatatactgttaa 2941 aatcatgtatgttttgacattgtttaaaattcagtttttgtatcttagggcaagactgca 3001 gacttttttataccttttggttataagccctgtgtttgccatccttgatcacttggcggt 3061 gactttgtagagattgaagtggaggagttaagacacattgactgtaccacagacacacat 3121 gtatactttctacctagttactagcgtaaataaaactgagtcactatacgaagtggaatt 3181 ctagatttggtttttaaaatgctttccttttgcacttttgagtccagtctcagtggcaag 3241 acaccttctgctaaatgacaggtggcagccagttgtaccatgcagcgctggttccctccc 3301 actctaccaggactttcccatggacactgtgcatcatgtgtagttggttattttttgagt 3361 ttttattttactgtagcaaaaaaaaaaaaaaaaacttggataaatagtgtgaataaaatc 3421 aagaccatggagatgtttttaccctgagagttttctgtgagttttaaattgcagtaggca 3481 tttgagctctggaaaccccgtgcatagcagttctctttgtgccaacagaaatgaccacgt 3541 cctgcagcctgctgcggaaggttccagaggctctgagaaaccagagtgctgcagtgactg 3601 gggtccatctcagcccagcgcacacagcgtgcgttgtaaaagctgcctctgtgtcttgtc 3661 ttctgtacttagggatgctttgtctcgggcctaatcttatctgtagaagtttggtgattt 3721 tttttttttaaatgttgtattgacagaattataaaaagataccttctctagaaatgcttg 3781 tcttcagatccgtttcacgatggccggggaacaggagtgagaagagagagtaagctgtag 3841 tgtaacgggtttttaagacccagctcatctgaccaggcagtgctgtaacttgatgcttcc 3901 tgttgtaccttatggaacctttcccatatttaatcatcttcagaaagtaggtgggaaata 3961 tttgctgggaagtatctcttcagagccaagccacttgtcttggttttcttactaagagcc 4021 atagaaatgatttctggttattgatgaaatttgtaatttgcctgtcctagtcttttttcc 4081 tttcacttcgctatctttgaataagacttttaaaaacttccctgagttgaaaaattttgg 4141 gataaaatagtttccctagttcttagagactgattatgatgtgggtatggttctgggtgg 4201 gttttttttctaagtcatagctcaaaagtctcccaagattaaatttcagtgggcacccag 4261 tttgaaaccattctacttttgtcttgtgcctttctttgcatgattaaagagaatctgtaa 4321 tggtattgcctttatttgcttggaagtagattcttttctgggatagagtctaccttaatc 4381 gttgtcctttaccgcccctgctgtacagatagatgctaagccactgccgggaacttgctt 4441 ttccatagacagtctttttatactgcctgaacccattgctcctgttcacagtataagttc 4501 acagacagggtgagccggccgaggcgcacacctgcagaatccagcaacaaccatgcttaa 4561 ctgtgtgtatttcaaagttagaaatccagttttgtggggaatggtgtggtttatattagc 4621 agctttgaaggcgaagtaactcagaggttttacagtctggagaagggaagcttcctggaa 4681 tgcttgtgaagtatctgtggtggccaaatgtgtttgctcctggccttgcttgtaactggc 4741 taattgtcactcttcagatttttaaaaatttttaatgagctgagacccccttggaaggag 4801 cttgtttggagctggccagagatgtttttggtagttcctgtcttcatccggtcttcatca 4861 ctgttttctttaatggtcagttagtaaagtataagttaggtcactgtcatgagtggagca 4921 ggaacaactctcccaggtgggggcctggaagggactcgttacatggagccatctgtaact 4981 agccctttaaatcctcctttgcatgacatagagaaaaggctgtgagactcctgcccaggc 5041 ctttctagttttcccttctagtaaccaagcaatcgcatctctgcggtgcagtaggctgta 5101 tgtaaaaagccgtggccttactcctagcagcacccttggcagggcctttttctcagcgca 5161 gtgaggctgtgcatctggcactcctgaggaatgaaagttttcatcatcttgccttattaa 5221 gcagtaaaacttttgaaaaatgagccgtttattggcaggagctatttacacaaatcagaa 5281 tattataccatttctttttctctctctcctgtctctgtggacctccggggcttctgagat 5341 agacagtactgcctagccattcgaaatgcccaagccagctggggttgttgggctctcctc 5401 tcccttcctccttcctcacagctcctgctcttgcgtggttagtgagcctctactcagtgt 5461 ttcctgtcctcgctgctcaggcgagggaagacgacaactgatagtcttagagttcacctt 5521 tctgtcgggggcggcattgttctgattgctgccatcgtctccgatccttgatgagtttta 5581 tacgattgatgtggagagaatttaattgatattcatagcccatagctgctcccctctccc 5641 tggtgttgtggaagatttagtttccaccgaattcactcaaaaagctgtcctgttggcacc 5701 agcaaaccacacgctcttttagaaaacatctttgcttgttttgtgtcctgaccctgctct 5761 ctggcctccttcctctgtagatacttctgacctataggtgcctttatgagaattgagggt 5821 ctgataccgtgccccaaggaatagctgatgcaatgagtgatgtttttcagggattttagc 5881 atcaaattaaataaatgaatgaaacttttaagtccttcttttcttttatttttttaatgc 5941 aggaaggactgaggagacgtcgggtgacgacaatcatttctctgtgttgctgtaaaggct 6001 ttcacacagtttaagatgcttttctcagtagctccagagttgatgttcttgttcaaccta 6061 aagcaggctctggactcgcccagaccgttgcacttgtagtttacgacttcatgtgtcctc 6121 cctcggcaagtcattcccttctctgggcctcagctgcctcgtctgtgaaatgaggggttg 6181 gactattgtgccagctctggcttctaagtgaccttgcccgccctgcagcaggttgagatg 6241 cgctctttaccttttttctgctgtgtgagggggaatcttactttttcctttgttactcag 6301 tgagactaggcttgatctttgagtacccgctctcctgtggacaagtagttacatatgtcc 6361 ttatgacttatttttaaccaaaggccgagcaccaccttaggggctgccgtaagtaccata 6421 cagaacactggggtggggggcggggggcaccttcatttcactgtgtcatcgtctgtgttc 6481 agagcctctgcaaaggccttcatctgtcatgacattctgactttgaagttagtatgtgta 6541 tgattctgtcctcctaagtgctggcaattcttcatctaaactggactgaaatcctgttgt 6601 aaatgcctggtaatattagagggcctttctttgggtcttttgtagcttaattcctctatg 6661 ttcaaaacaggaagttcttcagaaattatatcaatattttaattgatgctatgaaagaca 6721 gtcccagtgaatgactgtccactttatttttgcctcttttatatccattttgattgacaa 6781 cttttggctggatcatgcctttcagagagttttcttccagcctgcttggatgagtataat 6841 aaccgactttgttatttttacggacctgggaacctttctagggggtggggtggggtgggg 6901 tggggtggggagtcctggtagaggccacatctgtggcagctgtgaagaagggatgaagcc 6961 agctgctcttgctaaggctgcttgtcattggtagaaggactcaccggtttgggttactta 7021 aaaggctaaatatagagttggcaaacttctccaagcggggagggttttttttttgttcca 7081 tgcatctaacgtgatttaaaagcatgacttcctataggttatgaaaactggtgtgctgca 7141 gatccagtgtggaagaggtgactgggcgttggggacagctttgatggtgacacttctagc 7201 tctgagagtctcctactctgggtccactcttagcttggctcttaggaaaaactggtcagc 7261 taaaggcccaccactttctttctatagacttttgcctggttgaagtctgtggcttaaaaa 7321 aaatagttgaatctttcttgagaactctgtaacaaagtatgtttttgattaaaaagagaa 7381 agccaactaaa SEQIDNO:158MouseSMAD4isoform1aminoacidsequence(NP_001351896.1) 1 mdnmsitntptsndaclsivhslmchrqggesetfakraieslvkklkekkdeldslita 61 ittngahpskcvtiqrtldgrlqvagrkgfphviyarlwrwpdlhknelkhvkycqyafd 121 lkcdsvcvnpyhyervvspgidlsgltlqsnapsmlvkdeyvhdfegqpslpteghsiqt 181 iqhppsnrastetysapallapaesnatsttnfpnipvastrpvhnelafqppisnhpap 241 eywcsiayfemdvqvgetfkvpsscpvvtvdgyvdpsggdrfclgqlsnvhrteaierar 301 lhigkgvqleckgegdvwvrclsdhavfvqsyyldreagrapgdavhkiypsayikvsvy 361 mslicgsvtgrcsnrrplrklqlllrrrpwqgtslalgpwve SEQIDNO:159MouseSMAD4transcriptvariant2cDNAsequence (NM_001364968.1;CDS:491-1858) 1 agtgtccttccgacaagttggcagcaacaacacggccctggtcgtcgtcgccgctgcggt 61 aacggagcggctcgggtggcggagcccgtgttcgcgtccgtccgcccgcccgcccgccgt 121 cctccggaggcccttcccgcgccgcgctccgctccgcggccgtccccggggcgggagcgc 181 gtgaccggagccggcgcccgcgagcgaggccccccgcagcggggcggctccggagctcca 241 gcggcccggccggccggcgcggtccgcggcgcggcggggagagggggccgcctgggccgg 301 acgccgcgggcggggcccgggaagcgacagcgaggcgaggcgcggtgcggcgcggagccc 361 aggtcatcctgctcaccagatgtcttgacagtttttcttgcaacattggccattggtttt 421 cactgccttcaaaagatcaaaattactccagaaattggagagttggatttaaaagaaaaa 481 acttgaacaaatggacaatatgtctataacaaatacaccaacaagtaacgatgcctgtct 541 gagcattgtacatagtttgatgtgtcatagacaaggtggggaaagtgaaacctttgcaaa 601 aagagcaattgagagtttggtaaagaagctgaaagagaaaaaagatgaattggattcttt 661 aataacagctataactacaaatggagctcatcctagcaagtgtgtcaccatacagagaac 721 attggatggacgacttcaggtggctggtcggaaaggatttcctcatgtgatctatgcccg 781 tctgtggaggtggcctgatctacacaagaatgaactaaagcatgttaaatattgtcagta 841 tgcgtttgacttaaaatgtgacagtgtctgtgtgaatccatatcactatgagagggttgt 901 ctcacctggaattgatctctcaggattaacactgcagagtaatgctccaagtatgttagt 961 gaaggatgagtacgttcacgactttgaaggacagccgtccttacccactgaaggacattc 1021 gattcaaaccatccaacacccgccaagtaatcgcgcatcaacggagacgtacagcgcccc 1081 ggctctgttagccccggcagagtctaacgccaccagcaccaccaacttccccaacattcc 1141 tgtggcttccacaactcctgagtactggtgctccattgcttactttgaaatggacgttca 1201 ggtaggagagacgtttaaggtcccttcaagctgccctgttgtgactgtggatggctatgt 1261 ggatccttcgggaggagatcgcttttgcttgggtcaactctccaatgtccacaggacaga 1321 agcgattgagagagcgaggttgcacataggcaaaggagtgcagttggaatgtaaaggtga 1381 aggtgacgtttgggtcaggtgccttagtgaccacgcggtctttgtacagagttactacct 1441 ggacagagaagctggccgagcacctggcgacgctgttcataagatctacccaagcgcgta 1501 tataaaggtctttgatctgcggcagtgtcaccggcagatgcagcaacaggcggccactgc 1561 gcaagctgcagctgctgctcaggcggcggccgtggcagggaacatccctggccctgggtc 1621 cgtgggtggaatagctccagccatcagtctgtctgctgctgctggcatcggtgtggatga 1681 cctccggcgattgtgcattctcaggatgagctttgtgaagggctggggcccagactaccc 1741 caggcagagcatcaaggaaaccccgtgctggattgagattcaccttcaccgagctctgca 1801 gctcttggatgaagtcctgcacaccatgcccattgcggacccacagcctttagactgaga 1861 tctcacaccacggacgccctaaccatttccaggatggtggactatgaaatatactcgtgt 1921 ttataatctgaagatctattgcattttgttctgctctgtcttttcctaaagggttgagag 1981 atgtgtttgctgccttgctcttagcagacagaaactgaattaaaacttcttttctatttt 2041 agaactttcaggtgtggctcagtgcttgaagatcagaaagatgcagttcttgctgagtct 2101 tccctgctggttctgtatggaggagtcggccagtgctgggcgctcagccctttagtgtgt 2161 gcgagcgccttgcatgccgaggagagtcagagctgctgattgtaaggctgagaagttctc 2221 acagttaagccacctgccccttagtgggcgagttattaaacgcactgtgctcacgtggcg 2281 ctgggccagccagctctaccaagagcaactttactctcctttaaaaaccttttagcaacc 2341 tttgattcacaatggtttttgcaagttaaacagtgaaggtgaattaaattcatactgtct 2401 tgcagacttcagggtttcttccccaagacaaaacactaatctgtgtgcatattgacaatt 2461 ccttacaattatcagtcaaagaaatgccatttaaaattacaatttttttaatccctaatg 2521 gatgaccactatcaagatgtatactttgccctgttaaacagtaaatgaattcttctatat 2581 ttctaggcacaaggttagttatttaaaaaaaaaaaaaaaagcctaggggagggatttttc 2641 ccttaattcctagggagaaggttttgtataaaacactaaaagcagtgtcactctgcctgc 2701 tgcttcactgttctgcaaggtggcagtacttcaactgaaataatgaatattttggaaact 2761 gctaaattctatgttaaatactgtgcagaataatggaaacagtgcagttggtaacaggtg 2821 gtttggatatttttgtacttgatttgatgtgtgacttcttttcatatactgttaaaatca 2881 tgtatgttttgacattgtttaaaattcagtttttgtatcttagggcaagactgcagactt 2941 ttttataccttttggttataagccctgtgtttgccatccttgatcacttggcggtgactt 3001 tgtagagattgaagtggaggagttaagacacattgactgtaccacagacacacatgtata 3061 ctttctacctagttactagcgtaaataaaactgagtcactatacgaagtggaattctaga 3121 tttggtttttaaaatgctttccttttgcacttttgagtccagtctcagtggcaagacacc 3181 ttctgctaaatgacaggtggcagccagttgtaccatgcagcgctggttccctcccactct 3241 accaggactttcccatggacactgtgcatcatgtgtagttggttattttttgagttttta 3301 ttttactgtagcaaaaaaaaaaaaaaaaacttggataaatagtgtgaataaaatcaagac 3361 catggagatgtttttaccctgagagttttctgtgagttttaaattgcagtaggcatttga 3421 gctctggaaaccccgtgcatagcagttctctttgtgccaacagaaatgaccacgtcctgc 3481 agcctgctgcggaaggttccagaggctctgagaaaccagagtgctgcagtgactggggtc 3541 catctcagcccagcgcacacagcgtgcgttgtaaaagctgcctctgtgtcttgtcttctg 3601 tacttagggatgctttgtctcgggcctaatcttatctgtagaagtttggtgatttttttt 3661 ttttaaatgttgtattgacagaattataaaaagataccttctctagaaatgcttgtcttc 3721 agatccgtttcacgatggccggggaacaggagtgagaagagagagtaagctgtagtgtaa 3781 cgggtttttaagacccagctcatctgaccaggcagtgctgtaacttgatgcttcctgttg 3841 taccttatggaacctttcccatatttaatcatcttcagaaagtaggtgggaaatatttgc 3901 tgggaagtatctcttcagagccaagccacttgtcttggttttcttactaagagccataga 3961 aatgatttctggttattgatgaaatttgtaatttgcctgtcctagtcttttttcctttca 4021 cttcgctatctttgaataagacttttaaaaacttccctgagttgaaaaattttgggataa 4081 aatagtttccctagttcttagagactgattatgatgtgggtatggttctgggtgggtttt 4141 ttttctaagtcatagctcaaaagtctcccaagattaaatttcagtgggcacccagtttga 4201 aaccattctacttttgtcttgtgcctttctttgcatgattaaagagaatctgtaatggta 4261 ttgcctttatttgcttggaagtagattcttttctgggatagagtctaccttaatcgttgt 4321 cctttaccgcccctgctgtacagatagatgctaagccactgccgggaacttgcttttcca 4381 tagacagtctttttatactgcctgaacccattgctcctgttcacagtataagttcacaga 4441 cagggtgagccggccgaggcgcacacctgcagaatccagcaacaaccatgcttaactgtg 4501 tgtatttcaaagttagaaatccagttttgtggggaatggtgtggtttatattagcagctt 4561 tgaaggcgaagtaactcagaggttttacagtctggagaagggaagcttcctggaatgctt 4621 gtgaagtatctgtggtggccaaatgtgtttgctcctggccttgcttgtaactggctaatt 4681 gtcactcttcagatttttaaaaatttttaatgagctgagacccccttggaaggagcttgt 4741 ttggagctggccagagatgtttttggtagttcctgtcttcatccggtcttcatcactgtt 4801 ttctttaatggtcagttagtaaagtataagttaggtcactgtcatgagtggagcaggaac 4861 aactctcccaggtgggggcctggaagggactcgttacatggagccatctgtaactagccc 4921 tttaaatcctcctttgcatgacatagagaaaaggctgtgagactcctgcccaggcctttc 4981 tagttttcccttctagtaaccaagcaatcgcatctctgcggtgcagtaggctgtatgtaa 5041 aaagccgtggccttactcctagcagcacccttggcagggcctttttctcagcgcagtgag 5101 gctgtgcatctggcactcctgaggaatgaaagttttcatcatcttgccttattaagcagt 5161 aaaacttttgaaaaatgagccgtttattggcaggagctatttacacaaatcagaatatta 5221 taccatttctttttctctctctcctgtctctgtggacctccggggcttctgagatagaca 5281 gtactgcctagccattcgaaatgcccaagccagctggggttgttgggctctcctctccct 5341 tcctccttcctcacagctcctgctcttgcgtggttagtgagcctctactcagtgtttcct 5401 gtcctcgctgctcaggcgagggaagacgacaactgatagtcttagagttcacctttctgt 5461 cgggggcggcattgttctgattgctgccatcgtctccgatccttgatgagttttatacga 5521 ttgatgtggagagaatttaattgatattcatagcccatagctgctcccctctccctggtg 5581 ttgtggaagatttagtttccaccgaattcactcaaaaagctgtcctgttggcaccagcaa 5641 accacacgctcttttagaaaacatctttgcttgttttgtgtcctgaccctgctctctggc 5701 ctccttcctctgtagatacttctgacctataggtgcctttatgagaattgagggtctgat 5761 accgtgccccaaggaatagctgatgcaatgagtgatgtttttcagggattttagcatcaa 5821 attaaataaatgaatgaaacttttaagtccttcttttcttttatttttttaatgcaggaa 5881 ggactgaggagacgtcgggtgacgacaatcatttctctgtgttgctgtaaaggctttcac 5941 acagtttaagatgcttttctcagtagctccagagttgatgttcttgttcaacctaaagca 6001 ggctctggactcgcccagaccgttgcacttgtagtttacgacttcatgtgtcctccctcg 6061 gcaagtcattcccttctctgggcctcagctgcctcgtctgtgaaatgaggggttggacta 6121 ttgtgccagctctggcttctaagtgaccttgcccgccctgcagcaggttgagatgcgctc 6181 tttaccttttttctgctgtgtgagggggaatcttactttttcctttgttactcagtgaga 6241 ctaggcttgatctttgagtacccgctctcctgtggacaagtagttacatatgtccttatg 6301 acttatttttaaccaaaggccgagcaccaccttaggggctgccgtaagtaccatacagaa 6361 cactggggtggggggcggggggcaccttcatttcactgtgtcatcgtctgtgttcagagc 6421 ctctgcaaaggccttcatctgtcatgacattctgactttgaagttagtatgtgtatgatt 6481 ctgtcctcctaagtgctggcaattcttcatctaaactggactgaaatcctgttgtaaatg 6541 cctggtaatattagagggcctttctttgggtcttttgtagcttaattcctctatgttcaa 6601 aacaggaagttcttcagaaattatatcaatattttaattgatgctatgaaagacagtccc 6661 agtgaatgactgtccactttatttttgcctcttttatatccattttgattgacaactttt 6721 ggctggatcatgcctttcagagagttttcttccagcctgcttggatgagtataataaccg 6781 actttgttatttttacggacctgggaacctttctagggggtggggtggggtggggtgggg 6841 tggggagtcctggtagaggccacatctgtggcagctgtgaagaagggatgaagccagctg 6901 ctcttgctaaggctgcttgtcattggtagaaggactcaccggtttgggttacttaaaagg 6961 ctaaatatagagttggcaaacttctccaagcggggagggttttttttttgttccatgcat 7021 ctaacgtgatttaaaagcatgacttcctataggttatgaaaactggtgtgctgcagatcc 7081 agtgtggaagaggtgactgggcgttggggacagctttgatggtgacacttctagctctga 7141 gagtctcctactctgggtccactcttagcttggctcttaggaaaaactggtcagctaaag 7201 gcccaccactttctttctatagacttttgcctggttgaagtctgtggcttaaaaaaaata 7261 gttgaatctttcttgagaactctgtaacaaagtatgtttttgattaaaaagagaaagcca 7321 actaaa SEQIDNO:160MouseSMAD4isoform2aminoacidsequence(NP_001351897.1) 1 mdnmsitntptsndaclsivhslmchrqggesetfakraieslvkklkekkdeldslita 61 ittngahpskcvtiqrtldgrlqvagrkgfphviyarlwrwpdlhknelkhvkycqyafd 121 lkcdsvcvnpyhyervvspgidlsgltlqsnapsmlvkdeyvhdfegqpslpteghsiqt 181 iqhppsnrastetysapallapaesnatsttnfpnipvasttpeywcsiayfemdvqvge 241 tfkvpsscpvvtvdgyvdpsggdrfclgqlsnvhrteaierarlhigkgvqleckgegdv 301 wvrclsdhavfvqsyyldreagrapgdavhkiypsayikvfdlrqchrqmqqqaataqaa 361 aaaqaaavagnipgpgsvggiapaislsaaagigvddlrrlcilrmsfvkgwgpdyprqs 421 iketpcwieihlhralqlldevlhtmpiadpqpld SEQIDNO:161MouseSMAD4transcriptvariant3cDNAsequence(NM_008540.3; CDS:491-2146) 1 agtgtccttccgacaagttggcagcaacaacacggccctggtcgtcgtcgccgctgcggt 61 aacggagcggctcgggtggcggagcccgtgttcgcgtccgtccgcccgcccgcccgccgt 121 cctccggaggcccttcccgcgccgcgctccgctccgcggccgtccccggggcgggagcgc 181 gtgaccggagccggcgcccgcgagcgaggccccccgcagcggggcggctccggagctcca 241 gcggcccggccggccggcgcggtccgcggcgcggcggggagagggggccgcctgggccgg 301 acgccgcgggcggggcccgggaagcgacagcgaggcgaggcgcggtgcggcgcggagccc 361 aggtcatcctgctcaccagatgtcttgacagtttttcttgcaacattggccattggtttt 421 cactgccttcaaaagatcaaaattactccagaaattggagagttggatttaaaagaaaaa 481 acttgaacaaatggacaatatgtctataacaaatacaccaacaagtaacgatgcctgtct 541 gagcattgtacatagtttgatgtgtcatagacaaggtggggaaagtgaaacctttgcaaa 601 aagagcaattgagagtttggtaaagaagctgaaagagaaaaaagatgaattggattcttt 661 aataacagctataactacaaatggagctcatcctagcaagtgtgtcaccatacagagaac 721 attggatggacgacttcaggtggctggtcggaaaggatttcctcatgtgatctatgcccg 781 tctgtggaggtggcctgatctacacaagaatgaactaaagcatgttaaatattgtcagta 841 tgcgtttgacttaaaatgtgacagtgtctgtgtgaatccatatcactatgagagggttgt 901 ctcacctggaattgatctctcaggattaacactgcagagtaatgctccaagtatgttagt 961 gaaggatgagtacgttcacgactttgaaggacagccgtccttacccactgaaggacattc 1021 gattcaaaccatccaacacccgccaagtaatcgcgcatcaacggagacgtacagcgcccc 1081 ggctctgttagccccggcagagtctaacgccaccagcaccaccaacttccccaacattcc 1141 tgtggcttccacaagtcagccggccagtattctggcgggcagccatagtgaaggactgtt 1201 gcagatagcttcagggcctcagccaggacagcagcagaatggatttactgctcagccagc 1261 tacttaccatcataacagcactaccacctggactggaagtaggactgcaccatacacacc 1321 taatttgcctcaccaccaaaacggccatcttcagcaccacccgcctatgccgccccatcc 1381 tggacattactggccagttcacaatgagcttgcattccagcctcccatttccaatcatcc 1441 tgctcctgagtactggtgctccattgcttactttgaaatggacgttcaggtaggagagac 1501 gtttaaggtcccttcaagctgccctgttgtgactgtggatggctatgtggatccttcggg 1561 aggagatcgcttttgcttgggtcaactctccaatgtccacaggacagaagcgattgagag 1621 agcgaggttgcacataggcaaaggagtgcagttggaatgtaaaggtgaaggtgacgtttg 1681 ggtcaggtgccttagtgaccacgcggtctttgtacagagttactacctggacagagaagc 1741 tggccgagcacctggcgacgctgttcataagatctacccaagcgcgtatataaaggtctt 1801 tgatctgcggcagtgtcaccggcagatgcagcaacaggcggccactgcgcaagctgcagc 1861 tgctgctcaggcggcggccgtggcagggaacatccctggccctgggtccgtgggtggaat 1921 agctccagccatcagtctgtctgctgctgctggcatcggtgtggatgacctccggcgatt 1981 gtgcattctcaggatgagctttgtgaagggctggggcccagactaccccaggcagagcat 2041 caaggaaaccccgtgctggattgagattcaccttcaccgagctctgcagctcttggatga 2101 agtcctgcacaccatgcccattgcggacccacagcctttagactgagatctcacaccacg 2161 gacgccctaaccatttccaggatggtggactatgaaatatactcgtgtttataatctgaa 2221 gatctattgcattttgttctgctctgtcttttcctaaagggttgagagatgtgtttgctg 2281 ccttgctcttagcagacagaaactgaattaaaacttcttttctattttagaactttcagg 2341 tgtggctcagtgcttgaagatcagaaagatgcagttcttgctgagtcttccctgctggtt 2401 ctgtatggaggagtcggccagtgctgggcgctcagccctttagtgtgtgcgagcgccttg 2461 catgccgaggagagtcagagctgctgattgtaaggctgagaagttctcacagttaagcca 2521 cctgccccttagtgggcgagttattaaacgcactgtgctcacgtggcgctgggccagcca 2581 gctctaccaagagcaactttactctcctttaaaaaccttttagcaacctttgattcacaa 2641 tggtttttgcaagttaaacagtgaaggtgaattaaattcatactgtcttgcagacttcag 2701 ggtttcttccccaagacaaaacactaatctgtgtgcatattgacaattccttacaattat 2761 cagtcaaagaaatgccatttaaaattacaatttttttaatccctaatggatgaccactat 2821 caagatgtatactttgccctgttaaacagtaaatgaattcttctatatttctaggcacaa 2881 ggttagttatttaaaaaaaaaaaaaaaagcctaggggagggatttttcccttaattccta 2941 gggagaaggttttgtataaaacactaaaagcagtgtcactctgcctgctgcttcactgtt 3001 ctgcaaggtggcagtacttcaactgaaataatgaatattttggaaactgctaaattctat 3061 gttaaatactgtgcagaataatggaaacagtgcagttggtaacaggtggtttggatattt 3121 ttgtacttgatttgatgtgtgacttcttttcatatactgttaaaatcatgtatgttttga 3181 cattgtttaaaattcagtttttgtatcttagggcaagactgcagacttttttataccttt 3241 tggttataagccctgtgtttgccatccttgatcacttggcggtgactttgtagagattga 3301 agtggaggagttaagacacattgactgtaccacagacacacatgtatactttctacctag 3361 ttactagcgtaaataaaactgagtcactatacgaagtggaattctagatttggtttttaa 3421 aatgctttccttttgcacttttgagtccagtctcagtggcaagacaccttctgctaaatg 3481 acaggtggcagccagttgtaccatgcagcgctggttccctcccactctaccaggactttc 3541 ccatggacactgtgcatcatgtgtagttggttattttttgagtttttattttactgtagc 3601 aaaaaaaaaaaaaaaaacttggataaatagtgtgaataaaatcaagaccatggagatgtt 3661 tttaccctgagagttttctgtgagttttaaattgcagtaggcatttgagctctggaaacc 3721 ccgtgcatagcagttctctttgtgccaacagaaatgaccacgtcctgcagcctgctgcgg 3781 aaggttccagaggctctgagaaaccagagtgctgcagtgactggggtccatctcagccca 3841 gcgcacacagcgtgcgttgtaaaagctgcctctgtgtcttgtcttctgtacttagggatg 3901 ctttgtctcgggcctaatcttatctgtagaagtttggtgattttttttttttaaatgttg 3961 tattgacagaattataaaaagataccttctctagaaatgcttgtcttcagatccgtttca 4021 cgatggccggggaacaggagtgagaagagagagtaagctgtagtgtaacgggtttttaag 4081 acccagctcatctgaccaggcagtgctgtaacttgatgcttcctgttgtaccttatggaa 4141 cctttcccatatttaatcatcttcagaaagtaggtgggaaatatttgctgggaagtatct 4201 cttcagagccaagccacttgtcttggttttcttactaagagccatagaaatgatttctgg 4261 ttattgatgaaatttgtaatttgcctgtcctagtcttttttcctttcacttcgctatctt 4321 tgaataagacttttaaaaacttccctgagttgaaaaattttgggataaaatagtttccct 4381 agttcttagagactgattatgatgtgggtatggttctgggtgggttttttttctaagtca 4441 tagctcaaaagtctcccaagattaaatttcagtgggcacccagtttgaaaccattctact 4501 tttgtcttgtgcctttctttgcatgattaaagagaatctgtaatggtattgcctttattt 4561 gcttggaagtagattcttttctgggatagagtctaccttaatcgttgtcctttaccgccc 4621 ctgctgtacagatagatgctaagccactgccgggaacttgcttttccatagacagtcttt 4681 ttatactgcctgaacccattgctcctgttcacagtataagttcacagacagggtgagccg 4741 gccgaggcgcacacctgcagaatccagcaacaaccatgcttaactgtgtgtatttcaaag 4801 ttagaaatccagttttgtggggaatggtgtggtttatattagcagctttgaaggcgaagt 4861 aactcagaggttttacagtctggagaagggaagcttcctggaatgcttgtgaagtatctg 4921 tggtggccaaatgtgtttgctcctggccttgcttgtaactggctaattgtcactcttcag 4981 atttttaaaaatttttaatgagctgagacccccttggaaggagcttgtttggagctggcc 5041 agagatgtttttggtagttcctgtcttcatccggtcttcatcactgttttctttaatggt 5101 cagttagtaaagtataagttaggtcactgtcatgagtggagcaggaacaactctcccagg 5161 tgggggcctggaagggactcgttacatggagccatctgtaactagccctttaaatcctcc 5221 tttgcatgacatagagaaaaggctgtgagactcctgcccaggcctttctagttttccctt 5281 ctagtaaccaagcaatcgcatctctgcggtgcagtaggctgtatgtaaaaagccgtggcc 5341 ttactcctagcagcacccttggcagggcctttttctcagcgcagtgaggctgtgcatctg 5401 gcactcctgaggaatgaaagttttcatcatcttgccttattaagcagtaaaacttttgaa 5461 aaatgagccgtttattggcaggagctatttacacaaatcagaatattataccatttcttt 5521 ttctctctctcctgtctctgtggacctccggggcttctgagatagacagtactgcctagc 5581 cattcgaaatgcccaagccagctggggttgttgggctctcctctcccttcctccttcctc 5641 acagctcctgctcttgcgtggttagtgagcctctactcagtgtttcctgtcctcgctgct 5701 caggcgagggaagacgacaactgatagtcttagagttcacctttctgtcgggggcggcat 5761 tgttctgattgctgccatcgtctccgatccttgatgagttttatacgattgatgtggaga 5821 gaatttaattgatattcatagcccatagctgctcccctctccctggtgttgtggaagatt 5881 tagtttccaccgaattcactcaaaaagctgtcctgttggcaccagcaaaccacacgctct 5941 tttagaaaacatctttgcttgttttgtgtcctgaccctgctctctggcctccttcctctg 6001 tagatacttctgacctataggtgcctttatgagaattgagggtctgataccgtgccccaa 6061 ggaatagctgatgcaatgagtgatgtttttcagggattttagcatcaaattaaataaatg 6121 aatgaaacttttaagtccttcttttcttttatttttttaatgcaggaaggactgaggaga 6181 cgtcgggtgacgacaatcatttctctgtgttgctgtaaaggctttcacacagtttaagat 6241 gcttttctcagtagctccagagttgatgttcttgttcaacctaaagcaggctctggactc 6301 gcccagaccgttgcacttgtagtttacgacttcatgtgtcctccctcggcaagtcattcc 6361 cttctctgggcctcagctgcctcgtctgtgaaatgaggggttggactattgtgccagctc 6421 tggcttctaagtgaccttgcccgccctgcagcaggttgagatgcgctctttacctttttt 6481 ctgctgtgtgagggggaatcttactttttcctttgttactcagtgagactaggcttgatc 6541 tttgagtacccgctctcctgtggacaagtagttacatatgtccttatgacttatttttaa 6601 ccaaaggccgagcaccaccttaggggctgccgtaagtaccatacagaacactggggtggg 6661 gggcggggggcaccttcatttcactgtgtcatcgtctgtgttcagagcctctgcaaaggc 6721 cttcatctgtcatgacattctgactttgaagttagtatgtgtatgattctgtcctcctaa 6781 gtgctggcaattcttcatctaaactggactgaaatcctgttgtaaatgcctggtaatatt 6841 agagggcctttctttgggtcttttgtagcttaattcctctatgttcaaaacaggaagttc 6901 ttcagaaattatatcaatattttaattgatgctatgaaagacagtcccagtgaatgactg 6961 tccactttatttttgcctcttttatatccattttgattgacaacttttggctggatcatg 7021 cctttcagagagttttcttccagcctgcttggatgagtataataaccgactttgttattt 7081 ttacggacctgggaacctttctagggggtggggtggggtggggtggggtggggagtcctg 7141 gtagaggccacatctgtggcagctgtgaagaagggatgaagccagctgctcttgctaagg 7201 ctgcttgtcattggtagaaggactcaccggtttgggttacttaaaaggctaaatatagag 7261 ttggcaaacttctccaagcggggagggttttttttttgttccatgcatctaacgtgattt 7321 aaaagcatgacttcctataggttatgaaaactggtgtgctgcagatccagtgtggaagag 7381 gtgactgggcgttggggacagctttgatggtgacacttctagctctgagagtctcctact 7441 ctgggtccactcttagcttggctcttaggaaaaactggtcagctaaaggcccaccacttt 7501 ctttctatagacttttgcctggttgaagtctgtggcttaaaaaaaatagttgaatctttc 7561 ttgagaactctgtaacaaagtatgtttttgattaaaaagagaaagccaactaaa SEQIDNO:162MouseSMAD4isoform3aminoacidsequence(NP_032566.2) 1 mdnmsitntptsndaclsivhslmchrqggesetfakraieslvkklkekkdeldslita 61 ittngahpskcvtiqrtldgrlqvagrkgfphviyarlwrwpdlhknelkhvkycqyafd 121 lkcdsvcvnpyhyervvspgidlsgltlqsnapsmlvkdeyvhdfegqpslpteghsiqt 181 iqhppsnrastetysapallapaesnatsttnfpnipvastsqpasilagshsegllqia 241 sgpqpgqqqngftaqpatyhhnstttwtgsrtapytpnlphhqnghlqhhppmpphpghy 301 wpvhnelafqppisnhpapeywcsiayfemdvqvgetfkvpsscpvvtvdgyvdpsggdr 361 fclgqlsnvhrteaierarlhigkgvqleckgegdvwvrclsdhavfvqsyyldreagra 421 pgdavhkiypsayikvfdlrqchrqmqqqaataqaaaaaqaaavagnipgpgsvggiapa 481 islsaaagigvddlrrlcilrmsfvkgwgpdyprqsiketpcwieihlhralqlldevlh 541 tmpiadpqpld SEQIDNO:163HumanSMAD5transcriptvariant1cDNAsequence(NM_005903.7; CDS:363-1760) 1 atccgggtcctgggcgagcgggcgccgtgcgcgtgtcccgcggccgagctgctaataaag 61 ttgcagcgaggagaagcgcagcgacggcgtcgggagagcgcgcctagccggctcgcgaaa 121 aggaagctgttgaagttattgaagtacctgttgctatattctaagaaattaaaatgtcca 181 gaaatctgcctctgacttgacccaatgaaagaagcatatggcacttgtgaagataaatgt 241 tactcctccctttttaattggaacttctgcttaggacctgtgtatgacgtttcacctgtg 301 atctgttctttcggtagccactgactttgagttacaggaaggtctccgaagatttgtgtc 361 aaatgacgtcaatggccagcttgttttcttttactagtccagcagtaaagcgattgttgg 421 gctggaaacaaggtgatgaggaggagaaatgggcagaaaaggcagttgatgctttggtga 481 agaaactaaaaaagaaaaagggtgccatggaggaactggagaaagccttgagcagtccag 541 gacagccgagtaaatgtgtcactattcccagatctttagatggacgcctgcaggtttctc 601 acagaaaaggcttaccccatgttatatattgtcgtgtttggcgctggccggatttgcaga 661 gtcatcatgagctaaagccgttggatatttgtgaatttccttttggatctaagcaaaaag 721 aagtttgtatcaacccataccactataagagagtggagagtccagtcttacctccagtat 781 tagtgcctcgtcataatgaattcaatccacaacacagccttctggttcagtttaggaacc 841 tgagccacaatgaaccacacatgccacaaaatgccacgtttccagattctttccaccagc 901 ccaacaacactccttttcccttatctccaaacagcccttatcccccttctcctgctagca 961 gcacatatcccaactccccagcaagttctggaccaggaagtccatttcagctcccagctg 1021 atacgcctcctcctgcctatatgccacctgatgatcagatgggtcaagataattcccagc 1081 ctatggatacaagcaataatatgattcctcagattatgcccagtatatccagcagggatg 1141 ttcagcctgttgcctatgaagagcctaaacattggtgttcaatagtctactatgaattaa 1201 acaatcgtgttggagaagcttttcatgcatcttctactagtgtgttagtagatggattca 1261 cagatccttcaaataacaaaagtagattctgcttgggtttgttgtcaaatgttaatcgta 1321 attcgacaattgaaaacactaggcgacatattggaaaaggtgttcatctgtactatgttg 1381 gtggagaggtgtatgcggaatgcctcagtgacagcagcatatttgtacagagtaggaact 1441 gcaactttcatcatggctttcatcccaccactgtctgtaagattcccagcagctgcagcc 1501 tcaaaatttttaacaatcaggagtttgctcagcttctggctcaatctgtcaaccatgggt 1561 ttgaggcagtatatgagctcaccaaaatgtgtaccattcggatgagttttgtcaagggtt 1621 ggggagcagaatatcaccggcaggatgtaaccagcaccccatgttggattgagattcatc 1681 ttcatgggcctcttcagtggctggataaagtccttactcagatgggctcccctctgaacc 1741 ccatatcttctgtttcataatgcagaagtattcttttcaattatattgttagtggacttg 1801 ttttaattttagagaaactttgagtacagatactgtgagcttacattgaaaacagatatt 1861 acagcttatttttttctacataattgtgaccaatacatttgtattttgtgatgaatctac 1921 atttgtttgtattcatgttcatgtgattaactcttagaagtgttgtaaaagatgcagagt 1981 aagtattatgccccagttcagaaatttggcattgatcttaaactggaacatgcttttact 2041 ttattgccctaacaattttttattaaatttatttgaaaatgcatcacatgatgaaaaatt 2101 atagtagcttataagagggcatatacagtgaagagtaagttttccctcctactctcgatc 2161 ttccagaagctgtacttttaccagtttctttgtcccaccaacttaaaaaaaaaaagtaca 2221 attcattgttttgcaaaagtgtatggtaggggcttaaaagaaactataaagttttatttg 2281 aatgaacactatgcactgctgtaactggtagtgttcagtaaaagcaaaatgatagttttc 2341 tagatgacataaaatttacatttaatacagataagtgttcttcagtgtaatgtgacttca 2401 tgctatatatcttttgtaagacatttccttttttaaaaaaatttttgcaaataactgatc 2461 tcaagtatatgtcatttactcaaaatctgtcataagcattactttatagctagtgacagt 2521 gcatgcacagccttgttcaactatgtttgctgcttttggacaatgttgcaagaactctat 2581 ttttgacatgcattaatcttttattttgcacttttatgggtgacagtttttagcataacc 2641 tttgataaaatacactcaagtgacttggacttagatgcttatccttacgtccttggtacc 2701 ttttttgtattaacaaacactgcaatttatagattacatttgtaggaagttatgcttttt 2761 tctggtttttgttttactttcaacctaggttataagactgttattctatagctccaactt 2821 aaggtgcctttttaattccctacagttttatgggtgttatcagtgctggagaatcatgta 2881 gttaatcccattgctcttacaagtgtcagcttacttgtatcagcctccctacgcaaggac 2941 ctatgcactggagccgtaggaggctcttcagttgggccccaaggataaggctactgattt 3001 gatactaaatgaatcagcagtggatgtagggatagctgattttaaaacactcggctgggc 3061 acagtggctcacacctgtaatcccagcactttgggaggctgaggcaggcagatcatgatg 3121 tcaggagtttgagaccagcctggccaatatggtgaaaccctgtctctacaaaaaatacaa 3181 aaattagctgggcatggtggtgcgtgcctgaagtcccagctactcgggaagctgaggcag 3241 aagaatcacttgaacctgggaggcggaggttgtggtgagccgagatcgcaccactgcact 3301 ccagcctgggcgacagagcgagactctgcctcaaaaaacaaaacaaaacaaaacactcac 3361 ccatcaacgaatatagactcttctctcatttatcgatgatcctctttttccattttttaa 3421 gtacttatgtggaagctagtctcccaaaacacaatctttagagagaaaagacatgaacga 3481 actccaaaatatccatttaatcaatcatgtttttggctttggataaagaactttgaacca 3541 gtttttttctcaggagctgtcaaatggacacttaattatgacatgagaatgaagaaatta 3601 ttttggaaaaaaaaaatgacctaatttacctatcagtgaaagctttattttctggtgcct 3661 tttgaaagtatatggagtcatatcattcttctgtttaaaatgttagtttggtttgacttt 3721 ccactttgtcctttctgctcttgtgaagaaaaaaaaaagcattttcgaggaaagaattat 3781 gcaatttcttttgttttctgtgtcattatttattgctttttcaatgtgcagccagtggat 3841 ggttttagttctttcagatgaactgccatttgtgtttcagctcacagttctttgctgggt 3901 aaaagaaatactttctgacagtcacctgagccttaaatgtaagtattacatgacatgcat 3961 tctgtttcttccagagttctgtctgccacacgaaagagaatatttgcttacttgatagaa 4021 ctttggcattttcatcattcttttacttaaccaggcttatggcatgatctctggaacaaa 4081 tttgtaggaaaaaattactccaattgaatgactgatgtatgtaatcaacttcattgggct 4141 gcagtaaactagtggaaattagagagttgttttattggtgttttctactgtgagttaatt 4201 aaaaattgtttttatttggggtcattatgtcacagtcttgagttaacaagatcttacgtg 4261 attggccttttctttgttttctcttaggagttgtgtctcatgaatgacagtactaaagct 4321 attaacaactaagagtttgacagagaactataagcctgttgtatctcctaaaagttgtca 4381 actccccacccttggactttaaatgaaaattttattcagtccagctattcttacagtccc 4441 taaggattttcatatatctatgtataggagataaaatttgctagtaagatttttaaaaac 4501 tggctagtgaaaggaaagtacctctgaaagaaaccattttagcaaattatggttatatgt 4561 tttaatttaatctacagaatgttttatagtaaaattctagcaccactagaataatcacat 4621 agcatgtacaatatatttatgctggctgaaaagacagaatctgggaataataaaattgca 4681 accagtttggtaatgcaaacagcagaatagaatgaaatctcagtaatgaattaaagcaac 4741 aaaaagatattgattggcaaaaagcaagatataagagattcatttgcttaacatttctac 4801 ataatatttatggtctggtcagtattggtctggtcagtattgcctggctgacgtgaaatg 4861 taaactagtaggcgtgttattgatctgctaaaactaaccctctttttaagaggagattta 4921 aggaagacgtcaatcaaaatgtcaaatatgtgtgtcagaatataaataatttttcacatt 4981 gtattgttgctatataaaaaaaataatagaattggttgggtttctgaggtgaaatccaga 5041 gtaagagtactagacagttcaacaagccacatctaatggcacagatagaggatgtagcta 5101 ttttatacctttcataacatttgagagtaagatatccttcaggatgtgaagtgattatta 5161 agtactcatacctgaaatctgttgtcaagattagaactggggttcatgttaaaaaccttc 5221 catattacctgagggtacctgtggggaacagttccttcccctgtgtggtagtattttgtt 5281 ggaagagaatgtttatacaaaaaatgaaattcttccaacagcagagaaactctaaaaagt 5341 ttgatagtacctatcaaagtgctgtacttctgtgatagagaacatctgatgtaccaattt 5401 agatctatttctttatactttttctaatcaattgcttaatagtactttggatgattatca 5461 cctttgccacttaaaatatataaatatcctttttacttcatgaggaaggaagaatttttt 5521 gataattactgagttcagccttttgtgatgacttatattttggacttacattttaacttt 5581 aaagaatgtcagatcccttctttgtcttactagttaaatcctcacctaatctcttgggta 5641 tgaatataaatgtgtgtcatcgttatattgttcagctagatgagcaagtatcttagggta 5701 gtaggtagcctggtggttttagaagtgtttggtgatttttatggagagagttttcctaag 5761 tggtggtttataggtggtatcagatattattagggcagctttttggggagtaatctcagg 5821 tctcccagagcagcagcatttttctcattgatataagtaagattcttaggagcttttctt 5881 atcacacaagatgcctgaatcgaatgtgagaattgaaggcatttcttctgcataaacaaa 5941 gaattctacctgctggacagaaacctggaaagttctttggaattcgctgaattacagttt 6001 agtatgtcctgattacagagtgacaatatttatcaagcctttgttatattggattatctt 6061 ctctcttaaaatacaactgtattataattgaaatgacagcccaaaattggatggtttacc 6121 aaaaccaatgaaagggatttcacacatcaatttttatttctgttttgaagagcacatgct 6181 atataataattgctagtagcaactgcagtaaaacaggtgataagttattttctctgaaaa 6241 gatccagtcctagagcaggattcttcgatcattcatggcagagtgaaaaaggtttgtatg 6301 gttcttgtccaaataactcagttcttaaaattcttaaaatgatcgtaaaccattatcctt 6361 taaaggtttatttgaagatgctgttaaagtacagaattttgtgtacaggtagatttttcc 6421 gtccctcattaatagtgccttcttaattaatacagactggtgttagctataacaaaactc 6481 cagtaaggccaaagaatcccaagttctttgtggaaaaaaaaaaaaaatcttttagggtca 6541 gattttcccttctaatatcattgaagatgatgttgcattgatttattcataaagtatttt 6601 aactataggaactctagaagataatggttaggcaagtgattttttttttaaatatggttg 6661 gcgtaagttgtattttgaaattcacttattttaaaatcgaagaggattgtaatcatggaa 6721 atagaatgtttgtatctacctgcccacattttcttaaaaagatatttcatatacagataa 6781 tgaagaccaagctagtggctgcactgtaggtctgctgcttatttgtatttgttgtgcttc 6841 tgtttatgttgtagaagctgaaattctagcaacatgcttcaattctgttattttgatact 6901 tatgaaaatgtattaggttttactatattgtgcttttgaaagccataactcttaagaact 6961 ttgtttttgcatattgtttgctaattctttactttaataaacctcaaaacctg SEQIDNO:164HumanSMAD5transcriptvariant2cDNAsequence (NM_001001419.3;CDS:447-1844) 1 atccgggtcctgggcgagcgggcgccgtgcgcgtgtcccgcggccgagctgctaataaag 61 ttgcagcgaggagaagcgcagcgacggcgtcgggagagcgcgcctagccggctcgcgaaa 121 aggaagctgttgaagttattgaagtacctgttgctatattctaagaaattaaaatgtcca 181 gaaatctgcctctaaatgggatctcactatgttgctcagactggacgtgattgaactcct 241 gggctcaagtgagtctcccgaataactgggattacaggacttgacccaatgaaagaagca 301 tatggcacttgtgaagataaatgttactcctccctttttaattggaacttctgcttagga 361 cctgtgtatgacgtttcacctgtgatctgttctttcggtagccactgactttgagttaca 421 ggaaggtctccgaagatttgtgtcaaatgacgtcaatggccagcttgttttcttttacta 481 gtccagcagtaaagcgattgttgggctggaaacaaggtgatgaggaggagaaatgggcag 541 aaaaggcagttgatgctttggtgaagaaactaaaaaagaaaaagggtgccatggaggaac 601 tggagaaagccttgagcagtccaggacagccgagtaaatgtgtcactattcccagatctt 661 tagatggacgcctgcaggtttctcacagaaaaggcttaccccatgttatatattgtcgtg 721 tttggcgctggccggatttgcagagtcatcatgagctaaagccgttggatatttgtgaat 781 ttccttttggatctaagcaaaaagaagtttgtatcaacccataccactataagagagtgg 841 agagtccagtcttacctccagtattagtgcctcgtcataatgaattcaatccacaacaca 901 gccttctggttcagtttaggaacctgagccacaatgaaccacacatgccacaaaatgcca 961 cgtttccagattctttccaccagcccaacaacactccttttcccttatctccaaacagcc 1021 cttatcccccttctcctgctagcagcacatatcccaactccccagcaagttctggaccag 1081 gaagtccatttcagctcccagctgatacgcctcctcctgcctatatgccacctgatgatc 1141 agatgggtcaagataattcccagcctatggatacaagcaataatatgattcctcagatta 1201 tgcccagtatatccagcagggatgttcagcctgttgcctatgaagagcctaaacattggt 1261 gttcaatagtctactatgaattaaacaatcgtgttggagaagcttttcatgcatcttcta 1321 ctagtgtgttagtagatggattcacagatccttcaaataacaaaagtagattctgcttgg 1381 gtttgttgtcaaatgttaatcgtaattcgacaattgaaaacactaggcgacatattggaa 1441 aaggtgttcatctgtactatgttggtggagaggtgtatgcggaatgcctcagtgacagca 1501 gcatatttgtacagagtaggaactgcaactttcatcatggctttcatcccaccactgtct 1561 gtaagattcccagcagctgcagcctcaaaatttttaacaatcaggagtttgctcagcttc 1621 tggctcaatctgtcaaccatgggtttgaggcagtatatgagctcaccaaaatgtgtacca 1681 ttcggatgagttttgtcaagggttggggagcagaatatcaccggcaggatgtaaccagca 1741 ccccatgttggattgagattcatcttcatgggcctcttcagtggctggataaagtcctta 1801 ctcagatgggctcccctctgaaccccatatcttctgtttcataatgcagaagtattcttt 1861 tcaattatattgttagtggacttgttttaattttagagaaactttgagtacagatactgt 1921 gagcttacattgaaaacagatattacagcttatttttttctacataattgtgaccaatac 1981 atttgtattttgtgatgaatctacatttgtttgtattcatgttcatgtgattaactctta 2041 gaagtgttgtaaaagatgcagagtaagtattatgccccagttcagaaatttggcattgat 2101 cttaaactggaacatgcttttactttattgccctaacaattttttattaaatttatttga 2161 aaatgcatcacatgatgaaaaattatagtagcttataagagggcatatacagtgaagagt 2221 aagttttccctcctactctcgatcttccagaagctgtacttttaccagtttctttgtccc 2281 accaacttaaaaaaaaaaagtacaattcattgttttgcaaaagtgtatggtaggggctta 2341 aaagaaactataaagttttatttgaatgaacactatgcactgctgtaactggtagtgttc 2401 agtaaaagcaaaatgatagttttctagatgacataaaatttacatttaatacagataagt 2461 gttcttcagtgtaatgtgacttcatgctatatatcttttgtaagacatttccttttttaa 2521 aaaaatttttgcaaataactgatctcaagtatatgtcatttactcaaaatctgtcataag 2581 cattactttatagctagtgacagtgcatgcacagccttgttcaactatgtttgctgcttt 2641 tggacaatgttgcaagaactctatttttgacatgcattaatcttttattttgcactttta 2701 tgggtgacagtttttagcataacctttgataaaatacactcaagtgacttggacttagat 2761 gcttatccttacgtccttggtaccttttttgtattaacaaacactgcaatttatagatta 2821 catttgtaggaagttatgcttttttctggtttttgttttactttcaacctaggttataag 2881 actgttattctatagctccaacttaaggtgcctttttaattccctacagttttatgggtg 2941 ttatcagtgctggagaatcatgtagttaatcccattgctcttacaagtgtcagcttactt 3001 gtatcagcctccctacgcaaggacctatgcactggagccgtaggaggctcttcagttggg 3061 ccccaaggataaggctactgatttgatactaaatgaatcagcagtggatgtagggatagc 3121 tgattttaaaacactcggctgggcacagtggctcacacctgtaatcccagcactttggga 3181 ggctgaggcaggcagatcatgatgtcaggagtttgagaccagcctggccaatatggtgaa 3241 accctgtctctacaaaaaatacaaaaattagctgggcatggtggtgcgtgcctgaagtcc 3301 cagctactcgggaagctgaggcagaagaatcacttgaacctgggaggcggaggttgtggt 3361 gagccgagatcgcaccactgcactccagcctgggcgacagagcgagactctgcctcaaaa 3421 aacaaaacaaaacaaaacactcacccatcaacgaatatagactcttctctcatttatcga 3481 tgatcctctttttccattttttaagtacttatgtggaagctagtctcccaaaacacaatc 3541 tttagagagaaaagacatgaacgaactccaaaatatccatttaatcaatcatgtttttgg 3601 ctttggataaagaactttgaaccagtttttttctcaggagctgtcaaatggacacttaat 3661 tatgacatgagaatgaagaaattattttggaaaaaaaaaatgacctaatttacctatcag 3721 tgaaagctttattttctggtgccttttgaaagtatatggagtcatatcattcttctgttt 3781 aaaatgttagtttggtttgactttccactttgtcctttctgctcttgtgaagaaaaaaaa 3841 aagcattttcgaggaaagaattatgcaatttcttttgttttctgtgtcattatttattgc 3901 tttttcaatgtgcagccagtggatggttttagttctttcagatgaactgccatttgtgtt 3961 tcagctcacagttctttgctgggtaaaagaaatactttctgacagtcacctgagccttaa 4021 atgtaagtattacatgacatgcattctgtttcttccagagttctgtctgccacacgaaag 4081 agaatatttgcttacttgatagaactttggcattttcatcattcttttacttaaccaggc 4141 ttatggcatgatctctggaacaaatttgtaggaaaaaattactccaattgaatgactgat 4201 gtatgtaatcaacttcattgggctgcagtaaactagtggaaattagagagttgttttatt 4261 ggtgttttctactgtgagttaattaaaaattgtttttatttggggtcattatgtcacagt 4321 cttgagttaacaagatcttacgtgattggccttttctttgttttctcttaggagttgtgt 4381 ctcatgaatgacagtactaaagctattaacaactaagagtttgacagagaactataagcc 4441 tgttgtatctcctaaaagttgtcaactccccacccttggactttaaatgaaaattttatt 4501 cagtccagctattcttacagtccctaaggattttcatatatctatgtataggagataaaa 4561 tttgctagtaagatttttaaaaactggctagtgaaaggaaagtacctctgaaagaaacca 4621 ttttagcaaattatggttatatgttttaatttaatctacagaatgttttatagtaaaatt 4681 ctagcaccactagaataatcacatagcatgtacaatatatttatgctggctgaaaagaca 4741 gaatctgggaataataaaattgcaaccagtttggtaatgcaaacagcagaatagaatgaa 4801 atctcagtaatgaattaaagcaacaaaaagatattgattggcaaaaagcaagatataaga 4861 gattcatttgcttaacatttctacataatatttatggtctggtcagtattggtctggtca 4921 gtattgcctggctgacgtgaaatgtaaactagtaggcgtgttattgatctgctaaaacta 4981 accctctttttaagaggagatttaaggaagacgtcaatcaaaatgtcaaatatgtgtgtc 5041 agaatataaataatttttcacattgtattgttgctatataaaaaaaataatagaattggt 5101 tgggtttctgaggtgaaatccagagtaagagtactagacagttcaacaagccacatctaa 5161 tggcacagatagaggatgtagctattttatacctttcataacatttgagagtaagatatc 5221 cttcaggatgtgaagtgattattaagtactcatacctgaaatctgttgtcaagattagaa 5281 ctggggttcatgttaaaaaccttccatattacctgagggtacctgtggggaacagttcct 5341 tcccctgtgtggtagtattttgttggaagagaatgtttatacaaaaaatgaaattcttcc 5401 aacagcagagaaactctaaaaagtttgatagtacctatcaaagtgctgtacttctgtgat 5461 agagaacatctgatgtaccaatttagatctatttctttatactttttctaatcaattgct 5521 taatagtactttggatgattatcacctttgccacttaaaatatataaatatcctttttac 5581 ttcatgaggaaggaagaattttttgataattactgagttcagccttttgtgatgacttat 5641 attttggacttacattttaactttaaagaatgtcagatcccttctttgtcttactagtta 5701 aatcctcacctaatctcttgggtatgaatataaatgtgtgtcatcgttatattgttcagc 5761 tagatgagcaagtatcttagggtagtaggtagcctggtggttttagaagtgtttggtgat 5821 ttttatggagagagttttcctaagtggtggtttataggtggtatcagatattattagggc 5881 agctttttggggagtaatctcaggtctcccagagcagcagcatttttctcattgatataa 5941 gtaagattcttaggagcttttcttatcacacaagatgcctgaatcgaatgtgagaattga 6001 aggcatttcttctgcataaacaaagaattctacctgctggacagaaacctggaaagttct 6061 ttggaattcgctgaattacagtttagtatgtcctgattacagagtgacaatatttatcaa 6121 gcctttgttatattggattatcttctctcttaaaatacaactgtattataattgaaatga 6181 cagcccaaaattggatggtttaccaaaaccaatgaaagggatttcacacatcaattttta 6241 tttctgttttgaagagcacatgctatataataattgctagtagcaactgcagtaaaacag 6301 gtgataagttattttctctgaaaagatccagtcctagagcaggattcttcgatcattcat 6361 ggcagagtgaaaaaggtttgtatggttcttgtccaaataactcagttcttaaaattctta 6421 aaatgatcgtaaaccattatcctttaaaggtttatttgaagatgctgttaaagtacagaa 6481 ttttgtgtacaggtagatttttccgtccctcattaatagtgccttcttaattaatacaga 6541 ctggtgttagctataacaaaactccagtaaggccaaagaatcccaagttctttgtggaaa 6601 aaaaaaaaaaatcttttagggtcagattttcccttctaatatcattgaagatgatgttgc 6661 attgatttattcataaagtattttaactataggaactctagaagataatggttaggcaag 6721 tgattttttttttaaatatggttggcgtaagttgtattttgaaattcacttattttaaaa 6781 tcgaagaggattgtaatcatggaaatagaatgtttgtatctacctgcccacattttctta 6841 aaaagatatttcatatacagataatgaagaccaagctagtggctgcactgtaggtctgct 6901 gcttatttgtatttgttgtgcttctgtttatgttgtagaagctgaaattctagcaacatg 6961 cttcaattctgttattttgatacttatgaaaatgtattaggttttactatattgtgcttt 7021 tgaaagccataactcttaagaactttgtttttgcatattgtttgctaattctttacttta 7081 ataaacctcaaaacctg SEQIDNO:165HumanSMAD5transcriptvariant3cDNAsequence (NM_001001420.2;CDS:288-1685) 1 atccgggtcctgggcgagcgggcgccgtgcgcgtgtcccgcggccgagctgctaataaag 61 ttgcagcgaggagaagcgcagcgacggcgtcgggagagcgcgcctagccggctcgcgaga 121 cttgacccaatgaaagaagcatatggcacttgtgaagataaatgttactcctcccttttt 181 aattggaacttctgcttaggacctgtgtatgacgtttcacctgtgatctgttctttcggt 241 agccactgactttgagttacaggaaggtctccgaagatttgtgtcaaatgacgtcaatgg 301 ccagcttgttttcttttactagtccagcagtaaagcgattgttgggctggaaacaaggtg 361 atgaggaggagaaatgggcagaaaaggcagttgatgctttggtgaagaaactaaaaaaga 421 aaaagggtgccatggaggaactggagaaagccttgagcagtccaggacagccgagtaaat 481 gtgtcactattcccagatctttagatggacgcctgcaggtttctcacagaaaaggcttac 541 cccatgttatatattgtcgtgtttggcgctggccggatttgcagagtcatcatgagctaa 601 agccgttggatatttgtgaatttccttttggatctaagcaaaaagaagtttgtatcaacc 661 cataccactataagagagtggagagtccagtcttacctccagtattagtgcctcgtcata 721 atgaattcaatccacaacacagccttctggttcagtttaggaacctgagccacaatgaac 781 cacacatgccacaaaatgccacgtttccagattctttccaccagcccaacaacactcctt 841 ttcccttatctccaaacagcccttatcccccttctcctgctagcagcacatatcccaact 901 ccccagcaagttctggaccaggaagtccatttcagctcccagctgatacgcctcctcctg 961 cctatatgccacctgatgatcagatgggtcaagataattcccagcctatggatacaagca 1021 ataatatgattcctcagattatgcccagtatatccagcagggatgttcagcctgttgcct 1081 atgaagagcctaaacattggtgttcaatagtctactatgaattaaacaatcgtgttggag 1141 aagcttttcatgcatcttctactagtgtgttagtagatggattcacagatccttcaaata 1201 acaaaagtagattctgcttgggtttgttgtcaaatgttaatcgtaattcgacaattgaaa 1261 acactaggcgacatattggaaaaggtgttcatctgtactatgttggtggagaggtgtatg 1321 cggaatgcctcagtgacagcagcatatttgtacagagtaggaactgcaactttcatcatg 1381 gctttcatcccaccactgtctgtaagattcccagcagctgcagcctcaaaatttttaaca 1441 atcaggagtttgctcagcttctggctcaatctgtcaaccatgggtttgaggcagtatatg 1501 agctcaccaaaatgtgtaccattcggatgagttttgtcaagggttggggagcagaatatc 1561 accggcaggatgtaaccagcaccccatgttggattgagattcatcttcatgggcctcttc 1621 agtggctggataaagtccttactcagatgggctcccctctgaaccccatatcttctgttt 1681 cataatgcagaagtattcttttcaattatattgttagtggacttgttttaattttagaga 1741 aactttgagtacagatactgtgagcttacattgaaaacagatattacagcttattttttt 1801 ctacataattgtgaccaatacatttgtattttgtgatgaatctacatttgtttgtattca 1861 tgttcatgtgattaactcttagaagtgttgtaaaagatgcagagtaagtattatgcccca 1921 gttcagaaatttggcattgatcttaaactggaacatgcttttactttattgccctaacaa 1981 ttttttattaaatttatttgaaaatgcatcacatgatgaaaaattatagtagcttataag 2041 agggcatatacagtgaagagtaagttttccctcctactctcgatcttccagaagctgtac 2101 ttttaccagtttctttgtcccaccaacttaaaaaaaaaaagtacaattcattgttttgca 2161 aaagtgtatggtaggggcttaaaagaaactataaagttttatttgaatgaacactatgca 2221 ctgctgtaactggtagtgttcagtaaaagcaaaatgatagttttctagatgacataaaat 2281 ttacatttaatacagataagtgttcttcagtgtaatgtgacttcatgctatatatctttt 2341 gtaagacatttccttttttaaaaaaatttttgcaaataactgatctcaagtatatgtcat 2401 ttactcaaaatctgtcataagcattactttatagctagtgacagtgcatgcacagccttg 2461 ttcaactatgtttgctgcttttggacaatgttgcaagaactctatttttgacatgcatta 2521 atcttttattttgcacttttatgggtgacagtttttagcataacctttgataaaatacac 2581 tcaagtgacttggacttagatgcttatccttacgtccttggtaccttttttgtattaaca 2641 aacactgcaatttatagattacatttgtaggaagttatgcttttttctggtttttgtttt 2701 actttcaacctaggttataagactgttattctatagctccaacttaaggtgcctttttaa 2761 ttccctacagttttatgggtgttatcagtgctggagaatcatgtagttaatcccattgct 2821 cttacaagtgtcagcttacttgtatcagcctccctacgcaaggacctatgcactggagcc 2881 gtaggaggctcttcagttgggccccaaggataaggctactgatttgatactaaatgaatc 2941 agcagtggatgtagggatagctgattttaaaacactcggctgggcacagtggctcacacc 3001 tgtaatcccagcactttgggaggctgaggcaggcagatcatgatgtcaggagtttgagac 3061 cagcctggccaatatggtgaaaccctgtctctacaaaaaatacaaaaattagctgggcat 3121 ggtggtgcgtgcctgaagtcccagctactcgggaagctgaggcagaagaatcacttgaac 3181 ctgggaggcggaggttgtggtgagccgagatcgcaccactgcactccagcctgggcgaca 3241 gagcgagactctgcctcaaaaaacaaaacaaaacaaaacactcacccatcaacgaatata 3301 gactcttctctcatttatcgatgatcctctttttccattttttaagtacttatgtggaag 3361 ctagtctcccaaaacacaatctttagagagaaaagacatgaacgaactccaaaatatcca 3421 tttaatcaatcatgtttttggctttggataaagaactttgaaccagtttttttctcagga 3481 gctgtcaaatggacacttaattatgacatgagaatgaagaaattattttggaaaaaaaaa 3541 atgacctaatttacctatcagtgaaagctttattttctggtgccttttgaaagtatatgg 3601 agtcatatcattcttctgtttaaaatgttagtttggtttgactttccactttgtcctttc 3661 tgctcttgtgaagaaaaaaaaaagcattttcgaggaaagaattatgcaatttcttttgtt 3721 ttctgtgtcattatttattgctttttcaatgtgcagccagtggatggttttagttctttc 3781 agatgaactgccatttgtgtttcagctcacagttctttgctgggtaaaagaaatactttc 3841 tgacagtcacctgagccttaaatgtaagtattacatgacatgcattctgtttcttccaga 3901 gttctgtctgccacacgaaagagaatatttgcttacttgatagaactttggcattttcat 3961 cattcttttacttaaccaggcttatggcatgatctctggaacaaatttgtaggaaaaaat 4021 tactccaattgaatgactgatgtatgtaatcaacttcattgggctgcagtaaactagtgg 4081 aaattagagagttgttttattggtgttttctactgtgagttaattaaaaattgtttttat 4141 ttggggtcattatgtcacagtcttgagttaacaagatcttacgtgattggccttttcttt 4201 gttttctcttaggagttgtgtctcatgaatgacagtactaaagctattaacaactaagag 4261 tttgacagagaactataagcctgttgtatctcctaaaagttgtcaactccccacccttgg 4321 actttaaatgaaaattttattcagtccagctattcttacagtccctaaggattttcatat 4381 atctatgtataggagataaaatttgctagtaagatttttaaaaactggctagtgaaagga 4441 aagtacctctgaaagaaaccattttagcaaattatggttatatgttttaatttaatctac 4501 agaatgttttatagtaaaattctagcaccactagaataatcacatagcatgtacaatata 4561 tttatgctggctgaaaagacagaatctgggaataataaaattgcaaccagtttggtaatg 4621 caaacagcagaatagaatgaaatctcagtaatgaattaaagcaacaaaaagatattgatt 4681 ggcaaaaagcaagatataagagattcatttgcttaacatttctacataatatttatggtc 4741 tggtcagtattggtctggtcagtattgcctggctgacgtgaaatgtaaactagtaggcgt 4801 gttattgatctgctaaaactaaccctctttttaagaggagatttaaggaagacgtcaatc 4861 aaaatgtcaaatatgtgtgtcagaatataaataatttttcacattgtattgttgctatat 4921 aaaaaaaataatagaattggttgggtttctgaggtgaaatccagagtaagagtactagac 4981 agttcaacaagccacatctaatggcacagatagaggatgtagctattttatacctttcat 5041 aacatttgagagtaagatatccttcaggatgtgaagtgattattaagtactcatacctga 5101 aatctgttgtcaagattagaactggggttcatgttaaaaaccttccatattacctgaggg 5161 tacctgtggggaacagttccttcccctgtgtggtagtattttgttggaagagaatgttta 5221 tacaaaaaatgaaattcttccaacagcagagaaactctaaaaagtttgatagtacctatc 5281 aaagtgctgtacttctgtgatagagaacatctgatgtaccaatttagatctatttcttta 5341 tactttttctaatcaattgcttaatagtactttggatgattatcacctttgccacttaaa 5401 atatataaatatcctttttacttcatgaggaaggaagaattttttgataattactgagtt 5461 cagccttttgtgatgacttatattttggacttacattttaactttaaagaatgtcagatc 5521 ccttctttgtcttactagttaaatcctcacctaatctcttgggtatgaatataaatgtgt 5581 gtcatcgttatattgttcagctagatgagcaagtatcttagggtagtaggtagcctggtg 5641 gttttagaagtgtttggtgatttttatggagagagttttcctaagtggtggtttataggt 5701 ggtatcagatattattagggcagctttttggggagtaatctcaggtctcccagagcagca 5761 gcatttttctcattgatataagtaagattcttaggagcttttcttatcacacaagatgcc 5821 tgaatcgaatgtgagaattgaaggcatttcttctgcataaacaaagaattctacctgctg 5881 gacagaaacctggaaagttctttggaattcgctgaattacagtttagtatgtcctgatta 5941 cagagtgacaatatttatcaagcctttgttatattggattatcttctctcttaaaataca 6001 actgtattataattgaaatgacagcccaaaattggatggtttaccaaaaccaatgaaagg 6061 gatttcacacatcaatttttatttctgttttgaagagcacatgctatataataattgcta 6121 gtagcaactgcagtaaaacaggtgataagttattttctctgaaaagatccagtcctagag 6181 caggattcttcgatcattcatggcagagtgaaaaaggtttgtatggttcttgtccaaata 6241 actcagttcttaaaattcttaaaatgatcgtaaaccattatcctttaaaggtttatttga 6301 agatgctgttaaagtacagaattttgtgtacaggtagatttttccgtccctcattaatag 6361 tgccttcttaattaatacagactggtgttagctataacaaaactccagtaaggccaaaga 6421 atcccaagttctttgtggaaaaaaaaaaaaaatcttttagggtcagattttcccttctaa 6481 tatcattgaagatgatgttgcattgatttattcataaagtattttaactataggaactct 6541 agaagataatggttaggcaagtgattttttttttaaatatggttggcgtaagttgtattt 6601 tgaaattcacttattttaaaatcgaagaggattgtaatcatggaaatagaatgtttgtat 6661 ctacctgcccacattttcttaaaaagatatttcatatacagataatgaagaccaagctag 6721 tggctgcactgtaggtctgctgcttatttgtatttgttgtgcttctgtttatgttgtaga 6781 agctgaaattctagcaacatgcttcaattctgttattttgatacttatgaaaatgtatta 6841 ggttttactatattgtgcttttgaaagccataactcttaagaactttgtttttgcatatt 6901 gtttgctaattctttactttaataaacctcaaaacctgc SEQIDNO:166HumanSMAD5aminoacidsequence(NP_001001419.1, NP_001001420.1,NP_005894.3) 1 mtsmaslfsftspavkrllgwkqgdeeekwaekavdalvkklkkkkgameelekalsspg 61 qpskcvtiprsldgrlqvshrkglphviycrvwrwpdlqshhelkpldicefpfgskqke 121 vcinpyhykrvespvlppvlvprhnefnpqhsllvqfrnlshnephmpqnatfpdsfhqp 181 nntpfplspnspyppspasstypnspassgpgspfqlpadtpppaymppddqmgqdnsqp 241 mdtsnnmipqimpsissrdvqpvayeepkhwcsivyyelnnrvgeafhasstsvlvdgft 301 dpsnnksrfclgllsnvnrnstientrrhigkgvhlyyvggevyaeclsdssifvqsrnc 361 nfhhgfhpttvckipsscslkifnnqefaqllaqsvnhgfeavyeltkmctirmsfvkgw 421 gaeyhrqdvtstpcwieihlhgplqwldkvltqmgspinpissvs SEQIDNO:167MouseSMAD5transcriptvariant1cDNAsequence(NM_008541.3, CDS:288-1685) 1 atcatccgggtccccggcgagcgggcgccgagcgcttgtcccggggccgagctgctaata 61 aagttgcggcgcgtgcacagcgcggcgacggcgtgaggagagcgcgcctgggcggcgggg 121 aggacttgcactaagaagaagcctatggcacctgtcaagttaaatgtcactccccgcctc 181 cacttggactttctgcttaagacctgcatgtgacttttcacctgcgagccacgcttttgg 241 tatctactgactttgattacaggaaagtgtctgaagatttgtatcaaatgacgtcaatgg 301 ccagcttgttttctttcactagtccagccgtgaagcgattgttgggctggaaacaaggtg 361 acgaggaagagaaatgggcagaaaaggcagtggatgctttagtgaaaaagctgaagaaga 421 agaagggtgctatggaggagctggagaaagccttgagcagcccaggacagccaagcaagt 481 gtgtcacgatccccaggtccttggatggacgtctgcaagtttctcacaggaaaggcttgc 541 cccatgttatatattgccgtgtttggcgctggccagatttgcagagccatcacgagctaa 601 aaccattggatatttgtgaatttccttttggatctaagcaaaaggaagtttgtatcaatc 661 cataccactataagagagtggagagtccagtcttacctccagtattagtgcctcgtcaca 721 atgaattcaatccacaacacagccttctggttcagttcaggaacctgagccacaatgaac 781 cgcacatgccacaaaacgccacgtttcccgattctttccaccaacccaacaacgctcctt 841 tccccttatctcctaacagcccctatcctccttcccctgctagcagcacatatcccaact 901 ccccagcaagctctggacctggaagtccatttcaactcccagctgacacccctccccctg 961 cctatatgccacctgatgatcagatggccccagataattcccagcctatggatacaagca 1021 gtaacatgattcctcagaccatgcccagcatatccagcagagatgttcagcctgtcgcct 1081 atgaggagcccaaacactggtgttcgattgtctactatgaattaaacaatcgtgttgggg 1141 aagcttttcatgcatcttctactagtgtgttagtagatggatttacagatccttcaaata 1201 acaaaagtagattctgcctgggattgttgtcaaatgttaatcgtaattcaactattgaaa 1261 acactaggcggcatattggaaaaggtgttcatctatactacgttggtggggaggtgtacg 1321 ctgagtgtcttagtgacagcagcatctttgttcagagtaggaactgcaactttcaccatg 1381 gcttccatcccaccaccgtctgtaagatccccagcagctgcagcctcaagatttttaaca 1441 atcaggagtttgctcagcttctggctcagtcagtcaaccatggattcgaggctgtgtatg 1501 agctcaccaagatgtgtaccattcgaatgagctttgtcaagggctggggagcagagtacc 1561 accgacaggacgtcaccagtactccctgctggattgagattcacctccacgggcctctgc 1621 agtggctggataaagtccttactcagatgggctctccgctgaaccccatttcttctgttt 1681 catagtgcagaagtattctttcaactatatttttagtggacttgttttaattttagagga 1741 atttccagtacagatgctgtgagctgacatggaaaacagatattattttttctacgtaat 1801 tgtgaccaacacatttgtattttatgatgatattacatttgtttgtattcgtgttcattg 1861 tgattaactttcaaaagtattgtaaacgatgtagagtattttgcccctgttgaaatgttt 1921 agcattgatcttaaactggaacgtactttttcttattgtcccaacgttttttaatttgtt 1981 aaattttttttacaaagtagttcatcacataatgaaattttatcctataagagaacatat 2041 attgtggaaagcagtagatgatatttctctgggaatttctttgccttaccacctttgaaa 2101 aagcatacattgtttgcaaaacctcaaagtagggcttgcttaaaggaaactgttgaatct 2161 tgtttgaaggacactgcagtcctaacgtgttcagtgaaagcaaggtggtagatttctgga 2221 cgtcatacatttacatttaatataggtaatattcatcagtgtaatgtgacttcatgccat 2281 atatattttgtaaaacaattcctttttaaaaacttcaagtatttctcatttactcaaatt 2341 tgttgtaagtcctacttaacagttagttactatgtgctctgtggccttgttcagcattgt 2401 ttgctgctttgggccaacaattcaagaactctaattttcctgtgcattaatcttttcatt 2461 ttgcacttttatgggtgactgtcttagtgtagcctctggtaaaatactattaggtggcct 2521 ggttttagagctcctcctcgctgccttggcactcctttgtgcaacacgaccacttagaga 2581 tgacagctgtgagctgtgctgctttttctagcctttaatttccaatgtagtttataatgt 2641 tgttcttctatagctccagctaaggtgcctgttagtcccctacaatgttatgagcattat 2701 tgacattgaaaggttatgtatgtatgaatacctttgctccttaccagacttgtcatacaa 2761 ggactcgtgcagtgtagccagtagaggctctttggttggcccaagaatgaggctgttggt 2821 gtaagtgaatcacaatagggattgggatagttcatgtcatatgtcatatagcaagacaat 2881 gtagagtgtaggcttgtctctctgcatcaacgctctgcctctttctttttatccttttag 2941 aacctacatggacgctaatctccacaacactgttggatgtgaacactcttaagacactca 3001 tctagttcactgtgccttgtccttaggactcttaaccactttctagggagcagttatggc 3061 ctgagatggacagtcatggcctgagaatgaagacactactttgataaagaaaaaggcctc 3121 atttgcctatcagagtgagaaaggtttttttctggtgccttttgaaaatatacagagcca 3181 cttggttcttctgctgaaaatgtaattttggtttgactttttagagtgcccttcctgcct 3241 ttatgaggaaaacagctatttttttttttggggggggggattccttttgttttctgtgcc 3301 attatttattgcctttcagagtgcaaccattgggtggctttgctccttcagagagggctc 3361 cttgatagccttcagtagcttgagctgtagacataagtattccatagcaagagtgtgtca 3421 gctccatgagagagatgtctgctttatagccgaggcagaaaccgttcatgttcctttact 3481 tggcagccttcaggaacaggtttgtaagaacgtgtcttgagttgagtgagtgtatgtctg 3541 tgagctctgctgaagtctggacacaagggccttgcctgctccttttttcagcagtgggtt 3601 acatgttgtctctccacagtcttcatgtcataggtctcggacttgcagagtcctatgtgg 3661 cctgccatctgtacagtggcaggactgaagctctgagctgttctgaggttcatggagaaa 3721 tcccaacctattctgtggtcagtaaatggagactgtgtagtctacctgctcctgtactgt 3781 ccttactgtatgtaaggatatacagacgcctgtgggtaggcagtactcacagtgagatga 3841 agacagcaagtgtgcactgaaccacagagggcagggagtagggcctctgaagaagccacc 3901 agaccagaccagtgccggtacagtctttgtcagagatggctctgatggggcccagactga 3961 ccctgaccatgctgagttgctgagggtagccttcagttctctaccctctgaagtgctagg 4021 atgacagacatccgccatcatacccagcttccgtggtgctaaggatcagcctcagtcttc 4081 aggcgtgctaggcatgtactttgccaagtatttagtatacaaaatacattagtatctgcc 4141 agggaaaaaagatttgcaaataataaagattgccatcagtttgataaatgttgtaaatgg 4201 aagaatcaaaatctcagcgatggattacagcaacaagatgctgcctaggaaaagcaggac 4261 caagaggtacatttgactagtataccttcagcgtagcgtgatgacctcactgatgtcacc 4321 caactgaacttaagggctgtaagtaggcgtgctgtgggccttccagaactagagaaaatt 4381 ataggaggaagtcagttctaaagtatcaaaagctgggtaatggtggcacatgcctttgat 4441 tctagcactcgggaagcaggggctagcctagtctacagagcaacttctacacagagaaac 4501 tgtcttggaggaaaataaaaaaagaaaagtcaaagagcaaacaaatagaacagagtagga 4561 atccgtgtccccttttttctatgtttcacggttgcaggtgtaagaaaagtagtcatagat 4621 gtggctgagtttctaagatgaaaccagtagtaagattgctaaatataacacttcaaccaa 4681 gttaaacaccctttgggggtatgaatgaaagtaacactgcaatatgaaatgaaccgtgca 4741 agtaacacttggggttacctcacagtctccctatgcctgagaggactgtgggaaacattt 4801 ccatcccctgccagtatcgccattgggaggacagagtagatgaagaagtgaagtcttact 4861 ggtccagggcacgcctgtcagcaatgccatttgtgcttctgccacagagagcaccgagag 4921 gcttggctcagtatcctcgaaccttctctggtcacttccctggcagcacttgggtccctg 4981 tcactcactggtctcttaaaagtcccgtctctttgcttcctaaagattctctaaaaaaat 5041 tactattttttatttcttttttaaaagtctttgttattttgttttgggatacagtctctt 5101 tgtacagtcctggctggcctggaaattactatgtaggccagcctcaaacttgaagtaatt 5161 ctcttgcctctgcctctggagttctgggattacaggcatgcactgcagagtacagtgagc 5221 tctgatggcttttaaaattcagcccctttgagggtttggttttagatccattagctttgt 5281 ctgaacccatctttgtccggccgagtaaatcctctgctatccggggtctcggtagaaatg 5341 tgttctcagtatacatacgactaaacattggttgtttataggtagcctcagatatttggt 5401 agagcatcttttttgaaagtaatctccagctaggtgggtatttccctcacagcagtagga 5461 ttttccctttaggagataccagttcttcatctttcttgtgaaaataatgcctttatgggg 5521 agtgaagattaaggagttgtttctacactaacagaattctatttgatggacaacttggac 5581 agttctgtggacttgggtgggttctagtgtgctaagaaggataacagtatttaatagtgt 5641 ctgtcatcaggccttgctcatctccctgtctagggctgtaggtcagtgctcgagcactta 5701 gcaggcatcgagtctagtgttcagtgcccagcattgcacagaactcagaatatatctgta 5761 ctgaaactgaagtgaccacctacaaccaggtggtatgccagaaccacagaaaggagattc 5821 acggtgatgtgtttaaagcattgggctggtgacggttgctgtgtagtaatgacctcttcc 5881 tcagcaaagagagtcctggagcaggctgtcctcagaagagggaagggactggtgtgctcc 5941 ttgtgcagataacttagtgtataaatcggcatgagtagctatcctttaaggatttgtttg 6001 aagttactctttgtaaaaagttgagaattttgtgtgcagttgggcacatgcttgcccttc 6061 ccccacccgccatagtcctgcctctcttgctgtgaactggtgtcagctacaacactccag 6121 ctaggtctgagctcttttgagagaaggtctcgtagagcaccattctcagagagaagctaa 6181 agcatggggagccttaggacggtcaggcaatgcactctttaccacggctggctaaggctg 6241 cagcttgaccgtccttacctaaatcaggtaagaatgtgattacagagcgagtgcttgtgt 6301 tccccggcctgccttctccgaggaagatgcttcatccgaggatgatgcagagcagacgat 6361 ggctgcactgtaggtctgcctccttctgtgtatgggttctgctgctgcttacggcatagg 6421 aaagtacactagcagcgtgcttcaattctgccatcttttgatacttataaaaatgtatta 6481 ggttttactgtattgtgctctcaaagccataactcttaagaaatttggtttttttgcata 6541 ttgtttgctaatactttgttttaataaacctcaaaatctgcttac SEQIDNO:168MouseSMAD5transcriptvariant2cDNAsequence (NM_001164041.1;CDS:691-2088) 1 ggggccgagctgctaataaagttgcggcgcgtgcacagcgcggcgacggcgtgaggagag 61 cgcgcctgggcggcggggaggtgagtgaggggccccagggcgggcgctcggggcccggcg 121 gagggacaagcgccggcggcagcggcccgcgtgaggctggaggcctagaggctccccacg 181 cgggacctgacggcacgggacggggctccgcgcagcgcgggaggccccggtgctaaggag 241 gccccgcgcggccgacgaggccggcgcggacgaggccgctgccacctcggcgcgccaccg 301 acgcccgggcccgcgcgcggagccgcgcaggcggcctaggccgagcgcgcgccccgccgc 361 tttgtgtctgggagataaggatccgcgcttatcggtgggaattacactccggccagccgg 421 ctggcggcgacccgcccctgcgcccgcccgcccgcccgcccgcccgctcgcccgcccgtc 481 actctccggacgtcgcagaggctccctcgctgcgctaaactttgtgacttgcactaagaa 541 gaagcctatggcacctgtcaagttaaatgtcactccccgcctccacttggactttctgct 601 taagacctgcatgtgacttttcacctgcgagccacgcttttggtatctactgactttgat 661 tacaggaaagtgtctgaagatttgtatcaaatgacgtcaatggccagcttgttttctttc 721 actagtccagccgtgaagcgattgttgggctggaaacaaggtgacgaggaagagaaatgg 781 gcagaaaaggcagtggatgctttagtgaaaaagctgaagaagaagaagggtgctatggag 841 gagctggagaaagccttgagcagcccaggacagccaagcaagtgtgtcacgatccccagg 901 tccttggatggacgtctgcaagtttctcacaggaaaggcttgccccatgttatatattgc 961 cgtgtttggcgctggccagatttgcagagccatcacgagctaaaaccattggatatttgt 1021 gaatttccttttggatctaagcaaaaggaagtttgtatcaatccataccactataagaga 1081 gtggagagtccagtcttacctccagtattagtgcctcgtcacaatgaattcaatccacaa 1141 cacagccttctggttcagttcaggaacctgagccacaatgaaccgcacatgccacaaaac 1201 gccacgtttcccgattctttccaccaacccaacaacgctcctttccccttatctcctaac 1261 agcccctatcctccttcccctgctagcagcacatatcccaactccccagcaagctctgga 1321 cctggaagtccatttcaactcccagctgacacccctccccctgcctatatgccacctgat 1381 gatcagatggccccagataattcccagcctatggatacaagcagtaacatgattcctcag 1441 accatgcccagcatatccagcagagatgttcagcctgtcgcctatgaggagcccaaacac 1501 tggtgttcgattgtctactatgaattaaacaatcgtgttggggaagcttttcatgcatct 1561 tctactagtgtgttagtagatggatttacagatccttcaaataacaaaagtagattctgc 1621 ctgggattgttgtcaaatgttaatcgtaattcaactattgaaaacactaggcggcatatt 1681 ggaaaaggtgttcatctatactacgttggtggggaggtgtacgctgagtgtcttagtgac 1741 agcagcatctttgttcagagtaggaactgcaactttcaccatggcttccatcccaccacc 1801 gtctgtaagatccccagcagctgcagcctcaagatttttaacaatcaggagtttgctcag 1861 cttctggctcagtcagtcaaccatggattcgaggctgtgtatgagctcaccaagatgtgt 1921 accattcgaatgagctttgtcaagggctggggagcagagtaccaccgacaggacgtcacc 1981 agtactccctgctggattgagattcacctccacgggcctctgcagtggctggataaagtc 2041 cttactcagatgggctctccgctgaaccccatttcttctgtttcatagtgcagaagtatt 2101 ctttcaactatatttttagtggacttgttttaattttagaggaatttccagtacagatgc 2161 tgtgagctgacatggaaaacagatattattttttctacgtaattgtgaccaacacatttg 2221 tattttatgatgatattacatttgtttgtattcgtgttcattgtgattaactttcaaaag 2281 tattgtaaacgatgtagagtattttgcccctgttgaaatgtttagcattgatcttaaact 2341 ggaacgtactttttcttattgtcccaacgttttttaatttgttaaattttttttacaaag 2401 tagttcatcacataatgaaattttatcctataagagaacatatattgtggaaagcagtag 2461 atgatatttctctgggaatttctttgccttaccacctttgaaaaagcatacattgtttgc 2521 aaaacctcaaagtagggcttgcttaaaggaaactgttgaatcttgtttgaaggacactgc 2581 agtcctaacgtgttcagtgaaagcaaggtggtagatttctggacgtcatacatttacatt 2641 taatataggtaatattcatcagtgtaatgtgacttcatgccatatatattttgtaaaaca 2701 attcctttttaaaaacttcaagtatttctcatttactcaaatttgttgtaagtcctactt 2761 aacagttagttactatgtgctctgtggccttgttcagcattgtttgctgctttgggccaa 2821 caattcaagaactctaattttcctgtgcattaatcttttcattttgcacttttatgggtg 2881 actgtcttagtgtagcctctggtaaaatactattaggtggcctggttttagagctcctcc 2941 tcgctgccttggcactcctttgtgcaacacgaccacttagagatgacagctgtgagctgt 3001 gctgctttttctagcctttaatttccaatgtagtttataatgttgttcttctatagctcc 3061 agctaaggtgcctgttagtcccctacaatgttatgagcattattgacattgaaaggttat 3121 gtatgtatgaatacctttgctccttaccagacttgtcatacaaggactcgtgcagtgtag 3181 ccagtagaggctctttggttggcccaagaatgaggctgttggtgtaagtgaatcacaata 3241 gggattgggatagttcatgtcatatgtcatatagcaagacaatgtagagtgtaggcttgt 3301 ctctctgcatcaacgctctgcctctttctttttatccttttagaacctacatggacgcta 3361 atctccacaacactgttggatgtgaacactcttaagacactcatctagttcactgtgcct 3421 tgtccttaggactcttaaccactttctagggagcagttatggcctgagatggacagtcat 3481 ggcctgagaatgaagacactactttgataaagaaaaaggcctcatttgcctatcagagtg 3541 agaaaggtttttttctggtgccttttgaaaatatacagagccacttggttcttctgctga 3601 aaatgtaattttggtttgactttttagagtgcccttcctgcctttatgaggaaaacagct 3661 atttttttttttggggggggggattccttttgttttctgtgccattatttattgcctttc 3721 agagtgcaaccattgggtggctttgctccttcagagagggctccttgatagccttcagta 3781 gcttgagctgtagacataagtattccatagcaagagtgtgtcagctccatgagagagatg 3841 tctgctttatagccgaggcagaaaccgttcatgttcctttacttggcagccttcaggaac 3901 aggtttgtaagaacgtgtcttgagttgagtgagtgtatgtctgtgagctctgctgaagtc 3961 tggacacaagggccttgcctgctccttttttcagcagtgggttacatgttgtctctccac 4021 agtcttcatgtcataggtctcggacttgcagagtcctatgtggcctgccatctgtacagt 4081 ggcaggactgaagctctgagctgttctgaggttcatggagaaatcccaacctattctgtg 4141 gtcagtaaatggagactgtgtagtctacctgctcctgtactgtccttactgtatgtaagg 4201 atatacagacgcctgtgggtaggcagtactcacagtgagatgaagacagcaagtgtgcac 4261 tgaaccacagagggcagggagtagggcctctgaagaagccaccagaccagaccagtgccg 4321 gtacagtctttgtcagagatggctctgatggggcccagactgaccctgaccatgctgagt 4381 tgctgagggtagccttcagttctctaccctctgaagtgctaggatgacagacatccgcca 4441 tcatacccagcttccgtggtgctaaggatcagcctcagtcttcaggcgtgctaggcatgt 4501 actttgccaagtatttagtatacaaaatacattagtatctgccagggaaaaaagatttgc 4561 aaataataaagattgccatcagtttgataaatgttgtaaatggaagaatcaaaatctcag 4621 cgatggattacagcaacaagatgctgcctaggaaaagcaggaccaagaggtacatttgac 4681 tagtataccttcagcgtagcgtgatgacctcactgatgtcacccaactgaacttaagggc 4741 tgtaagtaggcgtgctgtgggccttccagaactagagaaaattataggaggaagtcagtt 4801 ctaaagtatcaaaagctgggtaatggtggcacatgcctttgattctagcactcgggaagc 4861 aggggctagcctagtctacagagcaacttctacacagagaaactgtcttggaggaaaata 4921 aaaaaagaaaagtcaaagagcaaacaaatagaacagagtaggaatccgtgtccccttttt 4981 tctatgtttcacggttgcaggtgtaagaaaagtagtcatagatgtggctgagtttctaag 5041 atgaaaccagtagtaagattgctaaatataacacttcaaccaagttaaacaccctttggg 5101 ggtatgaatgaaagtaacactgcaatatgaaatgaaccgtgcaagtaacacttggggtta 5161 cctcacagtctccctatgcctgagaggactgtgggaaacatttccatcccctgccagtat 5221 cgccattgggaggacagagtagatgaagaagtgaagtcttactggtccagggcacgcctg 5281 tcagcaatgccatttgtgcttctgccacagagagcaccgagaggcttggctcagtatcct 5341 cgaaccttctctggtcacttccctggcagcacttgggtccctgtcactcactggtctctt 5401 aaaagtcccgtctctttgcttcctaaagattctctaaaaaaattactattttttatttct 5461 tttttaaaagtctttgttattttgttttgggatacagtctctttgtacagtcctggctgg 5521 cctggaaattactatgtaggccagcctcaaacttgaagtaattctcttgcctctgcctct 5581 ggagttctgggattacaggcatgcactgcagagtacagtgagctctgatggcttttaaaa 5641 ttcagcccctttgagggtttggttttagatccattagctttgtctgaacccatctttgtc 5701 cggccgagtaaatcctctgctatccggggtctcggtagaaatgtgttctcagtatacata 5761 cgactaaacattggttgtttataggtagcctcagatatttggtagagcatcttttttgaa 5821 agtaatctccagctaggtgggtatttccctcacagcagtaggattttccctttaggagat 5881 accagttcttcatctttcttgtgaaaataatgcctttatggggagtgaagattaaggagt 5941 tgtttctacactaacagaattctatttgatggacaacttggacagttctgtggacttggg 6001 tgggttctagtgtgctaagaaggataacagtatttaatagtgtctgtcatcaggccttgc 6061 tcatctccctgtctagggctgtaggtcagtgctcgagcacttagcaggcatcgagtctag 6121 tgttcagtgcccagcattgcacagaactcagaatatatctgtactgaaactgaagtgacc 6181 acctacaaccaggtggtatgccagaaccacagaaaggagattcacggtgatgtgtttaaa 6241 gcattgggctggtgacggttgctgtgtagtaatgacctcttcctcagcaaagagagtcct 6301 ggagcaggctgtcctcagaagagggaagggactggtgtgctccttgtgcagataacttag 6361 tgtataaatcggcatgagtagctatcctttaaggatttgtttgaagttactctttgtaaa 6421 aagttgagaattttgtgtgcagttgggcacatgcttgcccttcccccacccgccatagtc 6481 ctgcctctcttgctgtgaactggtgtcagctacaacactccagctaggtctgagctcttt 6541 tgagagaaggtctcgtagagcaccattctcagagagaagctaaagcatggggagccttag 6601 gacggtcaggcaatgcactctttaccacggctggctaaggctgcagcttgaccgtcctta 6661 cctaaatcaggtaagaatgtgattacagagcgagtgcttgtgttccccggcctgccttct 6721 ccgaggaagatgcttcatccgaggatgatgcagagcagacgatggctgcactgtaggtct 6781 gcctccttctgtgtatgggttctgctgctgcttacggcataggaaagtacactagcagcg 6841 tgcttcaattctgccatcttttgatacttataaaaatgtattaggttttactgtattgtg 6901 ctctcaaagccataactcttaagaaatttggtttttttgcatattgtttgctaatacttt 6961 gttttaataaacctcaaaatctgcttac SEQIDNO:169MouseSMAD5transcriptvariant3cDNAsequence (NM_001164042.1;CDS:311-1708) 1 gccctttctcctctgcgcttctggctgcgccgagccgggaaccctaagctctgggaactt 61 ccccggtggcggccgtcttagggtcagagcatgctcagtggcccggacttttcggttgca 121 gaaggagctggcggggatggtcgaggacttgcactaagaagaagcctatggcacctgtca 181 agttaaatgtcactccccgcctccacttggactttctgcttaagacctgcatgtgacttt 241 tcacctgcgagccacgcttttggtatctactgactttgattacaggaaagtgtctgaaga 301 tttgtatcaaatgacgtcaatggccagcttgttttctttcactagtccagccgtgaagcg 361 attgttgggctggaaacaaggtgacgaggaagagaaatgggcagaaaaggcagtggatgc 421 tttagtgaaaaagctgaagaagaagaagggtgctatggaggagctggagaaagccttgag 481 cagcccaggacagccaagcaagtgtgtcacgatccccaggtccttggatggacgtctgca 541 agtttctcacaggaaaggcttgccccatgttatatattgccgtgtttggcgctggccaga 601 tttgcagagccatcacgagctaaaaccattggatatttgtgaatttccttttggatctaa 661 gcaaaaggaagtttgtatcaatccataccactataagagagtggagagtccagtcttacc 721 tccagtattagtgcctcgtcacaatgaattcaatccacaacacagccttctggttcagtt 781 caggaacctgagccacaatgaaccgcacatgccacaaaacgccacgtttcccgattcttt 841 ccaccaacccaacaacgctcctttccccttatctcctaacagcccctatcctccttcccc 901 tgctagcagcacatatcccaactccccagcaagctctggacctggaagtccatttcaact 961 cccagctgacacccctccccctgcctatatgccacctgatgatcagatggccccagataa 1021 ttcccagcctatggatacaagcagtaacatgattcctcagaccatgcccagcatatccag 1081 cagagatgttcagcctgtcgcctatgaggagcccaaacactggtgttcgattgtctacta 1141 tgaattaaacaatcgtgttggggaagcttttcatgcatcttctactagtgtgttagtaga 1201 tggatttacagatccttcaaataacaaaagtagattctgcctgggattgttgtcaaatgt 1261 taatcgtaattcaactattgaaaacactaggcggcatattggaaaaggtgttcatctata 1321 ctacgttggtggggaggtgtacgctgagtgtcttagtgacagcagcatctttgttcagag 1381 taggaactgcaactttcaccatggcttccatcccaccaccgtctgtaagatccccagcag 1441 ctgcagcctcaagatttttaacaatcaggagtttgctcagcttctggctcagtcagtcaa 1501 ccatggattcgaggctgtgtatgagctcaccaagatgtgtaccattcgaatgagctttgt 1561 caagggctggggagcagagtaccaccgacaggacgtcaccagtactccctgctggattga 1621 gattcacctccacgggcctctgcagtggctggataaagtccttactcagatgggctctcc 1681 gctgaaccccatttcttctgtttcatagtgcagaagtattctttcaactatatttttagt 1741 ggacttgttttaattttagaggaatttccagtacagatgctgtgagctgacatggaaaac 1801 agatattattttttctacgtaattgtgaccaacacatttgtattttatgatgatattaca 1861 tttgtttgtattcgtgttcattgtgattaactttcaaaagtattgtaaacgatgtagagt 1921 attttgcccctgttgaaatgtttagcattgatcttaaactggaacgtactttttcttatt 1981 gtcccaacgttttttaatttgttaaattttttttacaaagtagttcatcacataatgaaa 2041 ttttatcctataagagaacatatattgtggaaagcagtagatgatatttctctgggaatt 2101 tctttgccttaccacctttgaaaaagcatacattgtttgcaaaacctcaaagtagggctt 2161 gcttaaaggaaactgttgaatcttgtttgaaggacactgcagtcctaacgtgttcagtga 2221 aagcaaggtggtagatttctggacgtcatacatttacatttaatataggtaatattcatc 2281 agtgtaatgtgacttcatgccatatatattttgtaaaacaattcctttttaaaaacttca 2341 agtatttctcatttactcaaatttgttgtaagtcctacttaacagttagttactatgtgc 2401 tctgtggccttgttcagcattgtttgctgctttgggccaacaattcaagaactctaattt 2461 tcctgtgcattaatcttttcattttgcacttttatgggtgactgtcttagtgtagcctct 2521 ggtaaaatactattaggtggcctggttttagagctcctcctcgctgccttggcactcctt 2581 tgtgcaacacgaccacttagagatgacagctgtgagctgtgctgctttttctagccttta 2641 atttccaatgtagtttataatgttgttcttctatagctccagctaaggtgcctgttagtc 2701 ccctacaatgttatgagcattattgacattgaaaggttatgtatgtatgaatacctttgc 2761 tccttaccagacttgtcatacaaggactcgtgcagtgtagccagtagaggctctttggtt 2821 ggcccaagaatgaggctgttggtgtaagtgaatcacaatagggattgggatagttcatgt 2881 catatgtcatatagcaagacaatgtagagtgtaggcttgtctctctgcatcaacgctctg 2941 cctctttctttttatccttttagaacctacatggacgctaatctccacaacactgttgga 3001 tgtgaacactcttaagacactcatctagttcactgtgccttgtccttaggactcttaacc 3061 actttctagggagcagttatggcctgagatggacagtcatggcctgagaatgaagacact 3121 actttgataaagaaaaaggcctcatttgcctatcagagtgagaaaggtttttttctggtg 3181 ccttttgaaaatatacagagccacttggttcttctgctgaaaatgtaattttggtttgac 3241 tttttagagtgcccttcctgcctttatgaggaaaacagctatttttttttttgggggggg 3301 ggattccttttgttttctgtgccattatttattgcctttcagagtgcaaccattgggtgg 3361 ctttgctccttcagagagggctccttgatagccttcagtagcttgagctgtagacataag 3421 tattccatagcaagagtgtgtcagctccatgagagagatgtctgctttatagccgaggca 3481 gaaaccgttcatgttcctttacttggcagccttcaggaacaggtttgtaagaacgtgtct 3541 tgagttgagtgagtgtatgtctgtgagctctgctgaagtctggacacaagggccttgcct 3601 gctccttttttcagcagtgggttacatgttgtctctccacagtcttcatgtcataggtct 3661 cggacttgcagagtcctatgtggcctgccatctgtacagtggcaggactgaagctctgag 3721 ctgttctgaggttcatggagaaatcccaacctattctgtggtcagtaaatggagactgtg 3781 tagtctacctgctcctgtactgtccttactgtatgtaaggatatacagacgcctgtgggt 3841 aggcagtactcacagtgagatgaagacagcaagtgtgcactgaaccacagagggcaggga 3901 gtagggcctctgaagaagccaccagaccagaccagtgccggtacagtctttgtcagagat 3961 ggctctgatggggcccagactgaccctgaccatgctgagttgctgagggtagccttcagt 4021 tctctaccctctgaagtgctaggatgacagacatccgccatcatacccagcttccgtggt 4081 gctaaggatcagcctcagtcttcaggcgtgctaggcatgtactttgccaagtatttagta 4141 tacaaaatacattagtatctgccagggaaaaaagatttgcaaataataaagattgccatc 4201 agtttgataaatgttgtaaatggaagaatcaaaatctcagcgatggattacagcaacaag 4261 atgctgcctaggaaaagcaggaccaagaggtacatttgactagtataccttcagcgtagc 4321 gtgatgacctcactgatgtcacccaactgaacttaagggctgtaagtaggcgtgctgtgg 4381 gccttccagaactagagaaaattataggaggaagtcagttctaaagtatcaaaagctggg 4441 taatggtggcacatgcctttgattctagcactcgggaagcaggggctagcctagtctaca 4501 gagcaacttctacacagagaaactgtcttggaggaaaataaaaaaagaaaagtcaaagag 4561 caaacaaatagaacagagtaggaatccgtgtccccttttttctatgtttcacggttgcag 4621 gtgtaagaaaagtagtcatagatgtggctgagtttctaagatgaaaccagtagtaagatt 4681 gctaaatataacacttcaaccaagttaaacaccctttgggggtatgaatgaaagtaacac 4741 tgcaatatgaaatgaaccgtgcaagtaacacttggggttacctcacagtctccctatgcc 4801 tgagaggactgtgggaaacatttccatcccctgccagtatcgccattgggaggacagagt 4861 agatgaagaagtgaagtcttactggtccagggcacgcctgtcagcaatgccatttgtgct 4921 tctgccacagagagcaccgagaggcttggctcagtatcctcgaaccttctctggtcactt 4981 ccctggcagcacttgggtccctgtcactcactggtctcttaaaagtcccgtctctttgct 5041 tcctaaagattctctaaaaaaattactattttttatttcttttttaaaagtctttgttat 5101 tttgttttgggatacagtctctttgtacagtcctggctggcctggaaattactatgtagg 5161 ccagcctcaaacttgaagtaattctcttgcctctgcctctggagttctgggattacaggc 5221 atgcactgcagagtacagtgagctctgatggcttttaaaattcagcccctttgagggttt 5281 ggttttagatccattagctttgtctgaacccatctttgtccggccgagtaaatcctctgc 5341 tatccggggtctcggtagaaatgtgttctcagtatacatacgactaaacattggttgttt 5401 ataggtagcctcagatatttggtagagcatcttttttgaaagtaatctccagctaggtgg 5461 gtatttccctcacagcagtaggattttccctttaggagataccagttcttcatctttctt 5521 gtgaaaataatgcctttatggggagtgaagattaaggagttgtttctacactaacagaat 5581 tctatttgatggacaacttggacagttctgtggacttgggtgggttctagtgtgctaaga 5641 aggataacagtatttaatagtgtctgtcatcaggccttgctcatctccctgtctagggct 5701 gtaggtcagtgctcgagcacttagcaggcatcgagtctagtgttcagtgcccagcattgc 5761 acagaactcagaatatatctgtactgaaactgaagtgaccacctacaaccaggtggtatg 5821 ccagaaccacagaaaggagattcacggtgatgtgtttaaagcattgggctggtgacggtt 5881 gctgtgtagtaatgacctcttcctcagcaaagagagtcctggagcaggctgtcctcagaa 5941 gagggaagggactggtgtgctccttgtgcagataacttagtgtataaatcggcatgagta 6001 gctatcctttaaggatttgtttgaagttactctttgtaaaaagttgagaattttgtgtgc 6061 agttgggcacatgcttgcccttcccccacccgccatagtcctgcctctcttgctgtgaac 6121 tggtgtcagctacaacactccagctaggtctgagctcttttgagagaaggtctcgtagag 6181 caccattctcagagagaagctaaagcatggggagccttaggacggtcaggcaatgcactc 6241 tttaccacggctggctaaggctgcagcttgaccgtccttacctaaatcaggtaagaatgt 6301 gattacagagcgagtgcttgtgttccccggcctgccttctccgaggaagatgcttcatcc 6361 gaggatgatgcagagcagacgatggctgcactgtaggtctgcctccttctgtgtatgggt 6421 tctgctgctgcttacggcataggaaagtacactagcagcgtgcttcaattctgccatctt 6481 ttgatacttataaaaatgtattaggttttactgtattgtgctctcaaagccataactctt 6541 aagaaatttggtttttttgcatattgtttgctaatactttgttttaataaacctcaaaat 6601 ctgcttac SEQIDNO:170MouseSMAD5aminoacidsequence(NP_001157513.1; NP_001157514.1;NP_032567.1) 1 mtsmaslfsftspavkrllgwkqgdeeekwaekavdalvkklkkkkgameelekalsspg 61 qpskcvtiprsldgrlqvshrkglphviycrvwrwpdlqshhelkpldicefpfgskqke 121 vcinpyhykrvespvlppvlvprhnefnpqhsllvqfrnlshnephmpqnatfpdsfhqp 181 nnapfplspnspyppspasstypnspassgpgspfqlpadtpppaymppddqmapdnsqp 241 mdtssnmipqtmpsissrdvqpvayeepkhwcsivyyelnnrvgeafhasstsvlvdgft 301 dpsnnksrfclgllsnvnrnstientrrhigkgvhlyyvggevyaeclsdssifvqsrnc 361 nfhhgfhpttvckipsscslkifnnqefaqllaqsvnhgfeavyeltkmctirmsfvkgw 421 gaeyhrqdvtstpcwieihlhgplqwldkvltqmgspinpissvs SEQIDNO:171HumanSMAD9transcriptvariant1cDNAsequence (NM_001127217.2;CDS:344-1747) 1 cgcactaatacgggcgatgaggcttcgcggctccagtctgactgacgccggctggggccg 61 ccgccgccgccgccgccgccgccgctgctgcagccgctgtctcggtccccgccgccgccg 121 ccgggccctgcaggcgctgggcgcgcgcagccaggcaagttggccaccctgttcaagggc 181 ttaggagaaagtcaacacacttcgcaacttgaattggtcccagctgctcccagaagaacg 241 ggcgggttggtccctatgccacccctggagagctactcgccgcccactttgccgtgaagg 301 gctgtgcggttcccgtgcgcgccggagcctgctgtggcctcttatgcactccaccacccc 361 catcagctccctcttctccttcaccagccccgcagtgaagagactgctaggctggaagca 421 aggagatgaagaggaaaagtgggcagagaaggcagtggactctctagtgaagaagttaaa 481 gaagaagaagggagccatggacgagctggagagggctctcagctgcccggggcagcccag 541 caaatgcgtcacgattccccgctccctggacgggcggctgcaggtgtcccaccgcaaggg 601 cctgccccatgtgatttactgtcgcgtgtggcgctggccggatctgcagtcccaccacga 661 gctgaagccgctggagtgctgtgagttcccatttggctccaagcagaaagaagtgtgcat 721 taacccttaccactaccgccgggtggagactccagtactgcctcctgtgctcgtgccaag 781 acacagtgaatataacccccagctcagcctcctggccaagttccgcagcgcctccctgca 841 cagtgagccactcatgccacacaacgccacctatcctgactctttccagcagcctccgtg 901 ctctgcactccctccctcacccagccacgcgttctcccagtccccgtgcacggccagcta 961 ccctcactccccaggaagtccttctgagccagagagtccctatcaacactcagttgacac 1021 accacccctgccttatcatgccacagaagcctctgagacccagagtggccaacctgtaga 1081 tgccacagctgatagacatgtagtgctatcgataccaaatggagactttcgaccagtttg 1141 ttacgaggagccccagcactggtgctcggtcgcctactatgaactgaacaaccgagttgg 1201 ggagacattccaggcttcctcccgaagtgtgctcatagatgggttcaccgacccttcaaa 1261 taacaggaacagattctgtcttggacttctttctaatgtaaacagaaactcaacgataga 1321 aaataccaggagacatataggaaagggtgtgcacttgtactacgtcgggggagaggtgta 1381 tgccgagtgcgtgagtgacagcagcatctttgtgcagagccggaactgcaactatcaaca 1441 cggcttccacccagctaccgtctgcaagatccccagcggctgcagcctcaaggtcttcaa 1501 caaccagctcttcgctcagctcctggcccagtcagttcaccacggctttgaagtcgtgta 1561 tgaactgaccaagatgtgtactatccggatgagttttgttaagggttggggtgctgagta 1621 tcatcgccaggatgtcaccagcaccccctgctggattgagattcatcttcatgggccact 1681 gcagtggctggacaaagttctgactcagatgggctctccacataaccccatttcttcagt 1741 gtcttaacagtcatgtcttaagctgcatttccataggatagaggctattgcagggagtgg 1801 cttgtatcatttcagatttgcaactgaagtttctaaaaacatgtgtaaatacatagaatg 1861 tatactgttcttattttttttaatcaccgtttgttttgtgctttctagttaacctgatgc 1921 cagtacagtgcaattggaaaagcaggactttggtgcctgtgctataagcagcagattttg 1981 tgggaggaaacacttgagaggcgatattgtcaacagtatttgaagggtgttagcagaata 2041 aaagacagctttagtcagccgtgtcattataaagcatgttgtgtggcctcacagaaacat 2101 tgaaactgtttatacagcaaaagtcaggtattagcagcactaaagcaaatatcactcaga 2161 tgaaacaaagcagtgaaacccctacagtttaaatgatgtcacttttagtgctgttggcaa 2221 gaaaaaaaaaacaacaaacttgtacaatgaattaatgagataggccatagaaactttatt 2281 tctaaggttgacatacctatagctgggctcctgtgctcatattcagtggtacattttaaa 2341 caaactgtgatcggaaaagaaaaaaaactgtgaagccaaaagtcatgttccctcagtcta 2401 ccactgtaaaaacagagtctaatatgggaaaataaatatgaaaatagcatgaaatgctgt 2461 ttcccagattgcaagataagaccagaacttggtccaagagccagccacccagggagactc 2521 ctgctttccacagaggagaccaggttcctgtcgtgctggttgttcgtgtcaggcagtcct 2581 gcaaactttgagtctgcgcagcgtgccagaatagcttgtgtttcagtcctgtgtcaagaa 2641 gcaggtgaaaccaaaggttggagaaaagcatcacacgtcgacttacactttctcatttcc 2701 cacgttccagtctcctgggaagggcactctttcgccacgttttcctgcctcttggcaaat 2761 attaactctttgcagatcactaaagcaacagtaaagactttgagaaaatctagacacatt 2821 attggatcaatgagttatttaacctagtgtctagtgattatctaacctggaaataaattc 2881 ccaaggaaagtgataataatttcataatcatctgcaatttctggggaacagtggtactga 2941 ataataagacatcttttaaaaatatacacaatattaaaaacctgttcttattttacttta 3001 gatgagggaggaaaatcccccaaatttctaggtactttcatatatatacttgccatgcac 3061 taaacactgcattgcttggaaaaatatttcacaccctctttaaaaatgtacaatttaaga 3121 tggcagttatgcttgtaacagacagcacttcagtaatccaagaagtttcttcatttatac 3181 attttatctcaactctttctagcattagtgcacatggtagtttttctaattaaattgtat 3241 tcaaggtagaaatgatcatgtgagaaagatatatgattgagctactactgtcacctctta 3301 cagttactagtgttagctaatagaaactttcatatatacacatagaaaagaattattaca 3361 ttttacattgaaaaatgtaatatatggcccatgtagtgtatagaaaaatctgtagtttat 3421 tggttcatcaactatgtattgtgcacctacctatgggtgtcaggtacaatgttaggtact 3481 gtagaatcaaatgtaaataagagacagtcccagccctcagggagccgagaacctaatagt 3541 gaatctgtttgtacagacatcttcatgtttcagaacttttaaaacaaaacaaaataatgt 3601 aatctatcatcttttgcttgaaagaatgtgattgatttcttatctctgttttgaaattat 3661 ttccttactcttctgcaaagtcaggtaatggattccttgtataaatgctacttttcttcc 3721 atgtctcaaagttgttttttttcctcccctttcttccctgttttccaataattctccatg 3781 tccccttttcttagaaaaggcattaatatggtgaatcttgtatgggaaccattccatggg 3841 agaacttcaacacagtttttgctccagagatcaaacatagctttcgtgatctctctacca 3901 gctatctaacttatcctctggtaatctttttttttttttttttttttttgagatggagtc 3961 tcgctgtgtcaccaggccagagtgcagtggcgtgatcttggctcactgcaacctctgcct 4021 cccgggttcgagtgattctcctgcctcagcctcccaagtagttgggactacaggctacca 4081 cgcccagctaatttttatatttttagtagagacggggtttcaccatggtagccagaatgg 4141 tctctatctcttgaccttgtgatccgcccgcctcagcctcccaaagtgctgggattacag 4201 gcgtgagccactgcgcccggcttcctctggtaatcttacacctttacagaattaatctaa 4261 actggtggctcataaatgacattaaaaacaaaaaaaaaatctggatgcagtggctcattc 4321 ctatagtcccagcactttgggaggccaaggcgggaggatcatctgagcccaggagtttgg 4381 ggctgtagtgaactatgatcatacaacttcattctagcctgggtgacaaagtgacaccct 4441 gtctctaaacaaaaatcaagaaacaaaaaacttgtatttccctgcagctttgggaagcca 4501 gaacacaatattgcagtgaatctgaattttctgtgacaaataaattattaaattggcaca 4561 tatgatcatcaccagtcatgtctcatcaaaagcctttattatgatgcttgtacattttga 4621 agaatttagaattaatgagaagttaaccctttagtcattgtaacacaatcatattttaat 4681 cagctttttcttttgctaccaagagtttcaaaaaataaatgcagtatttgatttcaggct 4741 gctaaatgggctcatttagcattcattccttgatgtagacattaaaaaaaaaactgaata 4801 gcattctttccaggataactaataaagcagacatgctaagcctataaatacatcagcact 4861 gcagcacacgtttaaggttgccacggacaaggatcacacaatagagaacactgtagtaac 4921 atttcggtctgctcacaagacccagaacattgatcagtttttgttgttggtttattattt 4981 ttctgttaaaaaattgtgaaaagtttgttttagctagatgatattttaatagctgcgagt 5041 gctttggaactataaagatgtcactacttaacacatataccttatgttttgttttgtttt 5101 gttttacactcagtataaatcaggagaagttagccaaccatctagcatttagaatcctct 5161 tttttattgtcttctaaggatatggatgttcccataacagcaacaaaacagcaacaaaaa 5221 catttcataaatatcacttgatagactgtaagcacctgcttaactttgtgtcccaaatat 5281 ttagtgtgtatatatatatatatatatacacacacacacacatatatattcaacaaataa 5341 agcaaaatataacatgcatttcacattttgtctttccctgttacgattttaatagcagaa 5401 ctgtatgacaagtttaggtgatcctagcatatgttaaattcaaattaatgtaaaacagat 5461 taacaacaacaaagaaactgtctatttgagtgaagtcatgctttctattataataacttg 5521 gcttcggttatccatcaaatgcacacttatactgttatctgattgtttataataaagaat 5581 actgtacttata SEQIDNO:172HumanSMAD9isoform1aminoacidsequence(NP_001120689.1) 1 mhsttpisslfsftspavkrllgwkqgdeeekwaekavdslvkklkkkkgamdelerals 61 cpgqpskcvtiprsldgrlqvshrkglphviycrvwrwpdlqshhelkpleccefpfgsk 121 qkevcinpyhyrrvetpvlppvlvprhseynpqlsllakfrsaslhseplmphnatypds 181 fqqppcsalppspshafsqspctasyphspgspsepespyqhsvdtpplpyhateasetq 241 sgqpvdatadrhvvlsipngdfrpvcyeepqhwcsvayyelnnrvgetfqassrsvlidg 301 ftdpsnnrnrfclgllsnvnrnstientrrhigkgvhlyyvggevyaecvsdssifvqsr 361 ncnyqhgfhpatvckipsgcslkvfnnqlfaqllaqsvhhgfevvyeltkmctirmsfvk 421 gwgaeyhrqdvtstpcwieihlhgplqwldkvltqmgsphnpissvs SEQIDNO:173HumanSMAD9transcriptvariant2cDNAsequence(NM_005905.6; CDS:310-1602) 1 agtctgactgacgccggctggggccgccgccgccgccgccgccgccgccgctgctgcagc 61 cgctgtctcggtccccgccgccgccgccgggccctgcaggcgctgggcgcgcgcagccag 121 gcaagttggccaccctgttcaagggcttaggagaaagtcaacacacttcgcaacttgaat 181 tggtcccagctgctcccagaagaacgggcgggttggtccctatgccacccctggagagct 241 actcgccgcccactttgccgtgaagggctgtgcggttcccgtgcgcgccggagcctgctg 301 tggcctcttatgcactccaccacccccatcagctccctcttctccttcaccagccccgca 361 gtgaagagactgctaggctggaagcaaggagatgaagaggaaaagtgggcagagaaggca 421 gtggactctctagtgaagaagttaaagaagaagaagggagccatggacgagctggagagg 481 gctctcagctgcccggggcagcccagcaaatgcgtcacgattccccgctccctggacggg 541 cggctgcaggtgtcccaccgcaagggcctgccccatgtgatttactgtcgcgtgtggcgc 601 tggccggatctgcagtcccaccacgagctgaagccgctggagtgctgtgagttcccattt 661 ggctccaagcagaaagaagtgtgcattaacccttaccactaccgccgggtggagactcca 721 gtactgcctcctgtgctcgtgccaagacacagtgaatataacccccagctcagcctcctg 781 gccaagttccgcagcgcctccctgcacagtgagccactcatgccacacaacgccacctat 841 cctgactctttccagcagcctccgtgctctgcactccctccctcacccagccacgcgttc 901 tcccagtccccgtgcacggccagctaccctcactccccaggaagtccttctgagccagag 961 agtccctatcaacactcagactttcgaccagtttgttacgaggagccccagcactggtgc 1021 tcggtcgcctactatgaactgaacaaccgagttggggagacattccaggcttcctcccga 1081 agtgtgctcatagatgggttcaccgacccttcaaataacaggaacagattctgtcttgga 1141 cttctttctaatgtaaacagaaactcaacgatagaaaataccaggagacatataggaaag 1201 ggtgtgcacttgtactacgtcgggggagaggtgtatgccgagtgcgtgagtgacagcagc 1261 atctttgtgcagagccggaactgcaactatcaacacggcttccacccagctaccgtctgc 1321 aagatccccagcggctgcagcctcaaggtcttcaacaaccagctcttcgctcagctcctg 1381 gcccagtcagttcaccacggctttgaagtcgtgtatgaactgaccaagatgtgtactatc 1441 cggatgagttttgttaagggttggggtgctgagtatcatcgccaggatgtcaccagcacc 1501 ccctgctggattgagattcatcttcatgggccactgcagtggctggacaaagttctgact 1561 cagatgggctctccacataaccccatttcttcagtgtcttaacagtcatgtcttaagctg 1621 catttccataggatagaggctattgcagggagtggcttgtatcatttcagatttgcaact 1681 gaagtttctaaaaacatgtgtaaatacatagaatgtatactgttcttattttttttaatc 1741 accgtttgttttgtgctttctagttaacctgatgccagtacagtgcaattggaaaagcag 1801 gactttggtgcctgtgctataagcagcagattttgtgggaggaaacacttgagaggcgat 1861 attgtcaacagtatttgaagggtgttagcagaataaaagacagctttagtcagccgtgtc 1921 attataaagcatgttgtgtggcctcacagaaacattgaaactgtttatacagcaaaagtc 1981 aggtattagcagcactaaagcaaatatcactcagatgaaacaaagcagtgaaacccctac 2041 agtttaaatgatgtcacttttagtgctgttggcaagaaaaaaaaaacaacaaacttgtac 2101 aatgaattaatgagataggccatagaaactttatttctaaggttgacatacctatagctg 2161 ggctcctgtgctcatattcagtggtacattttaaacaaactgtgatcggaaaagaaaaaa 2221 aactgtgaagccaaaagtcatgttccctcagtctaccactgtaaaaacagagtctaatat 2281 gggaaaataaatatgaaaatagcatgaaatgctgtttcccagattgcaagataagaccag 2341 aacttggtccaagagccagccacccagggagactcctgctttccacagaggagaccaggt 2401 tcctgtcgtgctggttgttcgtgtcaggcagtcctgcaaactttgagtctgcgcagcgtg 2461 ccagaatagcttgtgtttcagtcctgtgtcaagaagcaggtgaaaccaaaggttggagaa 2521 aagcatcacacgtcgacttacactttctcatttcccacgttccagtctcctgggaagggc 2581 actctttcgccacgttttcctgcctcttggcaaatattaactctttgcagatcactaaag 2641 caacagtaaagactttgagaaaatctagacacattattggatcaatgagttatttaacct 2701 agtgtctagtgattatctaacctggaaataaattcccaaggaaagtgataataatttcat 2761 aatcatctgcaatttctggggaacagtggtactgaataataagacatcttttaaaaatat 2821 acacaatattaaaaacctgttcttattttactttagatgagggaggaaaatcccccaaat 2881 ttctaggtactttcatatatatacttgccatgcactaaacactgcattgcttggaaaaat 2941 atttcacaccctctttaaaaatgtacaatttaagatggcagttatgcttgtaacagacag 3001 cacttcagtaatccaagaagtttcttcatttatacattttatctcaactctttctagcat 3061 tagtgcacatggtagtttttctaattaaattgtattcaaggtagaaatgatcatgtgaga 3121 aagatatatgattgagctactactgtcacctcttacagttactagtgttagctaatagaa 3181 actttcatatatacacatagaaaagaattattacattttacattgaaaaatgtaatatat 3241 ggcccatgtagtgtatagaaaaatctgtagtttattggttcatcaactatgtattgtgca 3301 cctacctatgggtgtcaggtacaatgttaggtactgtagaatcaaatgtaaataagagac 3361 agtcccagccctcagggagccgagaacctaatagtgaatctgtttgtacagacatcttca 3421 tgtttcagaacttttaaaacaaaacaaaataatgtaatctatcatcttttgcttgaaaga 3481 atgtgattgatttcttatctctgttttgaaattatttccttactcttctgcaaagtcagg 3541 taatggattccttgtataaatgctacttttcttccatgtctcaaagttgttttttttcct 3601 cccctttcttccctgttttccaataattctccatgtccccttttcttagaaaaggcatta 3661 atatggtgaatcttgtatgggaaccattccatgggagaacttcaacacagtttttgctcc 3721 agagatcaaacatagctttcgtgatctctctaccagctatctaacttatcctctggtaat 3781 ctttttttttttttttttttttttgagatggagtctcgctgtgtcaccaggccagagtgc 3841 agtggcgtgatcttggctcactgcaacctctgcctcccgggttcgagtgattctcctgcc 3901 tcagcctcccaagtagttgggactacaggctaccacgcccagctaatttttatattttta 3961 gtagagacggggtttcaccatggtagccagaatggtctctatctcttgaccttgtgatcc 4021 gcccgcctcagcctcccaaagtgctgggattacaggcgtgagccactgcgcccggcttcc 4081 tctggtaatcttacacctttacagaattaatctaaactggtggctcataaatgacattaa 4141 aaacaaaaaaaaaatctggatgcagtggctcattcctatagtcccagcactttgggaggc 4201 caaggcgggaggatcatctgagcccaggagtttggggctgtagtgaactatgatcataca 4261 acttcattctagcctgggtgacaaagtgacaccctgtctctaaacaaaaatcaagaaaca 4321 aaaaacttgtatttccctgcagctttgggaagccagaacacaatattgcagtgaatctga 4381 attttctgtgacaaataaattattaaattggcacatatgatcatcaccagtcatgtctca 4441 tcaaaagcctttattatgatgcttgtacattttgaagaatttagaattaatgagaagtta 4501 accctttagtcattgtaacacaatcatattttaatcagctttttcttttgctaccaagag 4561 tttcaaaaaataaatgcagtatttgatttcaggctgctaaatgggctcatttagcattca 4621 ttccttgatgtagacattaaaaaaaaaactgaatagcattctttccaggataactaataa 4681 agcagacatgctaagcctataaatacatcagcactgcagcacacgtttaaggttgccacg 4741 gacaaggatcacacaatagagaacactgtagtaacatttcggtctgctcacaagacccag 4801 aacattgatcagtttttgttgttggtttattatttttctgttaaaaaattgtgaaaagtt 4861 tgttttagctagatgatattttaatagctgcgagtgctttggaactataaagatgtcact 4921 acttaacacatataccttatgttttgttttgttttgttttacactcagtataaatcagga 4981 gaagttagccaaccatctagcatttagaatcctcttttttattgtcttctaaggatatgg 5041 atgttcccataacagcaacaaaacagcaacaaaaacatttcataaatatcacttgataga 5101 ctgtaagcacctgcttaactttgtgtcccaaatatttagtgtgtatatatatatatatat 5161 atacacacacacacacatatatattcaacaaataaagcaaaatataacatgcatttcaca 5221 ttttgtctttccctgttacgattttaatagcagaactgtatgacaagtttaggtgatcct 5281 agcatatgttaaattcaaattaatgtaaaacagattaacaacaacaaagaaactgtctat 5341 ttgagtgaagtcatgctttctattataataacttggcttcggttatccatcaaatgcaca 5401 cttatactgttatctgattgtttataataaagaatactgtacttata SEQIDNO:174HumanSMAD9isoform2aminoacidsequence(NP_005896.1) 1 mhsttpisslfsftspavkrllgwkqgdeeekwaekavdslvkklkkkkgamdelerals 61 cpgqpskcvtiprsldgrlqvshrkglphviycrvwrwpdlqshhelkpleccefpfgsk 121 qkevcinpyhyrrvetpvlppvlvprhseynpqlsllakfrsaslhseplmphnatypds 181 fqqppcsalppspshafsqspctasyphspgspsepespyqhsdfrpvcyeepqhwcsva 241 yyelnnrvgetfqassrsvlidgftdpsnnrnrfclgllsnvnrnstientrrhigkgvh 301 lyyvggevyaecvsdssifvqsrncnyqhgfhpatvckipsgcslkvfnnqlfaqllaqs 361 vhhgfevvyeltkmctirmsfvkgwgaeyhrqdvtstpcwieihlhgplqwldkvltqmg 421 sphnpissvs SEQIDNO:175MouseSMAD9cDNAsequence(NM_019483.5;CDS:320-1612) 1 agcctgactgacgcctctggagccgctgtctcggtcccgccgccgcccggccgaccctgc 61 agctaccgcgcaaccggagtgcgcggggggcacgcgtggcacctctcggacagagtaagc 121 tggctccactttccaagagctttggaagacgtcagcccatctcccagtttgaatcggacc 181 ccactgcttccagaaggaaaggcaagcttgttcctatgacatccgtggacaggtacttgc 241 cgccgacctgcccggggccctgcaagccttgaaaggtctcatcctctttccccgtgcagc 301 agcctgagctctgcctcctatgcaccccagcacccccatcagctccctcttctccttcac 361 cagccccgcagtgaagcggctgctgggctggaagcagggagatgaagaggagaagtgggc 421 agagaaggcggtggactctttggtgaagaagttaaagaagaagaaaggcgccatggatga 481 actggagagggcgctgagctgcccgggtcagcctagcaagtgtgtcaccatcccacggtc 541 cctcgatggacgcctccaggtgtcccaccgaaaggggctgccccacgtcatctactgccg 601 cgtgtggcgctggccagacctgcagtcccatcatgagctgaagcccttggagtgctgtga 661 gttcccgttcggctccaagcagaaggaggtctgcatcaacccataccattaccgcagagt 721 ggagaccccagttctgcctccagtgctggtaccaagacacagcgagtacaaccctcagct 781 cagcctcctggccaagttccgaagtgcctcgctgcacagcgaacccctcatgccgcacaa 841 cgccacctaccctgactctttccagcagtctctctgtccggcaccgccctcctcgccagg 901 ccatgtgtttccgcagtctccatgccccaccagctacccgcactcccccggaagtccttc 961 cgagtcagacagtccctatcaacactcagacttccggccagtttgctacgaggaacccca 1021 gcactggtgttctgttgcctactacgaactaaacaaccgggtcggagagactttccaggc 1081 gtcctcgcggagcgtgctcatagacggcttcaccgacccttccaataacaggaataggtt 1141 ctgccttgggcttctctcaaatgtaaacagaaactcgaccatagaaaacaccaggaggca 1201 cattggaaagggtgtgcatttgtactacgttgggggcgaggtgtatgcggagtgcgtgag 1261 cgacagcagcatctttgtccagagccggaactgcaactaccagcacggcttccacccggc 1321 caccgtctgcaagatccccagcggctgcagcctcaaggtcttcaacaaccagctcttcgc 1381 ccagctgctcgcccagtccgtgcaccacggctttgaagtggtgtatgagctgacgaagat 1441 gtgcacgattcggatgagctttgtgaagggctggggagcagagtatcatcgccaggatgt 1501 cacgagcaccccctgctggatcgagatccatcttcatggaccgctgcagtggttggataa 1561 ggtgctcactcagatgggctccccacacaaccctatctcttcagtgtcttaagtcacgtc 1621 gtcagccacgttgccacagaacagactcgggcaggggcttccatcgtggcaaccgcagct 1681 aatgcagggttccggatgcagatgtaaatacacgtgtaacgcatccgagtcacgtttata 1741 tcaccgtttgttttgtgctacctacttaacctggggccagtgcggtgtggtcgaagaagc 1801 gtggtttctctctgatgggagccaagtcttctgtgagagggaaacagcacgtgagggcgt 1861 cggcaggactcaaggccaccgagtcagctcatcgtcactccacaggaggttgtgccccac 1921 atggaaaacacaaagctgcttacacagaaggaataggagcactagagcaaaatcagtcac 1981 acacaagtggttttaaaaagacctcacttgcaatgtgagtgtcaagaaagaaaaccaagc 2041 ttgtccagggacctgtgagataaagccacagaaactttatctccgaagctgaaatacaca 2101 tagccaggtactgtgctgacggcaggtacattcaaccagatctaaactgtgattggagag 2161 ggagaaactgtgaagcttggagtcagtggcctcaatctaaaacaagcaagcaggcaggca 2221 ggcaggcgggcgggcgggcgggcaggcgggtgggcaggcaggcaagcaaagccaaggctc 2281 ttaagggaaaccggcctgagaggaggcttgatccagggttagcccagaattcaggcccgg 2341 aagcacagggaactcctgcgtccactctggaagccatcttcccgtcttcccgtccctcct 2401 gtctgaccttgcagatggctgcctgccctgtgcacactacaaaccccgtgcagagatgaa 2461 gctgtagactggaaggttgggagggaagtgcaggctaggcagggcatcccttgcctcatt 2521 tttcctcctggtgacaaatagcaattagtgacagatgattcaaacaagagcaaagccttg 2581 ggaaagctcgaggcatctttggatcttatttatgcatctctcagcctggcacctatgtta 2641 agttattagctggttacatcagtgcagcctcttctaaagctattaaatacctggatatag 2701 cttcccaggtgaagtaggaatgtttcatatgccctacatttttttatttttatgaggaaa 2761 cagtggtagtgaataataaagcatctttaaaaaacaccttatgtgtatatagacatgcat 2821 atatcagctcattccctctgttggatgataagggaaatatcctccagacttcaaggtaca 2881 tgccactcattaggcaccccattgcttctaagtttacttcaagccctttgaaaaggatta 2941 tgtaggatggcatttattgtttaaaggatagagcttccataatatgatagagatattata 3001 tcggaaactcatttcgtctcaaactaccacttagagtgtataagaaaaaaaacccaagca 3061 tgtcgattcattaagtctgtcttgtgcatttgtgtgtactgggtacagtgtcaggtacca 3121 gggaatcaaacgcacattagaggcagtccccacctccataacgccagacatctaacggta 3181 aaccatttgcacagacatcaggtctcagaactttaaaaaccccacacatgtgaatcttct 3241 tgggctcgaaaaataacataatcgagttctgaacaatagttaagaactctattgtaataa 3301 ctatattgggattttatgtctcctcagaacacttgagtaatttatcttttcataactact 3361 tccattcctagccaccccacctcctggaatccctatttttttctgatatttctcctggtt 3421 tcttccttggaaaagccatgtgtacccatctaaggacacaaagcattgtcccagatttcc 3481 caccgcccctttgatctcctcacaagtggccaaatatccctggcaatctgtagttgtaag 3541 aaactattcaggagtaggagcttcagggtgtagtggtaccgtggtacctgcctttgatct 3601 cagcagcagggagacagaggcaggtggatccctgtgaattcaggcctgacctggtctata 3661 taaggagttacaggacagccagggctatacactgaaaccctgtctcaaaacaaaagtaga 3721 agcttaaaaacaaaactaaaaaccaaacaaacaagtaaactacttggacttccttgcagt 3781 gttaagaaatcaaaatattgaagcgtgtctgatttctttgagaaaggaatcatgacctag 3841 gttcatatgtatattatcagagaatttagctttgaagagatataagtcctatgcttgtat 3901 agcagagtcacattttaatgaattttccccctttggctgttaagagatctaaacgtatca 3961 taacgtaatccttgacttcaactcctctgagtgaccatgtggcgatcattccatgaagct 4021 gacaagcaaacttatgctgcgtaggttgttttacagggtgaaggggaaagtgggcagcca 4081 ggcctttgcacactgcaagttgcctcaggcagggtcaggcaatggagatctgtatcggtt 4141 tggcttgcccacaagacccagaatgtttatcactgtgtacaagtcagtatgtgtgagtct 4201 tagcaaaaataagacatgatcagtttgtttcagctaagtgattacaactgtttcagaact 4261 aagaagacaccaccttgttaacatacacacttcggtgttgtgttgtagagtcagcaaaac 4321 tctctagcatttagaatattcttttcattgtgttctaagggtggagttatcctcataacg 4381 acaacagaaagaagagtagcaaaatcattttataaaaatcgcttgctggactttaagctc 4441 ctgcttaatgctgagtatgttccagatatttcatgtatgtatttaataaagtaaaatata 4501 ccatgcattccacatcgtcttacctgctagagtcaagagccgaactttgcaagggtaggt 4561 aaccctcacatatgttcataataagttctttttttggggggagagggaggttcaagacag 4621 ggtttctctgtatagccctggctgtcctggaactcgctttgtagaacaggctggcctcaa 4681 actcagaaatctgcttgcctctgcctcccgagtgctgggattaaaggcgtgcaccaccac 4741 gtccggctctcatgataaattcgaatgtatataaaacagacagccaagattactctttga 4801 ttcccagaagccttgccttcctgaaatgccacacaccacactttggtagtctgtgctaga 4861 caatgatacaccttttggcttatttttctttcaaactctaggaaatacttctatgtatat 4921 gatctatggctccttaagatgcttaatcataaactgttctacttagaaaatgagcttttt 4981 aagaagtcttcatgctgtaaaaactttggtggcactataacaaaaaagacatcttcgaat 5041 atttggcattaatgtgtaattttaatgatactttgcagaatttttagaggtgtttaacta 5101 ctgctccccagcttagcaccaggacacacaactcaaaccctttgtatggtaaagctgttg 5161 ttattaaaaagtgaatttaatacacactgtcgtttgagcatcctaccttagcaactcaac 5221 agccacgtccatcaaggaacatgtctataggaagatgtttagcatgtgatgcttaaaaca 5281 cctggatatataggggaactttcactaaaaactcatttatttttcatatgccatgaaata 5341 tgtttaactgattaaaatgttttctaagagaagcttgtga SEQIDNO:176MouseSMAD9aminoacidsequence(NP_062356.3) 1 mhpstpisslfsftspavkrllgwkqgdeeekwaekavdslvkklkkkkgamdelerals 61 cpgqpskcvtiprsldgrlqvshrkglphviycrvwrwpdlqshhelkpleccefpfgsk 121 qkevcinpyhyrrvetpvlppvlvprhseynpqlsllakfrsaslhseplmphnatypds 181 fqqslcpappsspghvfpqspcptsyphspgspsesdspyqhsdfrpvcyeepqhwcsva 241 yyelnnrvgetfqassrsvlidgftdpsnnrnrfclgllsnvnrnstientrrhigkgvh 301 lyyvggevyaecvsdssifvqsrncnyqhgfhpatvckipsgcslkvfnnqlfaqllaqs 361 vhhgfevvyeltkmctirmsfvkgwgaeyhrqdvtstpcwieihlhgplqwldkvltqmg 421 sphnpissvs

(129) Included in Table 1 are nucleic acid molecules comprising a nucleic acid sequence having at least 30%, 40%, 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or more identity to the region encoding the DNA binding domain or across their full length with a nucleic acid sequence of any SEQ ID NO listed in Table 1. Such nucleic acid molecules can encode a polypeptide having a function of the full-length polypeptide as described further herein.

(130) Included in Table 1 are polypeptide molecules comprising an amino acid sequence having at least 30%, 40%, 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more identity to the DNA binding domain or across their full length with an amino acid sequence of any SEQ ID NO listed in Table 1. Such polypeptides can have a function of the full-length polypeptide as described further herein.

(131) TABLE-US-00003 TABLE2 Smad6 Smad7 SEQIDNO:177HumanSmad6cDNAsequence(NM_005585.5;CDS:1024-2514) 1 atatgatgggaggcagccaatgactccgcggcgctcctccgggggccctcagtgtgcgtt 61 tgaggagaacaaaaaagagagagagagccgagcgggggagcgatcgagggagctgagccg 121 agagaaagagccgccgggcgctgcctcgccagacctcgctgggaccccggggccaccggg 181 aggcacttttgtggaggggggagggggggcgacctcggcagcctcggcgcacgaagcgtc 241 cgagggcagcgtggggcgggctgcgacctctgcatcggtggactgcatttttaattaagg 301 attcccagcagctctttgggatttttacagcttccactcatgtgttgacacccgcgtcca 361 ggagaaactcgctccaagtgcatctagcgcctgggacctgagacggcgttggcctttcgt 421 gcatgcaaatccagggatttaggttttgtttgggatttccttttctttctttcctttttt 481 ttttctttttgcagggagtaagaagggagctgggggtatcaacaagcctgcctttcggat 541 cctgcgggaaaagcccatgtagttaagcgctttggtttaaaaaaaaggcaaggtaaaggc 601 agggctttccagacacatttaggggttcgcgcgagcgctttgtgctcatggaccagccgc 661 acaacttttgaaggctcgccggcccatgtggggtctttctggcggcgcgccgcctgcagc 721 ccccctaaagcgcgggggctggagttgttgagcagccccgccgctgtggtccatgtagcc 781 gctggccgcgcgcggactgcggctcggcgtgcgcgtgttcccggccgtcccgcctcggcg 841 agctccctcatgttgtcgccctgcggcgccccttcgacgacaggctgtgcgcggtctgca 901 cggcgctccgcggcggagcttcatgtggggctgcgacccgcgcagccggcgcctcgctga 961 gggaacggacccccggtaaccggagaccgcctcccccccacccctggcgccaaaggatat 1021 cgtatgttcaggtccaaacgctcggggctggtgcggcgactttggcgaagtcgtgtggtc 1081 cccgaccgggaggaaggcggcagcggcggcggcggtggcggcgacgaggatgggagcttg 1141 ggcagccgagctgagccggccccgcgggcaagagagggcggaggctgcggccgctccgaa 1201 gtccgcccggtagccccgcggcggccccgggacgcagtgggacagcgaggcgcccagggc 1261 gcggggaggcgccggcgcgcagggggccccccgaggcccatgtcggagccaggggccggc 1321 gctgggagctccctgctggacgtggcggagccgggaggcccgggctggctgcccgagagt 1381 gactgcgagacggtgacctgctgtctcttttcggagcgggacgccgccggcgcgccccgg 1441 gacgccagcgaccccctggccggggcggccctggagccggcgggcggcgggcggagtcgc 1501 gaagcgcgctcgcggctgctgctgctggagcaggaactcaaaaccgtcacgtactcgctg 1561 ctgaagcggctcaaggagcgctcgctggacacgctgctggaggcggtggagtcccgcggc 1621 ggcgtgccgggcggctgcgtgctggtgccgcgcgccgacctccgcctgggcggccagccc 1681 gcgccgccgcagctgctgctcggccgcctctttcgctggcccgacctgcagcacgccgtg 1741 gagctgaagcccctgtgcggctgccacagcttcgccgccgccgccgacggccctaccgtg 1801 tgctgcaacccctaccacttcagccggctctgcgggcccgaatctccgccacctccctac 1861 tctcggctgtctcctcgcgacgagtacaagccactggatctgtccgattccacattgtct 1921 tacactgaaacggaggctaccaactccctcatcactgctccgggtgaattctcagacgcc 1981 agcatgtctccggacgccaccaagccgagccactggtgcagcgtggcgtactgggagcac 2041 cggacgcgcgtgggccgcctctatgcggtgtacgaccaggccgtcagcatcttctacgac 2101 ctacctcagggcagcggcttctgcctgggccagctcaacctggagcagcgcagcgagtcg 2161 gtgcggcgaacgcgcagcaagatcggcttcggcatcctgctcagcaaggagcccgacggc 2221 gtgtgggcctacaaccgcggcgagcaccccatcttcgtcaactccccgacgctggacgcg 2281 cccggcggccgcgccctggtcgtgcgcaaggtgccccccggctactccatcaaggtgttc 2341 gacttcgagcgctcgggcctgcagcacgcgcccgagcccgacgccgccgacggcccctac 2401 gaccccaacagcgtccgcatcagcttcgccaagggctgggggccctgctactcccggcag 2461 ttcatcacctcctgcccctgctggctggagatcctcctcaacaaccccagatagtggcgg 2521 ccccggcgggaggggcgggtgggaggccgcggccaccgccacctgccggcctcgagaggg 2581 gccgatgcccagagacacagcccccacggacaaaaccccccagatatcatctacctagat 2641 ttaatataaagttttatatattatatggaaatatatattatacttgtaattatggagtca 2701 tttttacaatgtaattatttatgtatggtgcaatgtgtgtatatggacaaaacaagaaag 2761 acgcactttggcttataattctttcaatacagatatattttctttctcttcctccttcct 2821 cttccttactttttatatatatatataaagaaaatgatacagcagagctaggtggaaaag 2881 cctgggtttggtgtatggtttttgagatattaatgcccagacaaaaagctaataccagtc 2941 actcgataataaagtattcgcattatagttttttttaaactgtcttctttttacaaagag 3001 gggcaggtagggcttcagcggatttctgacccatcatgtaccttgaaacttgacctcagt 3061 tttcaagttttacttttattggataaagacagaacaaattgaaaagggaggaaagtcaca 3121 tttactcttaagtaaaccagagaaagttctgttgttccttcctgcccatggctatggggt 3181 gtccagtggatagggatggcggtggggaaaagaatacactggccatttatcctggacaag 3241 ctcttccagtctgatggaggaggttcatgccctagcctagaaaggcccaggtccatgccc 3301 cccatctttgagttatgagcaagctaaaagaagacactatttctcaccattttgtggaaa 3361 tggcctggggaacaaagactgaaatgggccttgagcccacctgctaccttgcagagaacc 3421 atctcgagccccgtagatctttttaggacctccacaggctatttcccaccccccagccaa 3481 aaatagctcagaatctgcccatccagggctgtattaatgatttatgtaaaggcagatggt 3541 ttatttctactttgtgaaagggaaaagttgaggttctggaaggttaaatgatttgctcat 3601 gagacaaaatcaaggttagaagttacatggaattgtaggaccagagccatatcattagat 3661 cagctttctgaagaatattctcaaaaaaagaaagtctccttggccagataactaagagga 3721 atgtttcattgtatatcttttttcttggagatttatattaacatattaagtgctctgaga 3781 agtcctgtgtattatctcttgctgcataataaattatccccaaactta SEQIDNO:178HumanSmad6aminoacidsequence(NP_005576.3) 1 mfrskrsglvrrlwrsrvvpdreeggsggggggdedgslgsraepapraregggcgrsev 61 rpvaprrprdavgqrgaqgagrrrraggpprpmsepgagagsslldvaepggpgwlpesd 121 cetvtcclfserdaagaprdasdplagaalepagggrsrearsrlllleqelktvtysll 181 krlkersldtlleavesrggvpggcvlvpradlrlggqpappqlllgrlfrwpdlqhave 241 lkplcgchsfaaaadgptvccnpyhfsrlcgpesppppysrlsprdeykpldlsdstlsy 301 teteatnslitapgefsdasmspdatkpshwcsvaywehrtrvgrlyavydqavsifydl 361 pqgsgfclgqlnleqrsesvrrtrskigfgillskepdgvwaynrgehpifvnsptldap 421 ggralvvrkvppgysikvfdfersglqhapepdaadgpydpnsvrisfakgwgpcysrqf 481 itscpcwleillnnpr SEQIDNO:179MouseSmad6cDNAsequence(NM_008542.3;CDS:1036-2523) 1 agactggcatatgatgggaggcagccaatgactccgcggcgctcctccgggggccctcag 61 tgtgcgtttgaggagaacaaaaaagagagagagcgccgagagggggaacgagcgagggag 121 ctgagtccagagaaagagccgccgggcgctgcctcgccaaacctcgctgggaccgcgggg 181 ccaccaggaggcactttggtgaaggggggggggggcgacctcggcagccgcggcgcccga 241 agcgacccagcgcagcgtggggcgggctgcgacctctgcttcggtggattgcatttttaa 301 ttaaggattcctagcagctctttgggattttttttttccggcttccactcatgtgttgac 361 acccgcgttcaggagagacttgccccaagtgcaccgagcgcccgggacctgagacggaat 421 tgcttttcgtgcgtgcaaaatccaagcattttgagttttgtttgggacctttttcttgct 481 ttgcttttatttctatttttattttgttgcagggatatgggagttatccacaagccttag 541 tttcggatcctgcagggaaagcccatgtagcatagcttggcttttgaaggcagagttgtg 601 cagacacatttgggggcacgacgcaagcgctttgtgctcgtgtaccagccgcgcaacttt 661 tgaaggctcgccggcccatgcagggtgtctctagcatcgtttcgctggtggcttccctaa 721 ggctccaaagcagctggagttgagcggtcccggcccatcgtgatccatgtagcccgctgg 781 tccctcgcggactgaggctcaacacgcgcgtgttcccggcccggcccggcccggcttggc 841 ccggcgcgagctccctcatgttgcagccctgcggtgccccttcgacgacaggctgtgcgc 901 ggtctgcacggcgccccgcggcagagcttcatgtggggctgcggcccgctcagccggcgc 961 ctcgttgagggaacggacccccggtaaccggagaccgcctcccctcccaccaccccaggc 1021 gccaaagggtatcgtatgttcaggtctaaacgttcggggctggtgcggcgactttggcga 1081 agtcgtgtggtccctgatcgggaggaaggcagcggcggcggcggtggtgtcgacgaggat 1141 gggagcctgggcagccgagctgagcctgccccgcgggcacgagagggcggaggctgcagc 1201 cgctccgaagtccgctcggtagccccgcggcggccccgggacgcggtgggaccgcgaggc 1261 gccgcgatcgcgggcaggcgccggcgcacagggggcctcccgaggcccgtgtcggagtcg 1321 ggggccggggctgggggctccccgctggatgtggcggagcctggaggcccaggctggctg 1381 cctgagagtgactgcgagacggtgacctgctgtctcttctccgaacgggacgcagcaggc 1441 gcgccccgggactctggcgatccccaagccagacagtccccggagccggaggagggcggc 1501 gggcctcggagtcgcgaagcccgctcgcgactgctgcttctggagcaggagctcaagacg 1561 gtcacgtactcgctgctcaagaggctcaaggagcgttcgctggacacgctgttggaggct 1621 gtggagtcccgaggcggcgtaccgggcggctgcgtgctggtgccgcgcgccgacctccgc 1681 ttgggcggccagcccgcgccaccgcagctgctgctcggccgcctcttccgctggccagac 1741 ctgcagcacgcagtggagctgaaacccctgtgcggctgccacagctttaccgccgccgcc 1801 gacgggcccacggtgtgttgcaacccctaccacttcagccggctctgcgggccagaatca 1861 ccgccgcccccctattctcggctgtctcctcctgaccagtacaagccactggatctgtcc 1921 gattctacattgtcttacactgaaaccgaggccaccaactccctcatcactgctccgggt 1981 gaattctcagatgccagcatgtctccggatgccaccaagccgagccactggtgcagcgtg 2041 gcgtactgggagcaccggacacgcgtgggccgcctctatgcggtgtacgaccaggctgtc 2101 agcattttctacgacctacctcagggcagcggcttctgcctgggccagctcaacctggag 2161 cagcgcagtgagtcggtgcggcgcacgcgcagcaagatcggttttggcatactgctcagc 2221 aaggagccagacggcgtgtgggcctacaaccggggcgagcaccccatcttcgtcaactcc 2281 ccgacgctggatgcgcccggaggccgcgccctggtcgtgcgcaaggtgccaccgggttac 2341 tccatcaaggtgttcgactttgagcgctcagggctgctgcagcacgcagacgccgctcac 2401 ggcccctacgacccgcacagtgtgcgcatcagcttcgccaagggctggggaccctgctac 2461 tcgcgacagttcatcacctcctgcccctgttggctggagatcctactcaacaaccacaga 2521 tagcaatgcggctgccactgtgccgcagcgtcccccaacctctggggggccagcgcccag 2581 agacaccaccccagggacaacctcgccctccccccagatatcatctacctagatttaata 2641 taaagttttatatattatatggaaatatatattatacttgtaattatggagtcattttta 2701 caacgtaattatttatatatggtgcaatgtgtgtatatggagaaacaagaaagacgcact 2761 ttggcttgtaattctttcaatacagatatatttttttctttctttccctctttccttttt 2821 taaagagaattatacagtagaactaggtggaaagcctaggtttggtgtatggctttttta 2881 aaaaatattaatgcccagaccaaaaaaaaacaaaacaaaaaacaaaaaaactaataccag 2941 tcactcttgataataaagtgtttgcattata SEQIDNO:180MouseSmad6aminoacidsequence(NP_032568.3) 1 mfrskrsglvrrlwrsrvvpdreegsgggggvdedgslgsraepapraregggcsrsevr 61 svaprrprdavgprgaaiagrrrrtgglprpvsesgagaggspldvaepggpgwlpesdc 121 etvtcclfserdaagaprdsgdpqarqspepeegggprsrearsrlllleqelktvtysl 181 lkrlkersldtlleavesrggvpggcvlvpradlrlggqpappqlllgrlfrwpdlqhav 241 elkplcgchsftaaadgptvccnpyhfsrlcgpesppppysrlsppdqykpldlsdstls 301 yteteatnslitapgefsdasmspdatkpshwcsvaywehrtrvgrlyavydqavsifyd 361 lpqgsgfclgqlnleqrsesvrrtrskigfgillskepdgvwaynrgehpifvnsptlda 421 pggralvvrkvppgysikvfdfersgllqhadaahgpydphsvrisfakgwgpcysrqfi 481 tscpcwleillnnhr SEQIDNO:181HumanSmad7transcriptvariant1cDNAsequence(NM_005904.3; CDS:288-1568) 1 cggagagccgcgcagggcgcgggccgcgcggggtggggcagccggagcgcaggcccccga 61 tccccggcgggcgcccccgggcccccgcgcgcgccccggcctccgggagactggcgcatg 121 ccacggagcgcccctcgggccgccgccgctcctgcccgggcccctgctgctgctgctgtc 181 gcctgcgcctgctgccccaactcggcgcccgacttcttcatggtgtgcggaggtcatgtt 241 cgctccttagcaggcaaacgacttttctcctcgcctcctcgccccgcatgttcaggacca 301 aacgatctgcgctcgtccggcgtctctggaggagccgtgcgcccggcggcgaggacgagg 361 aggagggcgcagggggaggtggaggaggaggcgagctgcggggagaaggggcgacggaca 421 gccgagcgcatggggccggtggcggcggcccgggcagggctggatgctgcctgggcaagg 481 cggtgcgaggtgccaaaggtcaccaccatccccacccgccagccgcgggcgccggcgcgg 541 ccgggggcgccgaggcggatctgaaggcgctcacgcactcggtgctcaagaaactgaagg 601 agcggcagctggagctgctgctccaggccgtggagtcccgcggcgggacgcgcaccgcgt 661 gcctcctgctgcccggccgcctggactgcaggctgggcccgggggcgcccgccggcgcgc 721 agcctgcgcagccgccctcgtcctactcgctccccctcctgctgtgcaaagtgttcaggt 781 ggccggatctcaggcattcctcggaagtcaagaggctgtgttgctgtgaatcttacggga 841 agatcaaccccgagctggtgtgctgcaacccccatcaccttagccgactctgcgaactag 901 agtctcccccccctccttactccagatacccgatggattttctcaaaccaactgcagact 961 gtccagatgctgtgccttcctccgctgaaacagggggaacgaattatctggcccctgggg 1021 ggctttcagattcccaacttcttctggagcctggggatcggtcacactggtgcgtggtgg 1081 catactgggaggagaagacgagagtggggaggctctactgtgtccaggagccctctctgg 1141 atatcttctatgatctacctcaggggaatggcttttgcctcggacagctcaattcggaca 1201 acaagagtcagctggtgcagaaggtgcggagcaaaatcggctgcggcatccagctgacgc 1261 gggaggtggatggtgtgtgggtgtacaaccgcagcagttaccccatcttcatcaagtccg 1321 ccacactggacaacccggactccaggacgctgttggtacacaaggtgttccccggtttct 1381 ccatcaaggctttcgactacgagaaggcgtacagcctgcagcggcccaatgaccacgagt 1441 ttatgcagcagccgtggacgggctttaccgtgcagatcagctttgtgaagggctggggcc 1501 agtgctacacccgccagttcatcagcagctgcccgtgctggctagaggtcatcttcaaca 1561 gccggtagccgcgtgcggaggggacagagcgtgagctgagcaggccacacttcaaactac 1621 tttgctgctaatattttcctcctgagtgcttgcttttcatgcaaactctttggtcgtttt 1681 ttttttgtttgttggttggttttcttcttctcgtcctcgtttgtgttctgttttgtttcg 1741 ctctttgagaaatagcttatgaaaagaattgttgggggtttttttggaagaaggggcagg 1801 tatgatcggcaggacaccctgataggaagaggggaagcagaaatccaagcaccaccaaac 1861 acagtgtatgaaggggggcggtcatcatttcacttgtcaggagtgtgtgtgagtgtgagt 1921 gtgcggctgtgtgtgcacgcgtgtgcaggagcggcagatggggagacaacgtgctctttg 1981 ttttgtgtctcttatggatgtccccagcagagaggtttgcagtcccaagcggtgtctctc 2041 ctgccccttggacacgctcagtggggcagaggcagtacctgggcaagctggcggctgggg 2101 tcccagcagctgccaggagcacggctctgtccccagcctgggaaagcccctgcccctcct 2161 ctccctcatcaaggacacgggcctgtccacaggcttctgagcagcgagcctgctagtggc 2221 cgaaccagaaccaattattttcatccttgtcttattcccttcctgccagcccctgccatt 2281 gtagcgtctttcttttttggccatctgctcctggatctccctgagatgggcttcccaagg 2341 gctgccggggcagccccctcacagtattgctcacccagtgccctctcccctcagcctctc 2401 ccctgcctgccctggtgacatcaggtttttcccggacttagaaaaccagctcagcactgc 2461 ctgctcccatcctgtgtgttaagctctgctattaggccagcaagcggggatgtccctggg 2521 agggacatgcttagcagtccccttccctccaagaaggatttggtccgtcataacccaagg 2581 taccatcctaggctgacacctaactcttctttcatttcttctacaactcatacactcgta 2641 tgatacttcgacactgttcttagctcaatgagcatgtttagactttaacataagctattt 2701 ttctaactacaaaggtttaaatgaacaagagaagcattctcattggaaatttagcattgt 2761 agtgctttgagagagaaaggactcctgaaaaaaaacctgagatttattaaagaaaaaaat 2821 gtattttatgttatatataaatatattattacttgtaaatataaagacgttttataagca 2881 tcattatttatgtattgtgcaatgtgtataaacaagaaaaataaagaaaagatgcacttt 2941 gctttaatataaatgcaaataacaaatgccaaattaaaaaagataaacacaagattggtg 3001 tttttttctatgggtgttatcacctagctgaatgtttttctaaaggagtttatgttccat 3061 taaacgatttttaaaatgtacacttgaa SEQIDNO:182HumanSmad7isoform1aminoacidsequence(NP_005895.1) 1 mfrtkrsalvrrlwrsrapggedeeegagggggggelrgegatdsrahgaggggpgragc 61 clgkavrgakghhhphppaagagaaggaeadlkalthsvlkklkerqlelllqavesrgg 121 trtaclllpgrldcrlgpgapagaqpaqppssyslplllckvfrwpdlrhssevkrlccc 181 esygkinpelvccnphhlsrlcelesppppysrypmdflkptadcpdavpssaetggtny 241 lapgglsdsqlllepgdrshwcvvayweektrvgrlycvqepsldifydlpqgngfclgq 301 lnsdnksqlvqkvrskigcgiqltrevdgvwvynrssypifiksatldnpdsrtllvhkv 361 fpgfsikafdyekayslqrpndhefmqqpwtgftvqisfvkgwgqcytrqfisscpcwle 421 vifnsr SEQIDNO:183HumanSmad7transcriptvariant2cDNAsequence (NM_001190821.1;CDS:288-1565) 1 cggagagccgcgcagggcgcgggccgcgcggggtggggcagccggagcgcaggcccccga 61 tccccggcgggcgcccccgggcccccgcgcgcgccccggcctccgggagactggcgcatg 121 ccacggagcgcccctcgggccgccgccgctcctgcccgggcccctgctgctgctgctgtc 181 gcctgcgcctgctgccccaactcggcgcccgacttcttcatggtgtgcggaggtcatgtt 241 cgctccttagcaggcaaacgacttttctcctcgcctcctcgccccgcatgttcaggacca 301 aacgatctgcgctcgtccggcgtctctggaggagccgtgcgcccggcggcgaggacgagg 361 aggagggcgcagggggaggtggaggaggaggcgagctgcggggagaaggggcgacggaca 421 gccgagcgcatggggccggtggcggcggcccgggcagggctggatgctgcctgggcaagg 481 cggtgcgaggtgccaaaggtcaccaccatccccacccgccagccgcgggcgccggcgcgg 541 ccgggggcgccgaggcggatctgaaggcgctcacgcactcggtgctcaagaaactgaagg 601 agcggcagctggagctgctgctccaggccgtggagtcccgcggcgggacgcgcaccgcgt 661 gcctcctgctgcccggccgcctggactgcaggctgggcccgggggcgcccgccggcgcgc 721 agcctgcgcagccgccctcgtcctactcgctccccctcctgctgtgcaaagtgttcaggt 781 ggccggatctcaggcattcctcggaagtcaagaggctgtgttgctgtgaatcttacggga 841 agatcaaccccgagctggtgtgctgcaacccccatcaccttagccgactctgcgaactag 901 agtctcccccccctccttactccagatacccgatggattttctcaaaccaactgactgtc 961 cagatgctgtgccttcctccgctgaaacagggggaacgaattatctggcccctggggggc 1021 tttcagattcccaacttcttctggagcctggggatcggtcacactggtgcgtggtggcat 1081 actgggaggagaagacgagagtggggaggctctactgtgtccaggagccctctctggata 1141 tcttctatgatctacctcaggggaatggcttttgcctcggacagctcaattcggacaaca 1201 agagtcagctggtgcagaaggtgcggagcaaaatcggctgcggcatccagctgacgcggg 1261 aggtggatggtgtgtgggtgtacaaccgcagcagttaccccatcttcatcaagtccgcca 1321 cactggacaacccggactccaggacgctgttggtacacaaggtgttccccggtttctcca 1381 tcaaggctttcgactacgagaaggcgtacagcctgcagcggcccaatgaccacgagttta 1441 tgcagcagccgtggacgggctttaccgtgcagatcagctttgtgaagggctggggccagt 1501 gctacacccgccagttcatcagcagctgcccgtgctggctagaggtcatcttcaacagcc 1561 ggtagccgcgtgcggaggggacagagcgtgagctgagcaggccacacttcaaactacttt 1621 gctgctaatattttcctcctgagtgcttgcttttcatgcaaactctttggtcgttttttt 1681 tttgtttgttggttggttttcttcttctcgtcctcgtttgtgttctgttttgtttcgctc 1741 tttgagaaatagcttatgaaaagaattgttgggggtttttttggaagaaggggcaggtat 1801 gatcggcaggacaccctgataggaagaggggaagcagaaatccaagcaccaccaaacaca 1861 gtgtatgaaggggggcggtcatcatttcacttgtcaggagtgtgtgtgagtgtgagtgtg 1921 cggctgtgtgtgcacgcgtgtgcaggagcggcagatggggagacaacgtgctctttgttt 1981 tgtgtctcttatggatgtccccagcagagaggtttgcagtcccaagcggtgtctctcctg 2041 ccccttggacacgctcagtggggcagaggcagtacctgggcaagctggcggctggggtcc 2101 cagcagctgccaggagcacggctctgtccccagcctgggaaagcccctgcccctcctctc 2161 cctcatcaaggacacgggcctgtccacaggcttctgagcagcgagcctgctagtggccga 2221 accagaaccaattattttcatocttgtottattcccttcctgccagcccctgccattgta 2281 gcgtctttcttttttggccatctgctcctggatctccctgagatgggcttcccaagggct 2341 gccggggcagccccctcacagtattgctcacccagtgccctctcccctcagcctctcccc 2401 tgcctgccctggtgacatcaggtttttcccggacttagaaaaccagctcagcactgcctg 2461 ctcccatcctgtgtgttaagctctgctattaggccagcaagcggggatgtccctgggagg 2521 gacatgcttagcagtccccttccctccaagaaggatttggtccgtcataacccaaggtac 2581 catcctaggctgacacctaactcttctttcatttcttctacaactcatacactcgtatga 2641 tacttcgacactgttcttagctcaatgagcatgtttagactttaacataagctatttttc 2701 taactacaaaggtttaaatgaacaagagaagcattctcattggaaatttagcattgtagt 2761 gctttgagagagaaaggactcctgaaaaaaaacctgagatttattaaagaaaaaaatgta 2821 ttttatgttatatataaatatattattacttgtaaatataaagacgttttataagcatca 2881 ttatttatgtattgtgcaatgtgtataaacaagaaaaataaagaaaagatgcactttgct 2941 ttaatataaatgcaaataacaaatgccaaattaaaaaagataaacacaagattggtgttt 3001 ttttctatgggtgttatcacctagctgaatgtttttctaaaggagtttatgttccattaa 3061 acgatttttaaaatgtacacttgaa SEQIDNO:184HumanSmad7isoform2aminoacidsequence(NP_001177750.1) 1 mfrtkrsalvrrlwrsrapggedeeegagggggggelrgegatdsrahgaggggpgragc 61 clgkavrgakghhhphppaagagaaggaeadlkalthsvlkklkerqlelllqavesrgg 121 trtaclllpgrldcrlgpgapagaqpaqppssyslplllckvfrwpdlrhssevkrlccc 181 esygkinpelvccnphhlsrlcelesppppysrypmdflkptdcpdavpssaetggtnyl 241 apgglsdsqlllepgdrshwcvvayweektrvgrlycvqepsldifydlpqgngfclgql 301 nsdnksqlvqkvrskigcgiqltrevdgvwvynrssypifiksatldnpdsrtllvhkvf 361 pgfsikafdyekayslqrpndhefmqqpwtgftvqisfvkgwgqcytrqfisscpcwlev 421 ifnsr SEQIDNO:185HumanSmad7transcriptvariant3cDNAsequence NM_001190822.2;CDS:138-773) 1 agtaaatacggagaatcacgtcgaacaccagtggcccagatactgtcgtggccgcgcacc 61 tttggagttttggggcaaagagagttggatggaaggccgaactggagtctcccccccctc 121 cttactccagatacccgatggattttctcaaaccaactgcagactgtccagatgctgtgc 181 cttcctccgctgaaacagggggaacgaattatctggcccctggggggctttcagattccc 241 aacttcttctggagcctggggatcggtcacactggtgcgtggtggcatactgggaggaga 301 agacgagagtggggaggctctactgtgtccaggagccctctctggatatcttctatgatc 361 tacctcaggggaatggcttttgcctcggacagctcaattcggacaacaagagtcagctgg 421 tgcagaaggtgcggagcaaaatcggctgcggcatccagctgacgcgggaggtggatggtg 481 tgtgggtgtacaaccgcagcagttaccccatcttcatcaagtccgccacactggacaacc 541 cggactccaggacgctgttggtacacaaggtgttccccggtttctccatcaaggctttcg 601 actacgagaaggcgtacagcctgcagcggcccaatgaccacgagtttatgcagcagccgt 661 ggacgggctttaccgtgcagatcagctttgtgaagggctggggccagtgctacacccgcc 721 agttcatcagcagctgcccgtgctggctagaggtcatcttcaacagccggtagccgcgtg 781 cggaggggacagagcgtgagctgagcaggccacacttcaaactactttgctgctaatatt 841 ttcctcctgagtgcttgcttttcatgcaaactctttggtcgttttttttttgtttgttgg 901 ttggttttcttcttctcgtcctcgtttgtgttctgttttgtttcgctctttgagaaatag 961 cttatgaaaagaattgttgggggtttttttggaagaaggggcaggtatgatcggcaggac 1021 accctgataggaagaggggaagcagaaatccaagcaccaccaaacacagtgtatgaaggg 1081 gggcggtcatcatttcacttgtcaggagtgtgtgtgagtgtgagtgtgcggctgtgtgtg 1141 cacgcgtgtgcaggagcggcagatggggagacaacgtgctctttgttttgtgtctcttat 1201 ggatgtccccagcagagaggtttgcagtcccaagcggtgtctctcctgccccttggacac 1261 gctcagtggggcagaggcagtacctgggcaagctggcggctggggtcccagcagctgcca 1321 ggagcacggctctgtccccagcctgggaaagcccctgcccctcctctccctcatcaagga 1381 cacgggcctgtccacaggcttctgagcagcgagcctgctagtggccgaaccagaaccaat 1441 tattttcatccttgtcttattcccttcctgccagcccctgccattgtagcgtctttcttt 1501 tttggccatctgctcctggatctccctgagatgggcttcccaagggctgccggggcagcc 1561 ccctcacagtattgctcacccagtgccctctcccctcagcctctcccctgcctgccctgg 1621 tgacatcaggtttttcccggacttagaaaaccagctcagcactgcctgctcccatcctgt 1681 gtgttaagctctgctattaggccagcaagcggggatgtccctgggagggacatgcttagc 1741 agtccccttccctccaagaaggatttggtccgtcataacccaaggtaccatcctaggctg 1801 acacctaactcttctttcatttcttctacaactcatacactcgtatgatacttcgacact 1861 gttcttagctcaatgagcatgtttagactttaacataagctatttttctaactacaaagg 1921 tttaaatgaacaagagaagcattctcattggaaatttagcattgtagtgctttgagagag 1981 aaaggactcctgaaaaaaaacctgagatttattaaagaaaaaaatgtattttatgttata 2041 tataaatatattattacttgtaaatataaagacgttttataagcatcattatttatgtat 2101 tgtgcaatgtgtataaacaagaaaaataaagaaaagatgcactttgctttaatataaatg 2161 caaataacaaatgccaaattaaaaaagataaacacaagattggtgtttttttctatgggt 2221 gttatcacctagctgaatgtttttctaaaggagtttatgttccattaaacgatttttaaa 2281 atgtacacttga SEQIDNO:186HumanSmad7isoform3aminoacidsequence(NP_001177751.1) 1 mdflkptadcpdavpssaetggtnylapgglsdsqlllepgdrshwcvvayweektrvgr 61 lycvqepsldifydlpqgngfclgqlnsdnksqlvqkvrskigcgiqltrevdgvwvynr 121 ssypifiksatldnpdsrtllvhkvfpgfsikafdyekayslqrpndhefmqqpwtgftv 181 qisfvkgwgqcytrqfisscpcwlevifnsr SEQIDNO:187HumanSmad7transcriptvariant4cDNAsequence NM_001190823.1;CDS:150-866) 1 agtctcattgagcctgactcgagtaatgattaactggctgcccggagcccagacgggtga 61 caaggtgctgtggtctgtcttacgatgggcagtgaagcctgagcagaccattaataatca 121 gcatcaaggccgcgagtcagccttttggaatgtgtggtttgtctttcatgctgtttagag 181 cgtgcttaaagatggatcttggtgtttttatttgtgtatttatttctttctctccccttt 241 tcaaatccacagcagactgtccagatgctgtgccttcctccgctgaaacagggggaacga 301 attatctggcccctggggggctttcagattcccaacttcttctggagcctggggatcggt 361 cacactggtgcgtggtggcatactgggaggagaagacgagagtggggaggctctactgtg 421 tccaggagccctctctggatatottctatgatctacctcaggggaatggcttttgcctcg 481 gacagctcaattcggacaacaagagtcagctggtgcagaaggtgcggagcaaaatcggct 541 gcggcatccagctgacgcgggaggtggatggtgtgtgggtgtacaaccgcagcagttacc 601 ccatcttcatcaagtccgccacactggacaacccggactccaggacgctgttggtacaca 661 aggtgttccccggtttctccatcaaggctttcgactacgagaaggcgtacagcctgcagc 721 ggcccaatgaccacgagtttatgcagcagccgtggacgggctttaccgtgcagatcagct 781 ttgtgaagggctggggccagtgctacacccgccagttcatcagcagctgcccgtgctggc 841 tagaggtcatcttcaacagccggtagccgcgtgcggaggggacagagcgtgagctgagca 901 ggccacacttcaaactactttgctgctaatattttcctcctgagtgcttgcttttcatgc 961 aaactctttggtcgttttttttttgtttgttggttggttttcttcttctcgtcctcgttt 1021 gtgttctgttttgtttcgctctttgagaaatagcttatgaaaagaattgttgggggtttt 1081 tttggaagaaggggcaggtatgatcggcaggacaccctgataggaagaggggaagcagaa 1141 atccaagcaccaccaaacacagtgtatgaaggggggcggtcatcatttcacttgtcagga 1201 gtgtgtgtgagtgtgagtgtgcggctgtgtgtgcacgcgtgtgcaggagcggcagatggg 1261 gagacaacgtgctctttgttttgtgtctcttatggatgtccccagcagagaggtttgcag 1321 tcccaagcggtgtctctcctgccccttggacacgctcagtggggcagaggcagtacctgg 1381 gcaagctggcggctggggtcccagcagctgccaggagcacggctctgtccccagcctggg 1441 aaagcccctgcccctcctctccctcatcaaggacacgggcctgtccacaggcttctgagc 1501 agcgagcctgctagtggccgaaccagaaccaattattttcatccttgtcttattcccttc 1561 ctgccagcccctgccattgtagcgtctttcttttttggccatctgctcctggatctccct 1621 gagatgggcttcccaagggctgccggggcagccccctcacagtattgctcacccagtgcc 1681 ctctcccctcagcctctcccctgcctgccctggtgacatcaggtttttcccggacttaga 1741 aaaccagctcagcactgcctgctcccatcctgtgtgttaagctctgctattaggccagca 1801 agcggggatgtccctgggagggacatgcttagcagtccccttccctccaagaaggatttg 1861 gtccgtcataacccaaggtaccatcctaggctgacacctaactcttctttcatttcttct 1921 acaactcatacactcgtatgatacttcgacactgttcttagctcaatgagcatgtttaga 1981 ctttaacataagctatttttctaactacaaaggtttaaatgaacaagagaagcattctca 2041 ttggaaatttagcattgtagtgctttgagagagaaaggactcctgaaaaaaaacctgaga 2101 tttattaaagaaaaaaatgtattttatgttatatataaatatattattacttgtaaatat 2161 aaagacgttttataagcatcattatttatgtattgtgcaatgtgtataaacaagaaaaat 2221 aaagaaaagatgcactttgctttaatataaatgcaaataacaaatgccaaattaaaaaag 2281 ataaacacaagattggtgtttttttctatgggtgttatcacctagctgaatgtttttcta 2341 aaggagtttatgttccattaaacgatttttaaaatgtacacttgaa SEQIDNO:188HumanSmad7isoform4aminoacidsequence(NP_001177752.1) 1 mcglsfmlfraclkmdlgvficvfisfsplfkstadcpdavpssaetggtnylapgglsd 61 sqlllepgdrshwavvayweektrvgrlycvqepsldifydlpqgngfclgqlnsdnksq 121 lvqkvrskigcgiqltrevdgvwvynrssypifiksatldnpdsrtllvhkvfpgfsika 181 fdyekayslqrpndhefmqqpwtgftvqisfvkgwgqcytrqfisscpcwlevifnsr SEQIDNO:189MouseSmad7cDNAsequence(NM_001042660.1;CDS:1592- 2872) 1 ttcgctcgctgatcggcgcacagaggatcttgtccccgagctgcgccagcagagccagcc 61 gggcgcctcgctcggtccgctcgccgcgccggagagagctgcctgagacgcagccagcca 121 gccagccggcgccacgccgccgagcgctcggccccggagtccctgagtgcggcgcggcga 181 gcccccagcggcggcagaaggactcgagcgccaggagagggcggacgggggacgaggagg 241 ctccggggcgcgacgaagagagtctccgaggaagaggctgcgagaggacacccgggcctc 301 ctgccgccactgtcgggtcggggccagcagctcatgagagcagccccggcggccacccgc 361 ggccaggagaaggagcaccggaggcccccacactagcctgtgccctcgggggcgagagct 421 tgcgacccgccggagcccgccgccgcgccgccctcccccgcgctgacagccoccoggggc 481 gcagccgccgccgcagcatcttctgtccctgcttccccagcgcggaggaagtccccgccg 541 aggacctgggcccccgggaacgcaggaggaaagaccagagactctaaaacacccagatac 601 gcaagattgaagcagcctagccagacctttctgtggattaaaagaaatacgatttttttt 661 ttttttttggcagaagaaaaggaaaggaagaccggctgggttcagcaaggaaaaaaaggg 721 ggatgtaactcgtggatacggtttttttcccccacccttccaacatcttgttttactttg 781 taaacattttctcttttaaacccgggctccatccggtgccctccagacctccgaggtgcg 841 aggaggtggtgtgttttttcattgggggctttgcatattttggttttgggggttttgaga 901 gaccctccagacatctcacgaggggtgaagtctactcggtcccctccctcaagtcttcgc 961 gtgcacagaattcgaggagatccggttactaaggatatagaagaaaaaaaataaatcgtg 1021 cctgccttttttttttaattgcctgcttctccccacccccaaattaagttgcttagcaag 1081 ggggaaagaggotttttcctccctttagtagctcagcctaacgtctttcgtttttttttt 1141 tttttttttgcccccgaggatcttccatgtaggaagccgaggctggcgagcccgacactc 1201 gggagccactgtaggggggccttttttgggggaggcgtctaccggggttgcctcggccgc 1261 ccccagggaagcggcggccgcgttcctccagggcacgccggggcccgaaagccgcgcagg 1321 gcgcgggccgcgccgggtggggcagccgaagcgcagccccccgatccccggcaggcgccc 1381 ctgggcccccgcgcgcgccccggcctctgggagactggcgcatgccacggagcgcccctc 1441 gggccgccgccgcttctgcccgggcccctgctgttgctgctgtcgcctgcgcctgctgcc 1501 ccaactcggcgcccgacttcttcatggtgtgcggaggtcatgttcgctccttagccggca 1561 aacgacttttctcctcgcctcctcgcccogcatgttcaggaccaaacgatctgcgctcgt 1621 ccggcgtctctggaggagccgtgcgcccggcggcgaggacgaggaggagggcgtgggggg 1681 tggcggcggaggaggcgagctgcggggagaaggggcgacggacggccgggcttatggggc 1741 tggtggcggcggtgcgggcagggctggctgctgcctgggcaaggcagtccgaggtgccaa 1801 aggtcaccaccatccccatcccccaacctcgggtgccggggcggccgggggcgccgaggc 1861 ggatctgaaggcgctcacgcactcggtgctcaagaaactcaaggagcggcagctggagct 1921 gctgcttcaggccgtggagtcccgcggcggtacgcgcaccgcgtgcctcctgctgcccgg 1981 ccgcctggactgcaggctgggcccgggggcgcccgccagcgcgcagcccgcgcagccgcc 2041 ctcgtcctactcgctccccctcctgctgtgcaaagtgttcaggtggccggatctcaggca 2101 ttcctcggaagtcaagaggctgtgttgctgtgaatcttacgggaagatcaaccccgagct 2161 ggtgtgctgcaacccccatcaccttagtcgactctgtgaactagagtctccccctcctcc 2221 ttactccagatacccaatggattttctcaaaccaactgcaggctgtccagatgctgtacc 2281 ttcctccgcggaaaccgggggaacgaattatctggcccctggggggctttcagattccca 2341 acttcttctggagcctggggatcggtcacactggtgcgtggtggcatactgggaggagaa 2401 gactcgcgtggggaggctctactgtgtccaagagccctccctggatatcttctatgatct 2461 acctcaggggaatggcttttgcctcggacagctcaattcggacaacaagagtcagctggt 2521 acagaaagtgcggagcaagatcggctgtggcatccagctgacgcgggaagtggatggcgt 2581 gtgggtttacaaccgcagcagttaccccatcttcatcaagtccgccacactggacaaccc 2641 ggactccaggacgctgttggtgcacaaagtgttccctggtttctccatcaaggcttttga 2701 ctatgagaaagcctacagcctgcagcggcccaatgaccacgagttcatgcagcaaccatg 2761 gacgggtttcaccgtgcagatcagctttgtgaagggctggggccagtgctacacccgcca 2821 gttcatcagcagctgcccgtgctggctggaggtcatcttcaacagccggtagtcggtcgt 2881 gtggtggggagaagaggacagggcggatcgtgagccgagcaggccaccgttcaaactact 2941 tgctgctaacctttcccgagtgattgcttttcatgcaaactctttggttggtgttgttat 3001 tgccattcattgttggttttgttttgttctgttctggtttgtttttttttttttttcctc 3061 ctcctttctcgtcatccgtgtgtcccgcttgtcttgttctttgagaaattagcttatggt 3121 gcggatttttgttgggttgtgtgtgtgtgttttgtttttgttttgaggtggtgggtgtgg 3181 ttggcaggacaccccctccccccatatacgaagacaggaaacgagagtcagcactgccaa 3241 gcatggtgtgtgaaagtgggcaccaccttccctttggatcagcgtttcggttgtccgtgc 3301 gtaggggtgtacccgagcgacagatgggggaagtgcttttttgtgtgtgtgttctttatg 3361 gatgcccccggctgagaggctcatagtgccaagctgtgtgtctctctagccttttggaca 3421 cgctcggtggggcagaggcagtacctgggcagactggcagcaggtgccaagctctgctcc 3481 agcctgccgaagctgccccgccccgccccgcccccgcccccacaggacacgggcctatcc 3541 acaggcttctgagaagccagcctgctagaaggctgaaccagaaccaattgttttcatccc 3601 tgtcttactgccgcctgtcacccgctgccattgtcgagtctgtcttttttggccatctgc 3661 tcctggatctctctcttgagatgggcttcccaagggctgccgggacagccccagtcacag 3721 tattgctaccccagtaccctctcaggcccttccaccgggtcccagccgtggtggtttttt 3781 catcaggtttctcccagatgtggaaagtcagctcagcaccccatcccccatcctgtgtgc 3841 tgagctctgtagaccagcgaggggcatcagggagggacctgcgcagtgcccccccttcct 3901 gctgagaagggtgtagccccgtcacaacaaaggtaccatcccttggctggctcccagccc 3961 ttctctcagctcatacgctcgctcgtatgatactttgacactgttcttagctcaatgagc 4021 atgtttagaatttaacataagctatttttctaactacaaaggtttaaatgaacaagagaa 4081 gcattctcattggaaatttagcattgtagtgctttgagagaggaaaggactccttaaaag 4141 aaaaaaaaagctgagatttattaaagaaaaatgtattttatgttatatataaatatatta 4201 ttacttgtaaatataaagacgttttataagcatcattatttatgtattgtgcaatgtgta 4261 taaacgagaagaataaagaaaagatgcactttgctttaatataaatgcaaataacatgcc 4321 aaattaaaaaaaaaaagataaacacaagattggtgtttttttctatgggtgttatcacct 4381 agctgaatgtttttctaaaggagtttatgttccattaaacaatttttaaaatgtatactg 4441 c SEQIDNO:190MouseSmadaminoacidsequence(NP_001036125.1) 1 mfrtkrsalvrriwrsrapggedeeegvgggggggelrgegatdgraygaggggagragc 61 clgkavrgakghhhphpptsgagaaggaeadlkalthsvlkklkerqlelllqavesrgg 121 trtaclllpgrldcrlgpgapasaqpaqppssyslplllckvfrwpdlrhssevkrlccc 181 esygkinpelvccnphhlsrlcelesppppysrypmdflkptagcpdavpssaetggtny 241 lapgglsdsqlllepgdrshwcvvayweektrvgrlycvqepsldifydlpqgngfclgq 301 lnsdnksqlvqkvrskigcgiqltrevdgvwvynrssypifiksatldnpdsrtllvhkv 361 fpgfsikafdyekayslqrpndhefmqqpwtgftvgisfvkgwgqcytrqfisscpcwle 421 vifnsr

(132) Included in Table 2 are nucleic acid molecules comprising a nucleic acid sequence having at least 30%, 40%, 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more identity to the region encoding the DNA binding domain or across their full length with a nucleic acid sequence of any SEQ ID NO listed in Table 2. Such nucleic acid molecules can encode a polypeptide having a function of the full-length polypeptide as described further herein.

(133) Included in Table 2 are polypeptide molecules comprising an amino acid sequence having at least 30%, 40%, 50%, 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more identity to the DNA binding domain or across their full length with an amino acid sequence of any SEQ ID NO listed in Table 2. Such polypeptides can have a function of the full-length polypeptide as described further herein.

II. Cancer Vaccine

(134) The present invention provides a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Smad/p63 signaling pathway. The cancer cells may be derived from a solid or hematological cancer (e.g., breast cancer). In certain embodiments, the breast cancer cells are triple-negative breast cancer (TNBC). In one embodiment, the cancer cells are derived from a subject. For example, the cancer cells may be derived from a breast cancer driven by co-loss of p53 and PTEN. In another embodiment, the cancer cells are derived from a cancer cell line. The cancer cells may be from any cancer cell line or primary cancer cells. For example, the cancer cells may be derived from a cell line selected from the group consisting of HCC1954, SUM149, BxPC-3, T3M4, 143B, A549, H520, H23, HaCaT, H357, H400, Detroit, OKF6, BICR6, H103, SPT, JHU12, JHU22, HSC3, SCC25, and NTERT cells. The cancer cells may have different kinds of additional genetic mutations. The cancer cells may be derived from the subject who is treated with the cancer vaccine. The cancer cells may also be derived from a different subject who is not treated with the cancer vaccine. The cancer cells may be derived from a cancer that is the same type as the cancer treated with the cancer vaccine. The cancer cells may also be derived from a cancer that is a different type from the cancer treated with the cancer vaccine. The cancer cells may be derived from a cancer that has the same genetic mutations as the cancer treated with the cancer vaccine. The cancer cells may also be derived from a cancer that has different genetic mutations from the cancer treated with the cancer vaccine.

(135) a. Cancer Cell Isolation and Purification

(136) In some embodiments, the cancer cells are derived from a subject. Isolation and purification of tumor cell from various tumor tissues such as surgical tumor tissues, ascites or carcinous hydrothorax is a common process to obtain the purified tumor cells. Cancer cells may be purified from fresh biopsy samples from cancer patients or animal tumor models. The biopsy samples often contain a heterogeneous population of cells that include normal tissue, blood, and cancer cells. Preferably, a purified cancer cell composition can have greater than 10%, 20% 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range in between or any value in between, total viable cancer cells. To purify cancer cells from the heterogeneous population, a number of methods can be used.

(137) In one embodiment, laser microdissection is used to isolate cancer cells. Cancer cells of interest can be carefully dissected from thin tissue slices prepared for microscopy. In this method, the tissue section is coated with a thin plastic film and an area containing the selected cells is irradiated with a focused infrared laser beam pulse. This melts a small circle in the plastic film, causing cell binding underneath. Those captured cells are removed for additional analysis. This technique is good for separating and analyzing cells from different parts of a tumor, which allows for a comparison of their similar and distinct properties. It was used recently to analyze pituitary cells from dissociated tissues and from cultured populations of heterogeneous pituitary, thyroid, and carcinoid tumor cells, as well as analyzing single cells found in various sarcomas.

(138) In another embodiment, fluorescence activated cell sorting (FACS), also referred to as flow cytometry, is used to sort and analyze the different cell populations. Cells having a cellular marker or other specific marker of interest are tagged with an antibody, or typically a mixture of antibodies, that bind the cellular markers. Each antibody directed to a different marker is conjugated to a detectable molecule, particularly a fluorescent dye that may be distinguished from other fluorescent dyes coupled to other antibodies. A stream of tagged or stained cells is passed through a light source that excites the fluorochrome and the emission spectrum from the cells detected to determine the presence of a particular labeled antibody. By concurrent detection of different fluorochromes, also referred to in the art as multicolor fluorescence cell sorting, cells displaying different sets of cell markers may be identified and isolated from other cells in the population. Other FACS parameters, including, by way of example and not limitation, side scatter (SSC), forward scatter (FSC), and vital dye staining (e.g., with propidium iodide) allow selection of cells based on size and viability. FACS sorting and analysis of HSC and related lineage cells is well-known in the art and described in, for example, U.S. Pat. Nos. 5,137,809; 5,750,397; 5,840,580; 6,465,249; Manz et al. (202) Proc. Natl. Acad. Sci. U.S.A. 99:11872-11877; and Akashi et al. (200) Nature 404:193-197. General guidance on fluorescence activated cell sorting is described in, for example, Shapiro (2003) Practical Flow Cytometry, 4th Ed., Wiley-Liss (2003) and Ormerod (2000) Flow Cytometry: A Practical Approach, 3rd Ed., Oxford University Press.

(139) Another method of isolating useful cell populations involves a solid or insoluble substrate to which is bound antibodies or ligands that interact with specific cell surface markers. In immunoadsorption techniques, cells are contacted with the substrate (e.g., column of beads, flasks, magnetic particles, etc.) containing the antibodies and any unbound cells removed. Immunoadsorption techniques may be scaled up to deal directly with the large numbers of cells in a clinical harvest. Suitable substrates include, by way of example and not limitation, plastic, cellulose, dextran, polyacrylamide, agarose, and others known in the art (e.g., Pharmacia Sepharose 6 MB macrobeads). When a solid substrate comprising magnetic or paramagnetic beads is used, cells bound to the beads may be readily isolated by a magnetic separator (see, e.g., Kato and Radbruch (1993) Cytometry 14:384-92). Affinity chromatographic cell separations typically involve passing a suspension of cells over a support bearing a selective ligand immobilized to its surface. The ligand interacts with its specific target molecule on the cell and is captured on the matrix. The bound cell is released by the addition of an elution agent to the running buffer of the column and the free cell is washed through the column and harvested as a homogeneous population. As apparent to the skilled artisan, adsorption techniques are not limited to those employing specific antibodies, and may use nonspecific adsorption. For example, adsorption to silica is a simple procedure for removing phagocytes from cell preparations. One of the most common uses of this technology is for isolating circulating tumor cells (CTCs) from the blood of breast, NSC lung cancer, prostate and colon cancer patients using an antibody against EpCAM, a cell surface glycoprotein that has been found to be highly expressed in epithelial cancers.

(140) FACS and most batch wise immunoadsorption techniques may be adapted to both positive and negative selection procedures (see, e.g., U.S. Pat. No. 5,877,299). In positive selection, the desired cells are labeled with antibodies and removed away from the remaining unlabeled/unwanted cells. In negative selection, the unwanted cells are labeled and removed. Another type of negative selection that may be employed is use of antibody/complement treatment or immunotoxins to remove unwanted cells.

(141) In still another embodiment, microfluidics, one of the newest technologies, is used to isolate cancer cells. This method used a microfluidic chip with a spiral channel that can isolate circulating tumor cells (CTCs) from blood based upon their size. A sample of blood is pumped into the device and as cells flow through the channel at high speeds, the inertial and centrifugal forces cause smaller cells to flow along the outer wall while larger cells, including CTCs, flow along the inner wall. Researchers have used this chip technology to isolate CTCs from the blood of patients with metastatic lung or breast cancer.

(142) Fluorescent nanodiamonds (FNDs), according to a recently published article (Lin et al. Small (2015) 11:4394-4402), can be used to label and isolate slow-proliferating/quiescent cancer stem cells, which, according to study authors, have been difficult to isolate and track over extended time periods using traditional fluorescent markers. It was concluded that nanoparticles do not cause DNA damage or impair cell growth, and that they outperformed EdU and CFSE fluorescent labels in terms of long-term tracking capability.

(143) It is to be understood that the purification or isolation of cells also includes combinations of the methods described above. A typical combination may comprise an initial procedure that is effective in removing the bulk of unwanted cells and cellular material. A second step may include isolation of cells expressing a marker common to one or more of the progenitor cell populations by immunoadsorption on antibodies bound to a substrate. An additional step providing higher resolution of different cell types, such as FACS sorting with antibodies to a set of specific cellular markers, may be used to obtain substantially pure populations of the desired cells.

(144) b. Cancer Cell Engineering and Modification

(145) The cancer cells comprised in the cancer vaccine are PTEN- and p53-deficient. In some embodiments, cancer cells are PTEN- and p53-deficient due to genetic mutations acquired by the cancer cells during cancer transformation or progression. In some other embodiments, cancer cells are engineered to become PTEN- and p53-deficient with an agent that reduces copy number, amount, and/or activity of PTEN and/or p53.

(146) The agent that reduces copy number, amount, and/or activity of PTEN and/or p53 could be a small molecule inhibitor, CRISPR guide RNA (gRNA), RNA interfering agent, antisense oligonucleotide, peptide or peptidomimetic inhibitor, aptamer, antibody, or intrabody.

(147) In one embodiment, peptides or peptide mimetics can be used to antagonize the activity of PTEN and/or p53. In one embodiment, variants of PTEN and/or p53 which function as a modulating agent for the respective full length protein, can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, for antagonist activity. In one embodiment, a variegated library of variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of variants can be produced, for instance, by enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential polypeptide sequences is expressible as individual polypeptides containing the set of polypeptide sequences therein. There are a variety of methods which can be used to produce libraries of polypeptide variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential polypeptide sequences. Methods for synthesizing degenerate oligonucleotides are known in the art (see, e.g., Narang, S. A. (1983) Tetrahedron 39:3; Itakura et al. (1984) Annu. Rev. Biochem. 53:323; Itakura et al. (1984) Science 198:1056; Ike et al. (1983) Nucleic Acid Res. 11:477.

(148) In addition, libraries of fragments of a polypeptide coding sequence can be used to generate a variegated population of polypeptide fragments for screening and subsequent selection of variants of a given polypeptide. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a polypeptide coding sequence with a nuclease under conditions wherein nicking occurs only about once per polypeptide, denaturing the double stranded DNA, renaturing the DNA to form double stranded DNA which can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, an expression library can be derived which encodes N-terminal, C-terminal and internal fragments of various sizes of the polypeptide.

(149) Several techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of polypeptides. The most widely used techniques, which are amenable to high through-put analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a technique which enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify variants of interest (Arkin and Youvan (1992) Proc. Natl. Acad. Sci. USA 89:7811-7815; Delagrave et al. (1993) Protein Eng. 6(3):327-331). In one embodiment, cell based assays can be exploited to analyze a variegated polypeptide library. For example, a library of expression vectors can be transfected into a cell line which ordinarily synthesizes PTEN and/or p53. The transfected cells are then cultured such that the full length polypeptide and a particular mutant polypeptide are produced and the effect of expression of the mutant on the full length polypeptide activity in cell supernatants can be detected, e.g., by any of a number of functional assays. Plasmid DNA can then be recovered from the cells which score for inhibition, or alternatively, potentiation of full length polypeptide activity, and the individual clones further characterized.

(150) Systematic substitution of one or more amino acids of a polypeptide amino acid sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) can be used to generate more stable peptides. In addition, constrained peptides comprising a polypeptide amino acid sequence of interest or a substantially identical sequence variation can be generated by methods known in the art (Rizo and Gierasch (1992) Annu. Rev. Biochem. 61:387, incorporated herein by reference); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.

(151) The amino acid sequences disclosed herein will enable those of skill in the art to produce polypeptides corresponding peptide sequences and sequence variants thereof. Such polypeptides can be produced in prokaryotic or eukaryotic host cells by expression of polynucleotides encoding the peptide sequence, frequently as part of a larger polypeptide. Alternatively, such peptides can be synthesized by chemical methods. Methods for expression of heterologous proteins in recombinant hosts, chemical synthesis of polypeptides, and in vitro translation are well-known in the art and are described further in Maniatis et al. Molecular Cloning: A Laboratory Manual (1989), 2nd Ed., Cold Spring Harbor, N.Y.; Berger and Kimmel, Methods in Enzymology, Volume 152, Guide to Molecular Cloning Techniques (1987), Academic Press, Inc., San Diego, Calif.; Merrifield, J. (1969) J. Am. Chem. Soc. 91:501; Chaiken I. M. (1981) CRC Crit. Rev. Biochem. 11: 255; Kaiser et al. (1989) Science 243:187; Merrifield, B. (1986) Science 232:342; Kent, S. B. H. (1988) Annu. Rev. Biochem. 57:957; and Offord, R. E. (1980) Semisynthetic Proteins, Wiley Publishing, which are incorporated herein by reference).

(152) Peptides can be produced, typically by direct chemical synthesis. Peptides can be produced as modified peptides, with nonpeptide moieties attached by covalent linkage to the N-terminus and/or C-terminus. In certain preferred embodiments, either the carboxy-terminus or the amino-terminus, or both, are chemically modified. The most common modifications of the terminal amino and carboxyl groups are acetylation and amidation, respectively. Amino-terminal modifications such as acylation (e.g., acetylation) or alkylation (e.g., methylation) and carboxy-terminal-modifications such as amidation, as well as other terminal modifications, including cyclization, can be incorporated into various embodiments of the invention. Certain amino-terminal and/or carboxy-terminal modifications and/or peptide extensions to the core sequence can provide advantageous physical, chemical, biochemical, and pharmacological properties, such as: enhanced stability, increased potency and/or efficacy, resistance to serum proteases, desirable pharmacokinetic properties, and others. Peptides disclosed herein can be used therapeutically to treat disease, e.g., by altering costimulation in a patient.

(153) Peptidomimetics (Fauchere (1986) Adv. Drug Res. 15:29; Veber and Freidinger (1985) TINS p. 392; and Evans et al. (1987) J. Med. Chem. 30:1229, which are incorporated herein by reference) are usually developed with the aid of computerized molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides can be used to produce an equivalent therapeutic or prophylactic effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a biological or pharmacological activity), but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of: CH2NH, CH.sub.2S, CH2CH2, CHCH (cis and trans), COCH2, CH(OH)CH2, and CH2SO, by methods known in the art and further described in the following references: Spatola, A. F. in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins Weinstein, B., ed., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., (1983) Vega Data Vol. 1, Issue 3, Peptide Backbone Modifications (general review); Morley, J. S. (1980) Trends Pharm. Sci. 463-468 (general review); Hudson, D. et al. (1979) Int. J. Pept. Prot. Res. 14:177-185 (CH2NH, CH2CH2); Spatola, A. F. et at (1986) Life Sci. 38:1243-1249 (CH2-S); Hann, M. M. (1982) J. Chem. Soc. Perkin Trans. I. 307-314 (CHCH, cis and trans); Almquist, R. G. et al. (1980) J. Med. Chem. 23:1392-1398 (COCH2); Jennings-White, C. et al. (1982) Tetrahedron Lett. 23:2533 (COCH2); Szelke, M. et al. (1982) European Appln. EP 45665 CA: 97:39405 (CH(OH)CH2); Holladay, M. W. et at (1983) Tetrahedron Lett. 24:4401-4404 (C(OH)CH2); and Hruby, V. J. (1982) Life Sci. 31:189-199 (CH2-S); each of which is incorporated herein by reference. A particularly preferred non-peptide linkage is CH2NH. Such peptide mimetics may have significant advantages over polypeptide embodiments, including, for example: more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others. Labeling of peptidomimetics usually involves covalent attachment of one or more labels, directly or through a spacer (e.g., an amide group), to non-interfering position(s) on the peptidomimetic that are predicted by quantitative structure-activity data and/or molecular modeling. Such non-interfering positions generally are positions that do not form direct contacts with the macropolypeptides(s) to which the peptidomimetic binds to produce the therapeutic effect. Derivatization (e.g., labeling) of peptidomimetics should not substantially interfere with the desired biological or pharmacological activity of the peptidomimetic.

(154) Also encompassed by the present invention are small molecules which can modulate (e.g., inhibit) activity of PTEN and/or p53 or their interactions with their natural binding partners. The small molecules of the present invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the one-bead one-compound library method; and synthetic library methods using affinity chromatography selection. (Lam, K. S. (1997) Anticancer Drug Des. 12:145).

(155) Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. USA 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994) J. Med. Chem. 37:2678; Cho et al (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and in Gallop et al (1994) J. Med. Chem. 37:1233.

(156) Libraries of compounds can be presented in solution (e.g., Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria (Ladner U.S. Pat. No. 5,223,409), spores (Ladner USP '409), plasmids (Cull et al. (1992) Proc. Natl. Acad. Sci. USA 89:1865-1869) or on phage (Scott and Smith (1990) Science 249:386-390); (Devlin (1990) Science 249:404-406); (Cwirla et al. (1990) Proc. Natl. Acad. Sci. USA 87:6378-6382); (Felici (1991)J Mol. Biol. 222:301-310); (Ladner supra.). Compounds can be screened in cell based or non-cell based assays. Compounds can be screened in pools (e.g. multiple compounds in each testing sample) or as individual compounds.

(157) Also provided herein are compositions comprising one or more nucleic acids comprising or capable of expressing at least 1, 2, 3, 4, 5, 10, 20 or more small nucleic acids or antisense oligonucleotides or derivatives thereof, wherein said small nucleic acids or antisense oligonucleotides or derivatives thereof in a cell specifically hybridize (e.g., bind) under cellular conditions, with cellular nucleic acids (e.g., small non-coding RNAS such as miRNAs, pre-miRNAs, pri-miRNAs, miRNA*, anti-miRNA, a miRNA binding site, a variant and/or functional variant thereof, cellular mRNAs or a fragments thereof). In one embodiment, expression of the small nucleic acids or antisense oligonucleotides or derivatives thereof in a cell can inhibit expression or biological activity of cellular nucleic acids and/or proteins, e.g., by inhibiting transcription, translation and/or small nucleic acid processing of, for example, PTEN and/or p53. In one embodiment, the small nucleic acids or antisense oligonucleotides or derivatives thereof are small RNAs (e.g., microRNAs) or complements of small RNAs. In another embodiment, the small nucleic acids or antisense oligonucleotides or derivatives thereof can be single or double stranded and are at least six nucleotides in length and are less than about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 40, 30, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, or 10 nucleotides in length. In another embodiment, a composition may comprise a library of nucleic acids comprising or capable of expressing small nucleic acids or antisense oligonucleotides or derivatives thereof, or pools of said small nucleic acids or antisense oligonucleotides or derivatives thereof. A pool of nucleic acids may comprise about 2-5, 5-10, 10-20, 10-30 or more nucleic acids comprising or capable of expressing small nucleic acids or antisense oligonucleotides or derivatives thereof.

(158) In one embodiment, binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix. In general, antisense refers to the range of techniques generally employed in the art, and includes any process that relies on specific binding to oligonucleotide sequences.

(159) It is well-known in the art that modifications can be made to the sequence of a miRNA or a pre-miRNA without disrupting miRNA activity. As used herein, the term functional variant of a miRNA sequence refers to an oligonucleotide sequence that varies from the natural miRNA sequence, but retains one or more functional characteristics of the miRNA (e.g. cancer cell proliferation inhibition, induction of cancer cell apoptosis, enhancement of cancer cell susceptibility to chemotherapeutic agents, specific miRNA target inhibition). In some embodiments, a functional variant of a miRNA sequence retains all of the functional characteristics of the miRNA. In certain embodiments, a functional variant of a miRNA has a nucleobase sequence that is a least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the miRNA or precursor thereof over a region of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more nucleobases, or that the functional variant hybridizes to the complement of the miRNA or precursor thereof under stringent hybridization conditions. Accordingly, in certain embodiments the nucleobase sequence of a functional variant is capable of hybridizing to one or more target sequences of the miRNA.

(160) MicroRNAs and their corresponding stem-loop sequences described herein may be found in miRBase, an online searchable database of miRNA sequences and annotation, found on the world wide web at microrna.sanger.ac.uk. Entries in the miRBase Sequence database represent a predicted hairpin portion of a miRNA transcript (the stem-loop), with information on the location and sequence of the mature miRNA sequence. The miRNA stem-loop sequences in the database are not strictly precursor miRNAs (pre-miRNAs), and may in some instances include the pre-miRNA and some flanking sequence from the presumed primary transcript. The miRNA nucleobase sequences described herein encompass any version of the miRNA, including the sequences described in Release 10.0 of the miRBase sequence database and sequences described in any earlier Release of the miRBase sequence database. A sequence database release may result in the re-naming of certain miRNAs. A sequence database release may result in a variation of a mature miRNA sequence.

(161) In some embodiments, miRNA sequences of the invention may be associated with a second RNA sequence that may be located on the same RNA molecule or on a separate RNA molecule as the miRNA sequence. In such cases, the miRNA sequence may be referred to as the active strand, while the second RNA sequence, which is at least partially complementary to the miRNA sequence, may be referred to as the complementary strand. The active and complementary strands are hybridized to create a double-stranded RNA that is similar to a naturally occurring miRNA precursor. The activity of a miRNA may be optimized by maximizing uptake of the active strand and minimizing uptake of the complementary strand by the miRNA protein complex that regulates gene translation. This can be done through modification and/or design of the complementary strand.

(162) In some embodiments, the complementary strand is modified so that a chemical group other than a phosphate or hydroxyl at its 5 terminus. The presence of the 5 modification apparently eliminates uptake of the complementary strand and subsequently favors uptake of the active strand by the miRNA protein complex. The 5 modification can be any of a variety of molecules known in the art, including NH.sub.2, NHCOCH.sub.3, and biotin.

(163) In another embodiment, the uptake of the complementary strand by the miRNA pathway is reduced by incorporating nucleotides with sugar modifications in the first 2-6 nucleotides of the complementary strand. It should be noted that such sugar modifications can be combined with the 5 terminal modifications described above to further enhance miRNA activities.

(164) In some embodiments, the complementary strand is designed so that nucleotides in the 3 end of the complementary strand are not complementary to the active strand. This results in double-strand hybrid RNAs that are stable at the 3 end of the active strand but relatively unstable at the 5 end of the active strand. This difference in stability enhances the uptake of the active strand by the miRNA pathway, while reducing uptake of the complementary strand, thereby enhancing miRNA activity.

(165) Small nucleic acid and/or antisense constructs of the methods and compositions presented herein can be delivered, for example, as an expression plasmid which, when transcribed in the cell, produces RNA which is complementary to at least a unique portion of cellular nucleic acids (e.g., small RNAs, mRNA, and/or genomic DNA). Alternatively, the small nucleic acid molecules can produce RNA which encodes mRNA, miRNA, pre-miRNA, pri-miRNA, miRNA*, anti-miRNA, or a miRNA binding site, or a variant thereof. For example, selection of plasmids suitable for expressing the miRNAs, methods for inserting nucleic acid sequences into the plasmid, and methods of delivering the recombinant plasmid to the cells of interest are within the skill in the art. See, for example, Zeng et al. (2002) Mol. Cell 9:1327-1333; Tuschl (2002), Nat. Biotechnol. 20:446-448; Brummelkamp et al. (2002) Science 296:550-553; Miyagishi et al. (2002) Nat. Biotechnol. 20:497-500; Paddison et al. (2002) Genes Dev. 16:948-958; Lee et al. (2002) Nat. Biotechnol. 20:500-505; and Paul et al. (2002) Nat. Biotechnol. 20:505-508, the entire disclosures of which are herein incorporated by reference.

(166) Alternatively, small nucleic acids and/or antisense constructs are oligonucleotide probes that are generated ex vivo and which, when introduced into the cell, results in hybridization with cellular nucleic acids. Such oligonucleotide probes are preferably modified oligonucleotides that are resistant to endogenous nucleases, e.g., exonucleases and/or endonucleases, and are therefore stable in vivo. Exemplary nucleic acid molecules for use as small nucleic acids and/or antisense oligonucleotides are phosphoramidate, phosphothioate and methylphosphonate analogs of DNA (see also U.S. Pat. Nos. 5,176,996; 5,264,564; and 5,256,775). Additionally, general approaches to constructing oligomers useful in antisense therapy have been reviewed, for example, by Van der Krol et al. (1988) BioTechniques 6:958-976; and Stein et al. (1988) Cancer Res 48:2659-2668.

(167) Antisense approaches may involve the design of oligonucleotides (either DNA or RNA) that are complementary to cellular nucleic acids (e.g., complementary to PTEN and/or p53 genes). Absolute complementarity is not required. In the case of double-stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with a nucleic acid (e.g., RNA) it may contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

(168) Oligonucleotides that are complementary to the 5 end of the mRNA, e.g., the 5 untranslated sequence up to and including the AUG initiation codon, should work most efficiently at inhibiting translation. However, sequences complementary to the 3 untranslated sequences of mRNAs have recently been shown to be effective at inhibiting translation of mRNAs as well (Wagner (1994) Nature 372:333). Therefore, oligonucleotides complementary to either the 5 or 3 untranslated, non-coding regions of genes could be used in an antisense approach to inhibit translation of endogenous mRNAs. Oligonucleotides complementary to the 5 untranslated region of the mRNA may include the complement of the AUG start codon. Antisense oligonucleotides complementary to mRNA coding regions are less efficient inhibitors of translation but could also be used in accordance with the methods and compositions presented herein. Whether designed to hybridize to the 5, 3 or coding region of cellular mRNAs, small nucleic acids and/or antisense nucleic acids should be at least six nucleotides in length, and can be less than about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 40, 30, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, or 10 nucleotides in length.

(169) Regardless of the choice of target sequence, it is preferred that in vitro studies are first performed to quantitate the ability of the antisense oligonucleotide to inhibit gene expression. In one embodiment these studies utilize controls that distinguish between antisense gene inhibition and nonspecific biological effects of oligonucleotides. In another embodiment these studies compare levels of the target nucleic acid or protein with that of an internal control nucleic acid or protein. Additionally, it is envisioned that results obtained using the antisense oligonucleotide are compared with those obtained using a control oligonucleotide. It is preferred that the control oligonucleotide is of approximately the same length as the test oligonucleotide and that the nucleotide sequence of the oligonucleotide differs from the antisense sequence no more than is necessary to prevent specific hybridization to the target sequence.

(170) Small nucleic acids and/or antisense oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. Small nucleic acids and/or antisense oligonucleotides can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, hybridization, etc., and may include other appended groups such as peptides (e.g., for targeting host cell receptors), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556; Lemaitre et al. (1987) Proc. Natl. Acad. Sci. U.S.A. 84:648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO89/10134), hybridization-triggered cleavage agents. (See, e.g., Krol et al. (1988) BioTech. 6:958-976) or intercalating agents. (See, e.g., Zon (1988) Pharm. Res. 5:539-549). To this end, small nucleic acids and/or antisense oligonucleotides may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.

(171) Small nucleic acids and/or antisense oligonucleotides may comprise at least one modified base moiety which is selected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxytiethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Small nucleic acids and/or antisense oligonucleotides may also comprise at least one modified sugar moiety selected from the group including but not limited to arabinose, 2-fluoroarabinose, xylulose, and hexose.

(172) In certain embodiments, a compound comprises an oligonucleotide (e.g., a miRNA or miRNA encoding oligonucleotide) conjugated to one or more moieties which enhance the activity, cellular distribution or cellular uptake of the resulting oligonucleotide. In certain such embodiments, the moiety is a cholesterol moiety (e.g., antagomirs) or a lipid moiety or liposome conjugate. Additional moieties for conjugation include carbohydrates, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. In certain embodiments, a conjugate group is attached directly to the oligonucleotide. In certain embodiments, a conjugate group is attached to the oligonucleotide by a linking moiety selected from amino, hydroxyl, carboxylic acid, thiol, unsaturations (e.g., double or triple bonds), 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), 6-aminohexanoic acid (AHEX or AHA), substituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, and substituted or unsubstituted C2-C10 alkynyl. In certain such embodiments, a substituent group is selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

(173) In certain such embodiments, the compound comprises the oligonucleotide having one or more stabilizing groups that are attached to one or both termini of the oligonucleotide to enhance properties such as, for example, nuclease stability. Included in stabilizing groups are cap structures. These terminal modifications protect the oligonucleotide from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5-terminus (5-cap), or at the 3-terminus (3-cap), or can be present on both termini. Cap structures include, for example, inverted deoxy abasic caps.

(174) Suitable cap structures include a 4,5-methylene nucleotide, a 1-(beta-D-erythrofuranosyl) nucleotide, a 4-thio nucleotide, a carbocyclic nucleotide, a 1,5-anhydrohexitol nucleotide, an L-nucleotide, an alpha-nucleotide, a modified base nucleotide, a phosphorodithioate linkage, a threo-pentofuranosyl nucleotide, an acyclic 3,4-seco nucleotide, an acyclic 3,4-dihydroxybutyl nucleotide, an acyclic 3,5-dihydroxypentyl nucleotide, a 3-3-inverted nucleotide moiety, a 3-3-inverted abasic moiety, a 3-2-inverted nucleotide moiety, a 3-2-inverted abasic moiety, a 1,4-butanediol phosphate, a 3-phosphoramidate, a hexylphosphate, an aminohexyl phosphate, a 3-phosphate, a 3-phosphorothioate, a phosphorodithioate, a bridging methylphosphonate moiety, and a non-bridging methylphosphonate moiety 5-amino-alkyl phosphate, a 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate, a 6-aminohexyl phosphate, a 1,2-aminododecyl phosphate, a hydroxypropyl phosphate, a 5-5-inverted nucleotide moiety, a 5-5-inverted abasic moiety, a 5-phosphoramidate, a 5-phosphorothioate, a 5-amino, a bridging and/or non-bridging 5-phosphoramidate, a phosphorothioate, and a 5-mercapto moiety.

(175) Small nucleic acids and/or antisense oligonucleotides can also contain a neutral peptide-like backbone. Such molecules are termed peptide nucleic acid (PNA)-oligomers and are described, e.g., in Perry-O'Keefe et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93:14670 and in Eglom et al. (1993) Nature 365:566. One advantage of PNA oligomers is their capability to bind to complementary DNA essentially independently from the ionic strength of the medium due to the neutral backbone of the DNA. In yet another embodiment, small nucleic acids and/or antisense oligonucleotides comprises at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

(176) In a further embodiment, small nucleic acids and/or antisense oligonucleotides are -anomeric oligonucleotides. An -anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual b-units, the strands run parallel to each other (Gautier et al. (1987) Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a 2-O-methylribonucleotide (Inoue et al. (1987) Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al. (1987) FEBS Lett. 215:327-330).

(177) Small nucleic acids and/or antisense oligonucleotides of the methods and compositions presented herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al. (1988) Nucl. Acids Res. 16:3209, methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc. For example, an isolated miRNA can be chemically synthesized or recombinantly produced using methods known in the art. In some instances, miRNA are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA/RNA synthesizer. Commercial suppliers of synthetic RNA molecules or synthesis reagents include, e.g., Proligo (Hamburg, Germany), Dharmacon Research (Lafayette, Colo., USA), Pierce Chemical (part of Perbio Science, Rockford, Ill., USA), Glen Research (Sterling, Va., USA), ChemGenes (Ashland, Mass., USA), Cruachem (Glasgow, UK), and Exiqon (Vedbaek, Denmark).

(178) Small nucleic acids and/or antisense oligonucleotides can be delivered to cells in vivo. A number of methods have been developed for delivering small nucleic acids and/or antisense oligonucleotides DNA or RNA to cells; e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (e.g., antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systematically.

(179) In one embodiment, small nucleic acids and/or antisense oligonucleotides may comprise or be generated from double stranded small interfering RNAs (siRNAs), in which sequences fully complementary to cellular nucleic acids (e.g. mRNAs) sequences mediate degradation or in which sequences incompletely complementary to cellular nucleic acids (e.g., mRNAs) mediate translational repression when expressed within cells. In another embodiment, double stranded siRNAs can be processed into single stranded antisense RNAs that bind single stranded cellular RNAs (e.g., microRNAs) and inhibit their expression. RNA interference (RNAi) is the process of sequence-specific, post-transcriptional gene silencing in animals and plants, initiated by double-stranded RNA (dsRNA) that is homologous in sequence to the silenced gene. In vivo, long dsRNA is cleaved by ribonuclease III to generate 21- and 22-nucleotide siRNAs. It has been shown that 21-nucleotide siRNA duplexes specifically suppress expression of endogenous and heterologous genes in different mammalian cell lines, including human embryonic kidney (293) and HeLa cells (Elbashir et al. (2001) Nature 411:494-498). Accordingly, translation of a gene in a cell can be inhibited by contacting the cell with short double stranded RNAs having a length of about 15 to 30 nucleotides or of about 18 to 21 nucleotides or of about 19 to 21 nucleotides. Alternatively, a vector encoding for such siRNAs or short hairpin RNAs (shRNAs) that are metabolized into siRNAs can be introduced into a target cell (see, e.g., McManus et al (2002) RNA 8:842; Xia et al. (2002) Nature Biotechnology 20:1006; and Brummelkamp et al. (2002) Science 296:550). Vectors that can be used are commercially available, e.g., from OligoEngine under the name pSuper RNAi System.

(180) Ribozyme molecules designed to catalytically cleave cellular mRNA transcripts can also be used to prevent translation of cellular mRNAs and expression of cellular polypeptides, or both (See, e.g., PCT International Publication WO90/11364, published Oct. 4, 1990; Sarver et al. (1990) Science 247:1222-1225 and U.S. Pat. No. 5,093,246). While ribozymes that cleave mRNA at site-specific recognition sequences can be used to destroy cellular mRNAs, the use of hammerhead ribozymes is preferred. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions that form complementary base pairs with the target mRNA. The sole requirement is that the target mRNA have the following sequence of two bases: 5-UG-3 The construction and production of hammerhead ribozymes is well-known in the art and is described more fully in Haseloff and Gerlach (1988) Nature 334:585-591. The ribozyme may be engineered so that the cleavage recognition site is located near the 5 end of cellular mRNAs; i.e., to increase efficiency and minimize the intracellular accumulation of non-functional mRNA transcripts.

(181) The ribozymes of the methods presented herein also include RNA endoribonucleases (hereinafter Cech-type ribozymes) such as the one which occurs naturally in Tetrahymena thermophila (known as the IVS, or L-19 IVS RNA) and which has been extensively described by Thomas Cech and collaborators (Zaug et al. (1984) Science 224:574-578; Zaug et al. (1986) Science 231:470-475; Zaug et al. (1986) Nature 324:429-433; WO 88/04300; and Been et al. (1986) Cell 47:207-216). The Cech-type ribozymes have an eight base pair active site which hybridizes to a target RNA sequence whereafter cleavage of the target RNA takes place. The methods and compositions presented herein encompasses those Cech-type ribozymes which target eight base-pair active site sequences that are present in cellular genes.

(182) As in the antisense approach, the ribozymes can be composed of modified oligonucleotides (e.g., for improved stability, targeting, etc.). A preferred method of delivery involves using a DNA construct encoding the ribozyme under the control of a strong constitutive pol III or pol II promoter, so that transfected cells will produce sufficient quantities of the ribozyme to destroy endogenous cellular messages and inhibit translation. Because ribozymes unlike antisense molecules, are catalytic, a lower intracellular concentration is required for efficiency.

(183) Nucleic acid molecules to be used in triple helix formation for the inhibition of transcription of cellular genes are preferably single stranded and composed of deoxyribonucleotides. The base composition of these oligonucleotides should promote triple helix formation via Hoogsteen base pairing rules, which generally require sizable stretches of either purines or pyrimidines to be present on one strand of a duplex. Nucleotide sequences may be pyrimidine-based, which will result in TAT and CGC triplets across the three associated strands of the resulting triple helix. The pyrimidine-rich molecules provide base complementarity to a purine-rich region of a single strand of the duplex in a parallel orientation to that strand. In addition, nucleic acid molecules may be chosen that are purine-rich, for example, containing a stretch of G residues. These molecules will form a triple helix with a DNA duplex that is rich in GC pairs, in which the majority of the purine residues are located on a single strand of the targeted duplex, resulting in CGC triplets across the three strands in the triplex.

(184) Alternatively, the potential sequences that can be targeted for triple helix formation may be increased by creating a so-called switchback nucleic acid molecule. Switchback molecules are synthesized in an alternating 5-3, 3-5 manner, such that they base pair with first one strand of a duplex and then the other, eliminating the necessity for a sizable stretch of either purines or pyrimidines to be present on one strand of a duplex.

(185) Small nucleic acids (e.g., miRNAs, pre-miRNAs, pri-miRNAs, miRNA*, anti-miRNA, or a miRNA binding site, or a variant thereof), antisense oligonucleotides, ribozymes, and triple helix molecules of the methods and compositions presented herein may be prepared by any method known in the art for the synthesis of DNA and RNA molecules. These include techniques for chemically synthesizing oligodeoxyribonucleotides and oligoribonucleotides well-known in the art such as for example solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors which incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.

(186) Moreover, various well-known modifications to nucleic acid molecules may be introduced as a means of increasing intracellular stability and half-life. Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5 and/or 3 ends of the molecule or the use of phosphorothioate or 2 O-methyl rather than phosphodiesterase linkages within the oligodeoxyribonucleotide backbone. One of skill in the art will readily understand that polypeptides, small nucleic acids, and antisense oligonucleotides can be further linked to another peptide or polypeptide (e.g., a heterologous peptide), e.g., that serves as a means of protein detection. Non-limiting examples of label peptide or polypeptide moieties useful for detection in the invention include, without limitation, suitable enzymes such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; epitope tags, such as FLAG, MYC, HA, or HIS tags; fluorophores such as green fluorescent protein; dyes; radioisotopes; digoxygenin; biotin; antibodies; polymers; as well as others known in the art, for example, in Principles of Fluorescence Spectroscopy, Joseph R. Lakowicz (Editor), Plenum Pub Corp, 2nd edition (July 1999).

(187) The present invention also contemplates well-known methods for genetically modifying the genome of an organism or cell to modify the expression and/or activity of PTEN and/or p53 without contacting the organism or cell with agent once the genetic modification has been completed. For example, cancer cells can be genetically modified using recombinant techniques in order to modulate the expression and/or activity of PTEN and/or p53, such that no agent needs to contact the cancer cells in order for the expression and/or activity PTEN and/or p53 to be modulated. For example, targeted or untargeted gene knockout methods can be used, such as to recombinantly engineer subject cancer cell ex vivo prior to infusion into the subject. For example, the target DNA in the genome can be manipulated by deletion, insertion, and/or mutation using retroviral insertion, artificial chromosome techniques, gene insertion, random insertion with tissue specific promoters, gene targeting, transposable elements and/or any other method for introducing foreign DNA or producing modified DNA/modified nuclear DNA. Other modification techniques include deleting DNA sequences from a genome and/or altering nuclear DNA sequences. Nuclear DNA sequences, for example, may be altered by site-directed mutagenesis. Such methods generally use host cells into which a recombinant expression vector of the invention has been introduced. The terms host cell and recombinant host cell are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms transformation and transfection are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (supra), and other laboratory manuals. For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

(188) Similarly, the CRISPR-Cas system can be used for precise editing of genomic nucleic acids (e.g., for creating null mutations). In such embodiments, the CRISPR guide RNA and/or the Cas enzyme may be expressed. For example, a vector containing only the guide RNA can be administered to an animal or cells transgenic for the Cas9 enzyme. Similar strategies may be used (e.g., designer zinc finger, transcription activator-like effectors (TALEs) or homing meganucleases). Such systems are well-known in the art (see, for example, U.S. Pat. No. 8,697,359; Sander and Joung (2014) Nat. Biotech. 32:347-355; Hale et al. (2009) Cell 139:945-956; Karginov and Hannon (2010) Mol. Cell 37:7; U.S. Pat. Publ. 2014/0087426 and 2012/0178169; Boch et al. (2011) Nat. Biotech. 29:135-136; Boch et al. (2009) Science 326:1509-1512; Moscou and Bogdanove (2009) Science 326:1501; Weber et al. (2011) PLoS One 6:e19722; Li et al. (2011) Nucl. Acids Res. 39:6315-6325; Zhang et al. (2011) Nat. Biotech. 29:149-153; Miller et al. (2011) Nat. Biotech. 29:143-148; Lin et al. (2014) Nucl. Acids Res. 42:e47). Such genetic strategies can use constitutive expression systems or inducible expression systems according to well-known methods in the art.

(189) In some embodiments, the cancer cells are non-replicative. In certain embodiments, the cancer cells are non-replicative due to irradiation (e.g., and/or UV irradiation), and/or administration of an agent rendering cell replication incompetent (e.g., compounds that disrupt the cell membrane, inhibitors of DNA replication, inhibitors of spindle formation during cell division, etc.). Typically a minimum dose of about 3500 rads radiation is sufficient, although doses up to about 30,000 rads are acceptable. In some embodiments, a sub-lethal dose of irradiation may be used. For example, the cancer cells may be irradiated to suppress cell proliferation before administration of the cancer vaccine to reduce the risk of giving rise to new neoplastic lesions. It is understood that irradiation is only one way to render the cells non-replicative, and that other methods which result in cancer cells incapable of cell division but that retain the ability to to trigger the antitumor immunity upon activation of the TGF-Smad/p63 signaling pathway are included in the present invention.

(190) c. Agents that Activate TGF-Smad/p63 Signaling Pathway

(191) It is demonstrated herein that activation of TGF-Smad/p63 axis in cancer cells regulates expression of multiple pathways that promote immune respons and ultimately activation of cytotoxic T cells and immunological memory. Thus, the cancer cells encompassed by the present invention described herein are modified to activate TGF-Smad/p63 signaling pathway. In one embodiments, the cancer cells are contacted with a TGF superfamily protein to activate TGF-Smad/p63 signaling pathway. In another embodiment, the cancer cells are contacted with a modulator of the copy number, the expression, and/or the activity of one or more biomarkers listed in Table 1 that can activate TGF-Smad/p63 signaling pathway. The cancer cells (e.g., cancer cell lines or tumor tissues) can be cultured in 2D or 3D (e.g., cultured as tumorspheres or organoids) in vitro or ex vivo.

(192) In some embodiments, cancer vaccine comprising the modified cancer cells described herein may be tested for certain desired characteristics or functions prior to administration into a subject. In one embodiment, the loss of PTEN and p53 is confirmed in the modified cancer cells. In another embodiment, the activation of the TGF-Smad/p63 signaling pathway is detected in the modified cancer cells. In still another embodiment, the modified cancer cells are tested for one or more of the following properties: a) reduced grow rate in either a 2D- or 3D-culture system; b) activation of the TGF-Smad/p63 signatures, such as upregulation of ICOSL, PYCARD, SFN, PERP, RIPK3, CASP9, and/or SESN1; and/or downregulation of KSR1, EIF4EBP1, ITGA5, EMILIN1, CD200, and/or CSF1; c) upregulation of one or more dendritic cells (DCs) activation markers, which include but are not limited to, CD40, CD80, CD86, CD8, HLA-DR, IL1-beta, etc.; and/or d) activation of T cells in the presence of DCs, such as increasing the secretion of TNF and/or IFN by T cells in the presence of DCs.
i. TGF Superfamily Proteins

(193) In one embodiment, PTEN- and p53-deficient cancer cells described herein are contacted with a TGF superfamily protein to activate the TGF-Smad/p63 signaling pathway. The TGF superfamily protein can be any member of the TGF superfamily that is capable of activating the TGF-Smad/p63 signaling pathway. The TGF superfamily protein may be from the TGF family, which includes but is not limitated to, LAP, TGF1, TGF2, TGF3, and TGF5. The TGF superfamily protein may be from the Activin family, which includes but is not limitated to, Activin A, Activin AB, Activin AC, Activin B, Activin C, C17ORF99, INHBA, INHBB, Inhibin, Inhibin A, and Inhibin B. The TGF superfamily protein may be from the BMP (Bone Morphogenetic Protein) family, BMP-1/PCP, BMP-2, BMP-2/BMP-6 Heterodimer, BMP-2/BMP-7 Heterodimer, BMP-2a, BMP-3, BMP-3b/GDF-10, BMP-4, BMP-4/BMP-7 Heterodimer, BMP-5, BMP-6, BMP-7, BMP-8, BMP-8a, BMP-8b, BMP-9, BMP-10, BMP-15/GDF-9B, and Decapentaplegic/DPP. The TGF superfamily protein may be from the GDNF Family, Artemin, GDNF, Neurturin, and Persephin. The TGF superfamily protein may be from a family other than the ones listed above, which includes but is not limitated to, Lefty A, Lefty B, MIS/AMH, Nodal, and SCUBE3. In certain embodiments, the TGF superfamily protein is TGF1, TGF2 and/or TGF3. In one embodiment, the cancer cells are contacted with a single TGF superfamily protein (e.g., TGF1, TGF2, or TGF3). In another embodiment, the cancer cells are contacted with a combination of TGF superfamily proteins (e.g., a combination of TGF1, TGF2 and TGF3).

(194) The cancer cells may be contacted with a TGF superfamily protein alone in vitro, in vivo, and/or ex vivo. In one embodiment, the cancer cells are contacted with a TGF superfamily protein in vitro or ex vivo, and then the cancer cells are administered to a subject without administration of the TGF superfamily protein to the subject in vivo. In another embodiment, the cancer cells are administered to a subject, wherein the TGF superfamily protein is administered to the subject to thereby contact the cancer cells in vivo. In still another embodiment, the cancer cells are contacted with a TGF superfamily protein in vitro or ex vivo, and then the cancer cells are administered to a subject with administration of the TGF superfamily protein to the subject in vivo. The TGF superfamily protein may be administered to the subject before, after, and/or concurrently with administration of the cancer cells. In some embodiments, the cancer cells are contacted with the TGF superfamily protein in combination with an immune checkpoint blockade in vitro, in vivo, and/or ex vivo. The subject may be administered with an immune checkpoint blockade before, after, and/or concurrently with administration of the cancer vaccine.

(195) The dosage of the TGF superfamily protein may be varied so as to obtain an amount of the activation of TGF-Smad/p63 signaling pathway which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

(196) The selected dosage level will depend upon a variety of factors including the activity of the particular TGF superfamily protein employed, the specific type of cancer cells to be contacted with, the route of administration, the time of administration, the rate of excretion or metabolism of the particular TGF superfamily protein being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular TGF superfamily protein employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated with the cancer vaccine, and like factors well known in the medical arts.

(197) In some embodiments, the cancer cells are contacted with a TGF superfamily protein at a dosage more than 0.1 ng/ml, such as more than 0.2 ng/ml, more than 0.3 ng/ml, more than 0.4 ng/ml, more than 0.5 ng/ml, more than 0.6 ng/ml, more than 0.7 ng/ml, more than 0.8 ng/ml, more than 0.9 ng/ml, more than 1 ng/ml, more than 1.5 ng/ml, more than 2 ng/ml, more than 2.5 ng/ml, more than 3 ng/ml, more than 3.5 ng/ml, more than 4 ng/ml, more than 4.5 ng/ml, more than 5 ng/ml, more than 5.5 ng/ml, more than 6 ng/ml, more than 6.5 ng/ml, more than 7 ng/ml, more than 7.5 ng/ml, more than 8 ng/ml, more than 8.5 ng/ml, more than 9 ng/ml, more than 9.5 ng/ml, more than 10 ng/ml, etc.

(198) In some embodiments, the cancer cells are contacted with a TGF superfamily protein at a dosage from about 0.1 ng/ml to about 100 ng/ml. In preferred embodiments, the cancer cells are contacted with a TGF superfamily protein at a dosage from about 1 ng/ml to about 10 ng/ml, such as about 1 ng/ml, 1.5 ng/ml, 2 ng/ml, 2.5 ng/ml, 3 ng/ml, 3.5 ng/ml, 4 ng/ml, 4.5 ng/ml, 5 ng/ml, 5.5 ng/ml, 6 ng/ml, 6.5 ng/ml, 7 ng/ml, 7.5 ng/ml, 8 ng/ml, 8.5 ng/ml, 9 ng/ml, 9.5 ng/ml, or 10 ng/ml or any value in between.

(199) In some embodiments, the cancer cells are contacted with a TGF superfamily protein for a period of time. The period of time may be from minutes to 4 weeks, such as 10 min, 30 min, 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 36 hours, 2 days, 2.5 days, 3 days, 3.5 days, 4 days, 4.5 days, 5 days, 5.5 days, 6 days, 6.5 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days or any value in between. Preferred ranges of the period of time are from about 6 hours to about 21 days, from about 12 hours to about 15 days, from about 1 day to about 10 days, or from about 3 days to about 7 days.

(200) ii. Agents that Increase the Copy Number, Amount, and/or Activity of at Least One Biomarker Listed in Table 1

(201) In another embodiment, the PTNE- and p53-deficient cancer cells described herein are contacted with a modulator of the copy number, the expression, and/or the activity of one or more biomarkers listed in Table 1 and thereby activate the TGF-Smad/p63 signaling pathway. Agents that increase the copy number, the expression, and/or the activity of one or more biomarkers listed in Table 1 can do so either directly or indirectly.

(202) Agents useful in the methods encompassed by the present invention include antibodies, small molecules, peptides, peptidomimetics, natural ligands, derivatives of natural ligands, etc. that can bind and/or modulate one or more biomarkers listed in Table 1, or fragments thereof; RNA interference, antisense, nucleic acid aptamers, nucleic acid, polypeptide, etc. that can increase the expression and/or activity of one or more biomarkers listed in Table 1, or fragments thereof.

(203) In one embodiment, isolated nucleic acid molecules that specifically hybridize with or encode one or more biomarkers listed in Table 1 or biologically active portions thereof. As used herein, the term nucleic acid molecule is intended to include DNA molecules (i.e., cDNA or genomic DNA) and RNA molecules (i.e., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA. An isolated nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an isolated nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5 and 3 ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated nucleic acid molecules corresponding to one or more biomarkers listed in Table 1 can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived (i.e., a lymphoma cell). Moreover, an isolated nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized.

(204) A nucleic acid molecule encompassed by the present invention, e.g., a nucleic acid molecule having the nucleotide sequence of one or more biomarkers listed in Table 1 or a nucleotide sequence which is at least about 50%, preferably at least about 60%, more preferably at least about 70%, yet more preferably at least about 80%, still more preferably at least about 90%, and most preferably at least about 95% or more (e.g., about 98%) homologous to the nucleotide sequence of one or more biomarkers listed in Table 1 or a portion thereof (i.e., 100, 200, 300, 400, 450, 500, or more nucleotides), can be isolated using standard molecular biology techniques and the sequence information provided herein. For example, a human cDNA can be isolated from a human cell line (from Stratagene, LaJolla, California, or Clontech, Palo Alto, CA) using all or portion of the nucleic acid molecule, or fragment thereof, as a hybridization probe and standard hybridization techniques (i.e., as described in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989). Moreover, a nucleic acid molecule encompassing all or a portion of the nucleotide sequence of one or more biomarkers listed in Table 1 or a nucleotide sequence which is at least about 50%, preferably at least about 60%, more preferably at least about 70%, yet more preferably at least about 80%, still more preferably at least about 90%, and most preferably at least about 95% or more homologous to the nucleotide sequence, or fragment thereof, can be isolated by the polymerase chain reaction using oligonucleotide primers designed based upon one or more biomarkers listed in Table 1, or fragment thereof, or the homologous nucleotide sequence. For example, mRNA can be isolated from muscle cells (i.e., by the guanidinium-thiocyanate extraction procedure of Chirgwin et al. (1979) Biochemistry 18: 5294-5299) and cDNA can be prepared using reverse transcriptase (i.e., Moloney MLV reverse transcriptase, available from Gibco/BRL, Bethesda, MD; or AMV reverse transcriptase, available from Seikagaku America, Inc., St. Petersburg, FL). Synthetic oligonucleotide primers for PCR amplification can be designed according to well-known methods in the art. A nucleic acid encompassed by the present invention can be amplified using cDNA or, alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to the nucleotide sequence of one or more biomarkers listed in Table 1 can be prepared by standard synthetic techniques, i.e., using an automated DNA synthesizer.

(205) Probes based on the nucleotide sequences of one or more biomarkers listed in Table 1 can be used to detect or confirm the desired transcripts or genomic sequences encoding the same or homologous proteins. In preferred embodiments, the probe further comprises a label group attached thereto, i.e., the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissue which express one or more biomarkers listed in Table 1, such as by measuring a level of nucleic acid of one or more biomarkers listed in Table 1 in a sample of cells from a subject, i.e., detecting mRNA levels of one or more biomarkers listed in Table 1.

(206) Nucleic acid molecules encoding proteins corresponding to one or more biomarkers listed in Table 1 from different species are also contemplated. For example, rat or monkey cDNA can be identified based on the nucleotide sequence of a human and/or mouse sequence and such sequences are well-known in the art. In one embodiment, the nucleic acid molecule(s) encompassed by the present invention encodes a protein or portion thereof which includes an amino acid sequence which is sufficiently homologous to an amino acid sequence of one or more biomarkers listed in Table 1, such that the protein or portion thereof modulates (e.g., enhance), one or more of the following biological activities: a) binding to the biomarker; b) modulating the copy number of the biomarker; c) modulating the expression level of the biomarker; and d) modulating the activity level of the biomarker.

(207) As used herein, the language sufficiently homologous refers to proteins or portions thereof which have amino acid sequences which include a minimum number of identical or equivalent (e.g., an amino acid residue which has a similar side chain as an amino acid residue in one or more biomarkers listed in Table 1, or fragment thereof) amino acid residues to an amino acid sequence of the biomarker, or fragment thereof, such that the protein or portion thereof modulates (e.g., enhance) one or more of the following biological activities: a) binding to the biomarker; b) modulating the copy number of the biomarker; c) modulating the expression level of the biomarker; and d) modulating the activity level of the biomarker.

(208) In another embodiment, the protein is at least about 30%, preferably at least about 60%, more preferably at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more homologous to the entire amino acid sequence of the biomarker, or a fragment thereof.

(209) Portions of proteins encoded by nucleic acid molecules of one or more biomarkers listed in Table 1 are preferably biologically active portions of the protein. As used herein, the term biologically active portion of one or more biomarkers listed in Table 1 is intended to include a portion, e.g., a domain/motif, that has one or more of the biological activities of the full-length protein.

(210) Standard binding assays, e.g., immunoprecipitations and yeast two-hybrid assays, as described herein, or functional assays, e.g., RNAi or overexpression experiments, can be performed to determine the ability of the protein or a biologically active fragment thereof to maintain a biological activity of the full-length protein.

(211) The invention further encompasses nucleic acid molecules that differ from the nucleotide sequence of one or more biomarkers listed in Table 1, or fragment thereof due to degeneracy of the genetic code and thus encode the same protein as that encoded by the nucleotide sequence, or fragment thereof. In another embodiment, an isolated nucleic acid molecule encompassed by the present invention has a nucleotide sequence encoding a protein having an amino acid sequence of one or more biomarkers listed in Table 1, or fragment thereof, or a protein having an amino acid sequence which is at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more homologous to the amino acid sequence of one or more biomarkers listed in Table 1, or fragment thereof. In another embodiment, a nucleic acid encoding a polypeptide consists of nucleic acid sequence encoding a portion of a full-length fragment of interest that is less than 195, 190, 185, 180, 175, 170, 165, 160, 155, 150, 145, 140, 135, 130, 125, 120, 115, 110, 105, 100, 95, 90, 85, 80, 75, or 70 amino acids in length.

(212) It will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of one or more biomarkers listed in Table 1 may exist within a population (e.g., a mammalian and/or human population). Such genetic polymorphisms may exist among individuals within a population due to natural allelic variation. As used herein, the terms gene and recombinant gene refer to nucleic acid molecules comprising an open reading frame encoding one or more biomarkers listed in Table 1, preferably a mammalian, e.g., human, protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of one or more biomarkers listed in Table 1. Any and all such nucleotide variations and resulting amino acid polymorphisms in one or more biomarkers listed in Table 1 that are the result of natural allelic variation and that do not alter the functional activity of one or more biomarkers listed in Table 1 are intended to be within the scope encompassed by the present invention. Moreover, nucleic acid molecules encoding proteins of one or more biomarkers listed in Table 1 from other species.

(213) In addition to naturally-occurring allelic variants of one or more biomarkers listed in Table 1 that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequence, or fragment thereof, thereby leading to changes in the amino acid sequence of the encoded one or more biomarkers listed in Table 1, without altering the functional ability of one or more biomarkers listed in Table 1. For example, nucleotide substitutions leading to amino acid substitutions at non-essential amino acid residues can be made in the sequence, or fragment thereof. A non-essential amino acid residue is a residue that can be altered from the wild-type sequence of one or more biomarkers listed in Table 1 without altering the activity of one or more biomarkers listed in Table 1, whereas an essential amino acid residue is required for the activity of one or more biomarkers listed in Table 1. Other amino acid residues, however, (e.g., those that are not conserved or only semi-conserved between mouse and human) may not be essential for activity and thus are likely to be amenable to alteration without altering the activity of one or more biomarkers listed in Table 1.

(214) The term sequence identity or homology refers to the sequence similarity between two polypeptide molecules or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous or sequence identical at that position. The percent of homology or sequence identity between two sequences is a function of the number of matching or homologous identical positions shared by the two sequences divided by the number of positions compared 100. For example, if 6 of 10, of the positions in two sequences are the same then the two sequences are 60% homologous or have 60% sequence identity. By way of example, the DNA sequences ATTGCC and TATGGC share 50% homology or sequence identity. Generally, a comparison is made when two sequences are aligned to give maximum homology. Unless otherwise specified loop out regions, e.g., those arising from, from deletions or insertions in one of the sequences are counted as mismatches.

(215) The comparison of sequences and determination of percent homology between two sequences can be accomplished using a mathematical algorithm. Preferably, the alignment can be performed using the Clustal Method. Multiple alignment parameters include GAP Penalty=10, Gap Length Penalty=10. For DNA alignments, the pairwise alignment parameters can be Htuple=2, Gap penalty=5, Window=4, and Diagonal saved=4. For protein alignments, the pairwise alignment parameters can be Ktuple=1, Gap penalty=3, Window=5, and Diagonals Saved=5.

(216) In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available online), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available online), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0) (available online), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

(217) An isolated nucleic acid molecule encoding a protein homologous to one or more biomarkers listed in Table 1, or fragment thereof, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence, or fragment thereof, or a homologous nucleotide sequence such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted non-essential amino acid residues. A conservative amino acid substitution is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted nonessential amino acid residue in one or more biomarkers listed in Table 1 is preferably replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of the coding sequence of one or more biomarkers listed in Table 1, such as by saturation mutagenesis, and the resultant mutants can be screened for an activity described herein to identify mutants that retain desired activity. Following mutagenesis, the encoded protein can be expressed recombinantly according to well-known methods in the art and the activity of the protein can be determined using, for example, assays described herein.

(218) The levels of one or more biomarkers listed in Table 1 may be assessed by any of a wide variety of well-known methods for detecting expression of a transcribed molecule or protein. Non-limiting examples of such methods include immunological methods for detection of proteins, protein purification methods, protein function or activity assays, nucleic acid hybridization methods, nucleic acid reverse transcription methods, and nucleic acid amplification methods.

(219) In preferred embodiments, the levels of one or more biomarkers listed in Table 1 are ascertained by measuring gene transcript (e.g., mRNA), by a measure of the quantity of translated protein, or by a measure of gene product activity. Expression levels can be monitored in a variety of ways, including by detecting mRNA levels, protein levels, or protein activity, any of which can be measured using standard techniques. Detection can involve quantification of the level of gene expression (e.g., genomic DNA, cDNA, mRNA, protein, or enzyme activity), or, alternatively, can be a qualitative assessment of the level of gene expression, in particular in comparison with a control level. The type of level being detected will be clear from the context.

(220) In a particular embodiment, the mRNA expression level can be determined both by in situ and by in vitro formats in a biological sample using methods known in the art. The term biological sample is intended to include tissues, cells, biological fluids and isolates thereof, isolated from a subject, as well as tissues, cells and fluids present within a subject. Many expression detection methods use isolated RNA. For in vitro methods, any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of RNA from cells (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York 1987-1999). Additionally, large numbers of tissue samples can readily be processed using techniques well-known to those of skill in the art, such as, for example, the single-step RNA isolation process of Chomczynski (1989, U.S. Pat. No. 4,843,155).

(221) The isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays. One preferred diagnostic method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to the mRNA encoded by the gene being detected. The nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to a mRNA or genomic DNA encoding one or more biomarkers listed in Table 1. Other suitable probes for use in the diagnostic assays encompassed by the present invention are described herein. Hybridization of an mRNA with the probe indicates that one or more biomarkers listed in Table 1 is being expressed.

(222) In one format, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative format, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in a gene chip array, e.g., an Affymetrix gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in detecting the level of one or more biomarkers listed in Table 1 mRNA expression levels.

(223) An alternative method for determining mRNA expression level in a sample involves the process of nucleic acid amplification, e.g., by RT-PCR (the experimental embodiment set forth in Mullis, 1987, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany, 1991, Proc. Natl. Acad. Sci. USA, 88:189-193), self sustained sequence replication (Guatelli et al., 1990, Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al., 1989, Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi et al., 1988, Bio/Technology 6:1197), rolling circle replication (Lizardi et al., U.S. Pat. No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well-known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. As used herein, amplification primers are defined as being a pair of nucleic acid molecules that can anneal to 5 or 3 regions of a gene (plus and minus strands, respectively, or vice-versa) and contain a short region in between. In general, amplification primers are from about 10 to 30 nucleotides in length and flank a region from about 50 to 200 nucleotides in length. Under appropriate conditions and with appropriate reagents, such primers permit the amplification of a nucleic acid molecule comprising the nucleotide sequence flanked by the primers.

(224) For in situ methods, mRNA does not need to be isolated from the cells prior to detection. In such methods, a cell or tissue sample is prepared/processed using known histological methods. The sample is then immobilized on a support, typically a glass slide, and then contacted with a probe that can hybridize to mRNA of one or more biomarkers listed in Table 1.

(225) As an alternative to making determinations based on the absolute expression level, determinations may be based on the normalized expression level of one or more biomarkers listed in Table 1. Expression levels are normalized by correcting the absolute expression level by comparing its expression to the expression of a non-biomarker gene, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene, or epithelial cell-specific genes. This normalization allows the comparison of the expression level in one sample, e.g., a subject sample, to another sample, e.g., a normal sample, or between samples from different sources.

(226) The level or activity of a protein corresponding to one or more biomarkers listed in Table 1 can also be detected and/or quantified by detecting or quantifying the expressed polypeptide. The polypeptide can be detected and quantified by any of a number of means well-known to those of skill in the art. These may include analytic biochemical methods such as electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitin reactions, immunodiffusion (single or double), immunoelectrophoresis, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, Western blotting, and the like. A skilled artisan can readily adapt known protein/antibody detection methods for use in determining whether cells express the biomarker of interest.

(227) The present invention further provides soluble, purified and/or isolated polypeptide forms of one or more biomarkers listed in Table 1, or fragments thereof. In addition, it is to be understood that any and all attributes of the polypeptides described herein, such as percentage identities, polypeptide lengths, polypeptide fragments, biological activities, antibodies, etc. can be combined in any order or combination with respect to one or more biomarkers listed in Table 1.

(228) In one aspect, a polypeptide may comprise a full-length amino acid sequence corresponding to one or more biomarkers listed in Table 1 or a full-length amino acid sequence with 1 to about 20 conservative amino acid substitutions. An amino acid sequence of any described herein can also be at least 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 99.5% identical to the full-length sequence of one or more biomarkers listed in Table 1, which is either described herein, well-known in the art, or a fragment thereof. In another aspect, the present invention contemplates a composition comprising an isolated polypeptide corresponding to polypeptide of one or more biomarkers listed in Table 1 and less than about 25%, or alternatively 15%, or alternatively 5%, contaminating biological macromolecules or polypeptides.

(229) The present invention further provides compositions related to producing, detecting, or characterizing such polypeptides, or fragment thereof, such as nucleic acids, vectors, host cells, and the like. Such compositions may serve as compounds that modulate (e.g., enhance) the expression and/or activity of one or more biomarkers listed in Table 1.

(230) An isolated polypeptide or a fragment thereof (or a nucleic acid encoding such a polypeptide) corresponding to one or more biomarkers listed in Table 1, can be used as an immunogen to generate antibodies that bind to said immunogen, using standard techniques for polyclonal and monoclonal antibody preparation according to well-known methods in the art. An antigenic peptide comprises at least 8 amino acid residues and encompasses an epitope present in the respective full length molecule such that an antibody raised against the peptide forms a specific immune complex with the respective full length molecule. Preferably, the antigenic peptide comprises at least 10 amino acid residues. In one embodiment such epitopes can be specific for a given polypeptide molecule from one species, such as mouse or human (i.e., an antigenic peptide that spans a region of the polypeptide molecule that is not conserved across species is used as immunogen; such non conserved residues can be determined using an alignment such as that provided herein).

(231) In one embodiment, an antibody, especially an intrabody, binds substantially specifically to one or more biomarkers listed in Table 1, and enhances its biological function. In another embodiment, an antibody, especially an intrabody, binds substantially specifically to a binding partner of one or more biomarkers listed in Table 1, and enhances its biological function.

(232) Antibodies for use according to the present invention can be generated according to well-known methods in the art. For example, a polypeptide immunogen typically is used to prepare antibodies by immunizing a suitable subject (e.g., rabbit, goat, mouse or other mammal) with the immunogen. An appropriate immunogenic preparation can contain, for example, a recombinantly expressed or chemically synthesized molecule or fragment thereof to which the immune response is to be generated. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or similar immunostimulatory agent. Immunization of a suitable subject with an immunogenic preparation induces a polyclonal antibody response to the antigenic peptide contained therein.

(233) Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a polypeptide immunogen. The polypeptide antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide. If desired, the antibody directed against the antigen can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A chromatography, to obtain the IgG fraction. At an appropriate time after immunization, e.g., when the antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique (originally described by Kohler and Milstein (1975) Nature 256:495-497) (see also Brown et al. (1981) J. Immunol. 127:539-46; Brown et al. (1980) J. Biol. Chem. 255:4980-83; Yeh et al. (1976) Proc. Natl. Acad. Sci. 76:2927-31; Yeh et al. (1982) Int. J. Cancer 29:269-75), the more recent human B cell hybridoma technique (Kozbor et al. (1983) Immunol. Today 4:72), the EBV-hybridoma technique (Cole et al. (1985) Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96) or trioma techniques. The technology for producing monoclonal antibody hybridomas is well-known (see generally Kenneth, R. H. in Monoclonal Antibodies: A New Dimension In Biological Analyses, Plenum Publishing Corp., New York, New York (1980); Lerner, E. A. (1981) Yale J. Biol. Med. 54:387-402; Gefter, M. L. et al. (1977) Somatic Cell Genet. 3:231-36). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with an immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds to the polypeptide antigen, preferably specifically.

(234) Any of the many well-known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating a monoclonal antibody against one or more biomarkers listed in Table 1, or a fragment thereof (see, e.g., Galfre, G. et al. (1977) Nature 266:55052; Gefter et al. (1977) supra; Lerner (1981) supra; Kenneth (1980) supra). Moreover, the ordinary skilled worker will appreciate that there are many variations of such methods which also would be useful. Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. For example, murine hybridomas can be made by fusing lymphocytes from a mouse immunized with an immunogenic preparation encompassed by the present invention with an immortalized mouse cell line. Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine (HAT medium). Any of a number of myeloma cell lines can be used as a fusion partner according to standard techniques, e.g., the P3-NS1/1-Ag4-1, P3-x63-Ag8.653 or Sp2/O-Ag14 myeloma lines. These myeloma lines are available from the American Type Culture Collection (ATCC), Rockville, MD Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol (PEG). Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed). Hybridoma cells producing a monoclonal antibody encompassed by the present invention are detected by screening the hybridoma culture supernatants for antibodies that bind a given polypeptide, e.g., using a standard ELISA assay.

(235) As an alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal specific for one of the above described polypeptides can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the appropriate polypeptide to thereby isolate immunoglobulin library members that bind the polypeptide. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening an antibody display library can be found in, for example, Ladner et al. U.S. Pat. No. 5,223,409; Kang et al. International Publication No. WO 92/18619; Dower et al. International Publication No. WO 91/17271; Winter et al. International Publication WO 92/20791; Markland et al. International Publication No. WO 92/15679; Breitling et al. International Publication WO 93/01288; McCafferty et al. International Publication No. WO 92/01047; Garrard et al. International Publication No. WO 92/09690; Ladner et al. International Publication No. WO 90/02809; Fuchs et al. (1991) Biotechnology (NY) 9:1369-1372; Hay et al. (1992) Hum. Antibod. Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffiths et al. (1993) EMBO J. 12:725-734; Hawkins et al. (1992)J Mol. Biol. 226:889-896; Clarkson et al. (1991) Nature 352:624-628; Gram et al. (1992) Proc. Natl. Acad. Sci. USA 89:3576-3580; Garrard et at (1991) Biotechnology (NY) 9:1373-1377; Hoogenboom et al. (1991) Nucleic Acids Res. 19:4133-4137; Barbas et al. (1991) Proc. Natl. Acad. Sci. USA 88:7978-7982; and McCafferty et al. (1990) Nature 348:552-554.

(236) Since it is well-known in the art that antibody heavy and light chain CDR3 domains play a particularly important role in the binding specificity/affinity of an antibody for an antigen, the recombinant monoclonal antibodies encompassed by the present invention prepared as set forth above preferably comprise the heavy and light chain CDR3s of variable regions of antibodies of interest. The antibodies further can comprise the CDR2s of variable regions encompassed by the present invention. The antibodies further can comprise the CDR's of variable regions encompassed by the present invention. In other embodiments, the antibodies can comprise any combinations of the CDRs.

(237) The CDR1, 2, and/or 3 regions of the engineered antibodies described above can comprise the exact amino acid sequence(s) as those of variable regions encompassed by the present invention. However, the ordinarily skilled artisan will appreciate that some deviation from the exact CDR sequences may be possible while still retaining the ability of the antibody to bind a target of interest, such as one or more biomarkers listed in Table 1 and/or one or more natural binding partners effectively (e.g., conservative sequence modifications). Accordingly, in another embodiment, the engineered antibody may be composed of one or more CDRs that are, for example, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical to one or more CDRs encompassed by the present invention.

(238) For example, the structural features of non-human or human antibodies (e.g., a rat anti-mouse/anti-human antibody) can be used to create structurally related human antibodies, especially introbodies, that retain at least one functional property of the antibodies encompassed by the present invention, such as binding to one or more biomarkers listed in Table 1, binding partners/substrates of one or more biomarkers listed in Table 1, and/or an immune checkpoint. Another functional property includes inhibiting binding of the original known, non-human or human antibodies in a competition ELISA assay.

(239) A skilled artisan will note that such percentage homology is equivalent to and can be achieved by introducing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more conservative amino acid substitutions within a given CDR.

(240) The monoclonal antibodies encompassed by the present invention can comprise a heavy chain, wherein the variable domain comprises at least a CDR having a sequence selected from the group consisting of the heavy chain variable domain CDRs described herein, and a light chain, wherein the variable domain comprises at least a CDR having a sequence selected from the group consisting of the light chain variable domain CDRs described herein.

(241) Such monoclonal antibodies can comprise a light chain, wherein the variable domain comprises at least a CDR having a sequence selected from the group consisting of CDR-L1, CDR-L2, and CDR-L3, as described herein; and/or a heavy chain, wherein the variable domain comprises at least a CDR having a sequence selected from the group consisting of CDR-H1, CDR-H2, and CDR-H3, as described herein. In some embodiments, the monoclonal antibodies capable of binding one or more biomarkers listed in Table 1, comprises or consists of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3, as described herein.

(242) The heavy chain variable domain of the monoclonal antibodies encompassed by the present invention can comprise or consist of the vH amino acid sequence set forth herein and/or the light chain variable domain of the monoclonal antibodies encompassed by the present invention can comprise or consist of the v amino acid sequence set forth herein.

(243) The present invention further provides fragments of said monoclonal antibodies which include, but are not limited to, Fv, Fab, F(ab)2, Fab, dsFv, scFv, sc(Fv)2 and diabodies; and multispecific antibodies formed from antibody fragments. For example, a number of immunoinhibitory molecules, such as PD-L1, PD-1, CTLA-4, and the like, can be bound in a bispecific or multispecific manner.

(244) Other fragments of the monoclonal antibodies encompassed by the present invention are also contemplated. For example, individual immunoglobulin heavy and/or light chains are provided, wherein the variable domains thereof comprise at least a CDR described herein. In one embodiment, the immunoglobulin heavy chain comprises at least a CDR having a sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100% identical from the group of heavy chain or light chain variable domain CDRs described herein. In another embodiment, an immunoglobulin light chain comprises at least a CDR having a sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100% identical from the group of light chain or heavy chain variable domain CDRs described herein, are also provided.

(245) In some embodiments, the immunoglobulin heavy and/or light chain comprises a variable domain comprising at least one of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, or CDR-H3 described herein. Such immunoglobulin heavy chains can comprise or consist of at least one of CDR-H1, CDR-H2, and CDR-H3. Such immunoglobulin light chains can comprise or consist of at least one of CDR-L1, CDR-L2, and CDR-L3.

(246) In other embodiments, an immunoglobulin heavy and/or light chain according to the present invention comprises or consists of a vH or v variable domain sequence, respectively, described herein.

(247) The present invention further provides polypeptides which have a sequence selected from the group consisting of vH variable domain, v variable domain, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences described herein.

(248) Antibodies, immunoglobulins, and polypeptides encompassed by the present invention can be use in an isolated (e.g., purified) form or contained in a vector, such as a membrane or lipid vesicle (e.g. a liposome).

(249) Amino acid sequence modification(s) of the antibodies described herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. It is known that when a humanized antibody is produced by simply grafting only CDRs in VH and VL of an antibody derived from a non-human animal in FRs of the VH and VL of a human antibody, the antigen binding activity is reduced in comparison with that of the original antibody derived from a non-human animal. It is considered that several amino acid residues of the VH and VL of the non-human antibody, not only in CDRs but also in FRs, are directly or indirectly associated with the antigen binding activity. Hence, substitution of these amino acid residues with different amino acid residues derived from FRs of the VH and VL of the human antibody would reduce binding activity and can be corrected by replacing the amino acids with amino acid residues of the original antibody derived from a non-human animal.

(250) Modifications and changes may be made in the structure of the antibodies encompassed by the present invention, and in the DNA sequences encoding them, and still obtain a functional molecule that encodes an antibody and polypeptide with desirable characteristics. For example, certain amino acids may be substituted by other amino acids in a protein structure without appreciable loss of activity. Since the interactive capacity and nature of a protein define the protein's biological functional activity, certain amino acid substitutions can be made in a protein sequence, and, of course, in its DNA encoding sequence, while nevertheless obtaining a protein with like properties. It is thus contemplated that various changes may be made in the antibodies sequences encompassed by the present invention, or corresponding DNA sequences which encode said polypeptides, without appreciable loss of their biological activity.

(251) In making the changes in the amino sequences of polypeptide, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art. It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. Each amino acid has been assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (0.4); threonine (0.7); serine (0.8); tryptophane (0.9); tyrosine (1.3); proline (1.6); histidine (3.2); glutamate (3.5); glutamine (3.5); aspartate (<RTI 3.5); asparagine (3.5); lysine (3.9); and arginine (4.5).

(252) It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, i.e. still obtain a biological functionally equivalent protein.

(253) As outlined above, amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions which take various of the foregoing characteristics into consideration are well-known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

(254) Another type of amino acid modification of the antibody encompassed by the present invention may be useful for altering the original glycosylation pattern of the antibody to, for example, increase stability. By altering is meant deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that are not present in the antibody. Glycosylation of antibodies is typically N-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagines-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). Another type of covalent modification involves chemically or enzymatically coupling glycosides to the antibody. These procedures are advantageous in that they do not require production of the antibody in a host cell that has glycosylation capabilities for N- or O-linked glycosylation. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. For example, such methods are described in WO87/05330.

(255) Similarly, removal of any carbohydrate moieties present on the antibody may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the antibody to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), while leaving the antibody intact. Chemical deglycosylation is described by Sojahr et al. (1987) and by Edge et al. (1981). Enzymatic cleavage of carbohydrate moieties on antibodies can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al. (1987).

(256) Other modifications can involve the formation of immunoconjugates. For example, in one type of covalent modification, antibodies or proteins are covalently linked to one of a variety of non proteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.

(257) Conjugation of antibodies or other proteins encompassed by the present invention with heterologous agents can be made using a variety of bifunctional protein coupling agents including but not limited to N-succinimidyl (2-pyridyldithio) propionate (SPDP), succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, carbon labeled 1-isothiocyanatobenzyl methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody (WO 94/11026).

(258) In another aspect, the present invention features antibodies conjugated to a therapeutic moiety, such as a cytotoxin, a drug, and/or a radioisotope. When conjugated to a cytotoxin, these antibody conjugates are referred to as immunotoxins. A cytotoxin or cytotoxic agent includes any agent that is detrimental to (e.g., kills) cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine). An antibody encompassed by the present invention can be conjugated to a radioisotope, e.g., radioactive iodine, to generate cytotoxic radiopharmaceuticals for treating a related disorder, such as a cancer.

(259) Conjugated antibodies can be used diagnostically or prognostically to monitor polypeptide levels in tissue as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, P-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin (PE); an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include .sup.125I, .sup.35S, or .sup.3H. [0134] As used herein, the term labeled, with regard to the antibody, is intended to encompass direct labeling of the antibody by coupling (i.e., physically linking) a detectable substance, such as a radioactive agent or a fluorophore (e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5)) to the antibody, as well as indirect labeling of the antibody by reactivity with a detectable substance.

(260) The antibody conjugates encompassed by the present invention can be used to modify a given biological response. The therapeutic moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, an enzymatically active toxin, or active fragment thereof, such as abrin, ricin A, Pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor or interferon-.gamma.; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), or other cytokines or growth factors.

(261) Techniques for conjugating such therapeutic moiety to antibodies are well-known, see, e.g., Arnon et al., Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243 56 (Alan R. Liss, Inc. 1985); Hellstrom et al., Antibodies For Drug Delivery, in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623 53 (Marcel Dekker, Inc. 1987); Thorpe, Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review, in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475 506 (1985); Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303 16 (Academic Press 1985), and Thorpe et al., The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates, Immunol. Rev., 62:119 58 (1982).

(262) In some embodiments, conjugations can be made using a cleavable linker facilitating release of the cytotoxic agent or growth inhibitory agent in a cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (See e.g. U.S. Pat. No. 5,208,020) may be used. Alternatively, a fusion protein comprising the antibody and cytotoxic agent or growth inhibitory agent may be made, by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.

(263) Additionally, recombinant polypeptide antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope encompassed by the present invention. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al. International Patent Publication PCT/US86/02269; Akira et al. European Patent Application 184,187; Taniguchi, M. European Patent Application 171,496; Morrison et al. European Patent Application 173,494; Neuberger et al. PCT Application WO 86/01533; Cabilly et al. U.S. Pat. No. 4,816,567; Cabilly et al. European Patent Application 125,023; Better et al. (1988) Science 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. 84:214-218; Nishimura et al. (1987) Cancer Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; Shaw et al. (1988) J. Natl. Cancer Inst. 80:1553-1559); Morrison, S. L. (1985) Science 229:1202-1207; Oi et al. (1986) Biotechniques 4:214; Winter U.S. Pat. No. 5,225,539; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) J. Immunol. 141:4053-4060.

(264) In addition, humanized antibodies can be made according to standard protocols such as those disclosed in U.S. Pat. No. 5,565,332. In another embodiment, antibody chains or specific binding pair members can be produced by recombination between vectors comprising nucleic acid molecules encoding a fusion of a polypeptide chain of a specific binding pair member and a component of a replicable generic display package and vectors containing nucleic acid molecules encoding a second polypeptide chain of a single binding pair member using techniques known in the art, e.g., as described in U.S. Pat. Nos. 5,565,332, 5,871,907, or 5,733,743. The use of intracellular antibodies to inhibit protein function in a cell is also known in the art (see e.g., Carlson, J. R. (1988) Mol. Cell. Biol. 8:2638-2646; Biocca, S. et al. (1990) EMBO J 9:101-108; Werge, T. M. et al. (1990) FEES Lett. 274:193-198; Carlson, J. R. (1993) Proc. Natl. Acad. Sci. USA 90:7427-7428; Marasco, W. A. et al. (1993) Proc. Natl. Acad. Sci. USA 90:7889-7893; Biocca, S. et al. (1994) Biotechnology (IVY) 12:396-399; Chen, S-Y. et al. (1994) Hum. Gene Ther. 5:595-601; Duan, L et al. (1994) Proc. Natl. Acad. Sci. USA 91:5075-5079; Chen, S-Y. et al. (1994) Proc. Natl. Acad. Sci. USA 91:5932-5936; Beerli, R. R. et al. (1994) J. Biol. Chem. 269:23931-23936; Beerli, R. R. et al. (1994) Biochem. Biophys. Res. Commun. 204:666-672; Mhashilkar, A. M. et al. (1995) EMBO J 14:1542-1551; Richardson, J. H. et at (1995) Proc. Natl. Acad. Sci. USA 92:3137-3141; PCT Publication No. WO 94/02610 by Marasco et al.; and PCT Publication No. WO 95/03832 by Duan et al.).

(265) Additionally, fully human antibodies could be made against one or more biomarkers listed in Table 1, or fragments thereof. Fully human antibodies can be made in mice that are transgenic for human immunoglobulin genes, e.g. according to Hogan et al., Manipulating the Mouse Embryo: A Laboratory Manuel, Cold Spring Harbor Laboratory. Briefly, transgenic mice are immunized with purified immunogen. Spleen cells are harvested and fused to myeloma cells to produce hybridomas. Hybridomas are selected based on their ability to produce antibodies which bind to the immunogen. Fully human antibodies would reduce the immunogenicity of such antibodies in a human.

(266) In one embodiment, an antibody for use in the instant invention is a bispecific antibody. A bispecific antibody has binding sites for two different antigens within a single antibody polypeptide. Antigen binding may be simultaneous or sequential. Triomas and hybrid hybridomas are two examples of cell lines that can secrete bispecific antibodies. Examples of bispecific antibodies produced by a hybrid hybridoma or a trioma are disclosed in U.S. Pat. No. 4,474,893. Bispecific antibodies have been constructed by chemical means (Staerz et al. (1985) Nature 314:628, and Perez et al. (1985) Nature 316:354) and hybridoma technology (Staerz and Bevan (1986) Proc. Natl. Acad. Sci. USA, 83:1453, and Staerz and Bevan (1986) Immunol. Today 7:241). Bispecific antibodies are also described in U.S. Pat. No. 5,959,084. Fragments of bispecific antibodies are described in U.S. Pat. No. 5,798,229.

(267) Bispecific agents can also be generated by making heterohybridomas by fusing hybridomas or other cells making different antibodies, followed by identification of clones producing and co-assembling both antibodies. They can also be generated by chemical or genetic conjugation of complete immunoglobulin chains or portions thereof such as Fab and Fv sequences. The antibody component can bind to a polypeptide or a fragment thereof of one or more biomarkers encompassed by the present invention, including one or more biomarkers listed in Table 1, or a fragment thereof. In one embodiment, the bispecific antibody could specifically bind to both a polypeptide or a fragment thereof and its natural binding partner(s) or a fragment(s) thereof.

(268) In another aspect encompassed by the present invention, peptides or peptide mimetics can be used to agonize the activity of one or more biomarkers encompassed by the present invention, including one or more biomarkers listed in Table 1, or a fragment(s) thereof. In one embodiment, variants of one or more biomarkers listed in Table 1 which function as a modulating agent for the respective full length protein, can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, for agonist activity. In one embodiment, a variegated library of variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of variants can be produced and screened using methods described above. The production of peptides and peptidomimetics are also described herein.

(269) Also encompassed by the present invention are small molecules which can modulate (e.g., enhance) interactions, e.g., between one or more biomarkers listed in Table 1 and their natural binding partners. The small molecules encompassed by the present invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the one-bead one-compoundlibrary method; and synthetic library methods using affinity chromatography selection. (Lam, K. S. (1997) Anticancer Drug Des. 12:145).

(270) Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. USA 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994) J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and in Gallop et al. (1994) J. Med. Chem. 37:1233.

(271) Libraries of compounds can be presented in solution (e.g., Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria (Ladner U.S. Pat. No. 5,223,409), spores (Ladner USP '409), plasmids (Cull et al. (1992) Proc. Natl. Acad. Sci. USA 89:1865-1869) or on phage (Scott and Smith (1990) Science 249:386-390); (Devlin (1990) Science 249:404-406); (Cwirla et al. (1990) Proc. Natl. Acad. Sci. USA 87:6378-6382); (Felici (1991) J. Mol. Biol. 222:301-310); (Ladner supra.). Compounds can be screened in cell based or non-cell based assays. Compounds can be screened in pools (e.g. multiple compounds in each testing sample) or as individual compounds.

(272) The invention also relates to chimeric or fusion proteins of the biomarkers encompassed by the present invention, including one or more biomarkers listed in Table 1, or fragments thereof. As used herein, a chimeric protein or fusion protein comprises one or more biomarkers encompassed by the present invention, including one or more biomarkers listed in Table 1, or a fragment thereof, operatively linked to another polypeptide having an amino acid sequence corresponding to a protein which is not substantially homologous to the respective biomarker. In a preferred embodiment, the fusion protein comprises at least one biologically active portion of one or more biomarkers encompassed by the present invention, including one or more biomarkers listed in Table 1, or fragments thereof. Within the fusion protein, the term operatively linked is intended to indicate that the biomarker sequences and the non-biomarker sequences are fused in-frame to each other in such a way as to preserve functions exhibited when expressed independently of the fusion. The another sequences can be fused to the N-terminus or C-terminus of the biomarker sequences, respectively.

(273) Such a fusion protein can be produced by recombinant expression of a nucleotide sequence encoding the first peptide and a nucleotide sequence encoding the second peptide. The second peptide may optionally correspond to a moiety that alters the solubility, affinity, stability or valency of the first peptide, for example, an immunoglobulin constant region. In another preferred embodiment, the first peptide consists of a portion of a biologically active molecule (e.g. the extracellular portion of the polypeptide or the ligand binding portion). The second peptide can include an immunoglobulin constant region, for example, a human C1 domain or C4 domain (e.g., the hinge, CH2 and CH3 regions of human IgC1, or human IgC4, see e.g., Capon et al. U.S. Pat. Nos. 5,116,964; 5,580,756; 5,844,095 and the like, incorporated herein by reference). Such constant regions may retain regions which mediate effector function (e.g. Fc receptor binding) or may be altered to reduce effector function. A resulting fusion protein may have altered solubility, binding affinity, stability and/or valency (i.e., the number of binding sites available per polypeptide) as compared to the independently expressed first peptide, and may increase the efficiency of protein purification. Fusion proteins and peptides produced by recombinant techniques can be secreted and isolated from a mixture of cells and medium containing the protein or peptide. Alternatively, the protein or peptide can be retained cytoplasmically and the cells harvested, lysed and the protein isolated. A cell culture typically includes host cells, media and other byproducts. Suitable media for cell culture are well-known in the art. Protein and peptides can be isolated from cell culture media, host cells, or both using techniques known in the art for purifying proteins and peptides. Techniques for transfecting host cells and purifying proteins and peptides are known in the art.

(274) Preferably, a fusion protein encompassed by the present invention is produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, for example employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Current Protocols in Molecular Biology, eds. Ausubel et al. John Wiley & Sons: 1992).

(275) In another embodiment, the fusion protein contains a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a polypeptide can be increased through use of a heterologous signal sequence.

(276) The fusion proteins encompassed by the present invention can be used as immunogens to produce antibodies in a subject. Such antibodies may be used to purify the respective natural polypeptides from which the fusion proteins were generated, or in screening assays to identify polypeptides which inhibit the interactions between one or more biomarkers polypeptide or a fragment thereof and its natural binding partner(s) or a fragment(s) thereof.

(277) The modulatory agents described herein (e.g., nucleic acids, peptides, antibodies, small molecules, or fusion proteins) can be incorporated into pharmaceutical compositions and administered to a subject in vivo. The compositions may contain a single such molecule or agent or any combination of agents described herein. Single active agents described herein can be combined with other pharmacologically active compounds (second active agents) known in the art according to the methods and compositions provided herein. It is believed that certain combinations work synergistically in the treatment of conditions that would benefit from the mouldation of immune responses. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

(278) Biomarker nucleic acids and/or biomarker polypeptides can be analyzed according to the methods described herein and techniques known to the skilled artisan to identify such genetic or expression alterations useful for the present invention including, but not limited to, 1) an alteration in the level of a biomarker transcript or polypeptide, 2) a deletion or addition of one or more nucleotides from a biomarker gene, 4) a substitution of one or more nucleotides of a biomarker gene, 5) aberrant modification of a biomarker gene, such as an expression regulatory region, and the like.

(279) 1. Methods for Detection of Copy Number

(280) Methods of evaluating the copy number of a biomarker nucleic acid are well-known to those of skill in the art. The presence or absence of chromosomal gain or loss can be evaluated simply by a determination of copy number of the regions or markers identified herein.

(281) In one embodiment, a biological sample is tested for the presence of copy number changes in genomic loci containing the genomic marker.

(282) Methods of evaluating the copy number of a biomarker locus include, but are not limited to, hybridization-based assays. Hybridization-based assays include, but are not limited to, traditional direct probe methods, such as Southern blots, in situ hybridization (e.g., FISH and FISH plus SKY) methods, and comparative probe methods, such as comparative genomic hybridization (CGH), e.g., cDNA-based or oligonucleotide-based CGH. The methods can be used in a wide variety of formats including, but not limited to, substrate (e.g. membrane or glass) bound methods or array-based approaches.

(283) In one embodiment, evaluating the biomarker gene copy number in a sample involves a Southern Blot. In a Southern Blot, the genomic DNA (typically fragmented and separated on an electrophoretic gel) is hybridized to a probe specific for the target region. Comparison of the intensity of the hybridization signal from the probe for the target region with control probe signal from analysis of normal genomic DNA (e.g., a non-amplified portion of the same or related cell, tissue, organ, etc.) provides an estimate of the relative copy number of the target nucleic acid. Alternatively, a Northern blot may be utilized for evaluating the copy number of encoding nucleic acid in a sample. In a Northern blot, mRNA is hybridized to a probe specific for the target region. Comparison of the intensity of the hybridization signal from the probe for the target region with control probe signal from analysis of normal RNA (e.g., a non-amplified portion of the same or related cell, tissue, organ, etc.) provides an estimate of the relative copy number of the target nucleic acid. Alternatively, other methods well-known in the art to detect RNA can be used, such that higher or lower expression relative to an appropriate control (e.g., a non-amplified portion of the same or related cell tissue, organ, etc.) provides an estimate of the relative copy number of the target nucleic acid.

(284) An alternative means for determining genomic copy number is in situ hybridization (e.g., Angerer (1987)Meth. Enzymol 152: 649). Generally, in situ hybridization comprises the following steps: (1) fixation of tissue or biological structure to be analyzed; (2) prehybridization treatment of the biological structure to increase accessibility of target DNA, and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in the hybridization and (5) detection of the hybridized nucleic acid fragments. The reagent used in each of these steps and the conditions for use vary depending on the particular application. In a typical in situ hybridization assay, cells are fixed to a solid support, typically a glass slide. If a nucleic acid is to be probed, the cells are typically denatured with heat or alkali. The cells are then contacted with a hybridization solution at a moderate temperature to permit annealing of labeled probes specific to the nucleic acid sequence encoding the protein. The targets (e.g., cells) are then typically washed at a predetermined stringency or at an increasing stringency until an appropriate signal to noise ratio is obtained. The probes are typically labeled, e.g., with radioisotopes or fluorescent reporters. In one embodiment, probes are sufficiently long so as to specifically hybridize with the target nucleic acid(s) under stringent conditions. Probes generally range in length from about 200 bases to about 1000 bases. In some applications it is necessary to block the hybridization capacity of repetitive sequences. Thus, in some embodiments, tRNA, human genomic DNA, or Cot-I DNA is used to block non-specific hybridization.

(285) An alternative means for determining genomic copy number is comparative genomic hybridization. In general, genomic DNA is isolated from normal reference cells, as well as from test cells (e.g., tumor cells) and amplified, if necessary. The two nucleic acids are differentially labeled and then hybridized in situ to metaphase chromosomes of a reference cell. The repetitive sequences in both the reference and test DNAs are either removed or their hybridization capacity is reduced by some means, for example by prehybridization with appropriate blocking nucleic acids and/or including such blocking nucleic acid sequences for said repetitive sequences during said hybridization. The bound, labeled DNA sequences are then rendered in a visualizable form, if necessary. Chromosomal regions in the test cells which are at increased or decreased copy number can be identified by detecting regions where the ratio of signal from the two DNAs is altered. For example, those regions that have decreased in copy number in the test cells will show relatively lower signal from the test DNA than the reference compared to other regions of the genome. Regions that have been increased in copy number in the test cells will show relatively higher signal from the test DNA. Where there are chromosomal deletions or multiplications, differences in the ratio of the signals from the two labels will be detected and the ratio will provide a measure of the copy number. In another embodiment of CGH, array CGH (aCGH), the immobilized chromosome element is replaced with a collection of solid support bound target nucleic acids on an array, allowing for a large or complete percentage of the genome to be represented in the collection of solid support bound targets. Target nucleic acids may comprise cDNAs, genomic DNAs, oligonucleotides (e.g., to detect single nucleotide polymorphisms) and the like. Array-based CGH may also be performed with single-color labeling (as opposed to labeling the control and the possible tumor sample with two different dyes and mixing them prior to hybridization, which will yield a ratio due to competitive hybridization of probes on the arrays). In single color CGH, the control is labeled and hybridized to one array and absolute signals are read, and the possible tumor sample is labeled and hybridized to a second array (with identical content) and absolute signals are read. Copy number difference is calculated based on absolute signals from the two arrays. Methods of preparing immobilized chromosomes or arrays and performing comparative genomic hybridization are well-known in the art (see, e.g., U.S. Pat. Nos. 6,335,167; 6,197,501; 5,830,645; and 5,665,549 and Albertson (1984) EMBO J. 3: 1227-1234; Pinkel (1988) Proc. Natl. Acad. Sci. USA 85: 9138-9142; EPO Pub. No. 430,402; Methods in Molecular Biology, Vol. 33: In situ Hybridization Protocols, Choo, ed., Humana Press, Totowa, N.J. (1994), etc.). In another embodiment, the hybridization protocol of Pinkel et al. (1998) Nature Genetics 20: 207-211, or of Kallioniemi (1992) Proc. Natl Acad Sci USA 89:5321-5325 (1992) is used.

(286) In still another embodiment, amplification-based assays can be used to measure copy number. In such amplification-based assays, the nucleic acid sequences act as a template in an amplification reaction (e.g., Polymerase Chain Reaction (PCR). In a quantitative amplification, the amount of amplification product will be proportional to the amount of template in the original sample. Comparison to appropriate controls, e.g. healthy tissue, provides a measure of the copy number.

(287) Methods of quantitative amplification are well-known to those of skill in the art. For example, quantitative PCR involves simultaneously co-amplifying a known quantity of a control sequence using the same primers. This provides an internal standard that may be used to calibrate the PCR reaction. Detailed protocols for quantitative PCR are provided in Innis et al. (1990) PCR Protocols, A Guide to Methods and Applications, Academic Press, Inc. N.Y.). Measurement of DNA copy number at microsatellite loci using quantitative PCR analysis is described in Ginzonger et al. (2000) Cancer Research 60:5405-5409. The known nucleic acid sequence for the genes is sufficient to enable one of skill in the art to routinely select primers to amplify any portion of the gene. Fluorogenic quantitative PCR may also be used in the methods encompassed by the present invention. In fluorogenic quantitative PCR, quantitation is based on amount of fluorescence signals, e.g., TaqMan and SYBR green.

(288) Other suitable amplification methods include, but are not limited to, ligase chain reaction (LCR) (see Wu and Wallace (1989) Genomics 4: 560, Landegren et al. (1988) Science 241:1077, and Barringer et al. (1990) Gene 89: 117), transcription amplification (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86: 1173), self-sustained sequence replication (Guatelli et al. (1990) Proc. Nat. Acad. Sci. USA 87: 1874), dot PCR, and linker adapter PCR, etc.

(289) Loss of heterozygosity (LOH) and major copy proportion (MCP) mapping (Wang, Z. C. et al. (2004) Cancer Res 64(1):64-71; Seymour, A. B. et al. (1994) Cancer Res 54, 2761-4; Hahn, S. A. et al. (1995) Cancer Res 55, 4670-5; Kimura, M. et al. (1996) Genes Chromosomes Cancer 17, 88-93; Li et at, (2008) MBC Bioinform. 9, 204-219) may also be used to identify regions of amplification or deletion.

(290) 2. Methods for Detection of Biomarker Nucleic Acid Expression

(291) Biomarker expression may be assessed by any of a wide variety of well-known methods for detecting expression of a transcribed molecule or protein. Non-limiting examples of such methods include immunological methods for detection of secreted, cell-surface, cytoplasmic, or nuclear proteins, protein purification methods, protein function or activity assays, nucleic acid hybridization methods, nucleic acid reverse transcription methods, and nucleic acid amplification methods.

(292) In preferred embodiments, activity of a particular gene is characterized by a measure of gene transcript (e.g. mRNA), by a measure of the quantity of translated protein, or by a measure of gene product activity. Marker expression can be monitored in a variety of ways, including by detecting mRNA levels, protein levels, or protein activity, any of which can be measured using standard techniques. Detection can involve quantification of the level of gene expression (e.g., genomic DNA, cDNA, mRNA, protein, or enzyme activity), or, alternatively, can be a qualitative assessment of the level of gene expression, in particular in comparison with a control level. The type of level being detected will be clear from the context.

(293) In another embodiment, detecting or determining expression levels of a biomarker and functionally similar homologs thereof, including a fragment or genetic alteration thereof (e.g., in regulatory or promoter regions thereof) comprises detecting or determining RNA levels for the marker of interest. In one embodiment, one or more cells from the subject to be tested are obtained and RNA is isolated from the cells. In a preferred embodiment, a sample of breast tissue cells is obtained from the subject.

(294) In one embodiment, RNA is obtained from a single cell. For example, a cell can be isolated from a tissue sample by laser capture microdissection (LCM). Using this technique, a cell can be isolated from a tissue section, including a stained tissue section, thereby assuring that the desired cell is isolated (see, e.g., Bonner et al. (1997) Science 278: 1481; Emmert-Buck et ed. (1996) Science 274:998; Fend et al. (1999) Am. J. Path. 154: 61 and Murakami et al. (2000) Kidney Int. 58:1346). For example, Murakami et al., supra, describe isolation of a cell from a previously immunostained tissue section.

(295) It is also be possible to obtain cells from a subject and culture the cells in vitro, such as to obtain a larger population of cells from which RNA can be extracted. Methods for establishing cultures of non-transformed cells, i.e., primary cell cultures, are known in the art.

(296) When isolating RNA from tissue samples or cells from individuals, it may be important to prevent any further changes in gene expression after the tissue or cells has been removed from the subject. Changes in expression levels are known to change rapidly following perturbations, e.g., heat shock or activation with lipopolysaccharide (LPS) or other reagents. In addition, the RNA in the tissue and cells may quickly become degraded. Accordingly, in a preferred embodiment, the tissue or cells obtained from a subject is snap frozen as soon as possible.

(297) RNA can be extracted from the tissue sample by a variety of methods, e.g., the guanidium thiocyanate lysis followed by CsCl centrifugation (Chirgwin et al., 1979, Biochemistry 18:5294-5299). RNA from single cells can be obtained as described in methods for preparing cDNA libraries from single cells, such as those described in Dulac, C. (1998) Curr. Top. Dev. Biol. 36, 245 and Jena et al. (1996) J. Immunol. Methods 190:199. Care to avoid RNA degradation must be taken, e.g., by inclusion of RNAsin. The RNA sample can then be enriched in particular species. In one embodiment, poly(A)+ RNA is isolated from the RNA sample. In general, such purification takes advantage of the poly-A tails on mRNA. In particular and as noted above, poly-T oligonucleotides may be immobilized within on a solid support to serve as affinity ligands for mRNA. Kits for this purpose are commercially available, e.g., the MessageMaker kit (Life Technologies, Grand Island, NY).

(298) In a preferred embodiment, the RNA population is enriched in marker sequences. Enrichment can be undertaken, e.g., by primer-specific cDNA synthesis, or multiple rounds of linear amplification based on cDNA synthesis and template-directed in vitro transcription (see, e.g., Wang et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86: 9717; Dulac et al., supra, and Jena et al., supra).

(299) The population of RNA, enriched or not in particular species or sequences, can further be amplified. As defined herein, an amplification process is designed to strengthen, increase, or augment a molecule within the RNA. For example, where RNA is mRNA, an amplification process such as RT-PCR can be utilized to amplify the mRNA, such that a signal is detectable or detection is enhanced. Such an amplification process is beneficial particularly when the biological, tissue, or tumor sample is of a small size or volume.

(300) Various amplification and detection methods can be used. For example, it is within the scope encompassed by the present invention to reverse transcribe mRNA into cDNA followed by polymerase chain reaction (RT-PCR); or, to use a single enzyme for both steps as described in U.S. Pat. No. 5,322,770, or reverse transcribe mRNA into cDNA followed by symmetric gap ligase chain reaction (RT-AGLCR) as described by R. L. Marshall et al., PCR Methods and Applications 4: 80-84 (1994). Real time PCR may also be used.

(301) Other known amplification methods which can be utilized herein include but are not limited to the so-called NASBA or 3SR technique described in PNAS USA 87: 1874-1878 (1990) and also described in Nature 350 (No. 6313): 91-92 (1991); Q-beta amplification as described in published European Patent Application (EPA) No. 4544610; strand displacement amplification (as described in G. T. Walker et al., Clin. Chem. 42: 9-13 (1996) and European Patent Application No. 684315; target mediated amplification, as described by PCT Publication WO9322461; PCR; ligase chain reaction (LCR) (see, e.g., Wu and Wallace, Genomics 4, 560 (1989), Landegren et al., Science 241, 1077 (1988)); self-sustained sequence replication (SSR) (see, e.g., Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990)); and transcription amplification (see, e.g., Kwoh et al., Proc. Natl. Acad. Sci. USA 86, 1173 (1989)).

(302) Many techniques are known in the state of the art for determining absolute and relative levels of gene expression, commonly used techniques suitable for use in the present invention include Northern analysis, RNase protection assays (RPA), microarrays and PCR-based techniques, such as quantitative PCR and differential display PCR. For example, Northern blotting involves running a preparation of RNA on a denaturing agarose gel, and transferring it to a suitable support, such as activated cellulose, nitrocellulose or glass or nylon membranes. Radiolabeled cDNA or RNA is then hybridized to the preparation, washed and analyzed by autoradiography.

(303) In situ hybridization visualization may also be employed, wherein a radioactively labeled antisense RNA probe is hybridized with a thin section of a biopsy sample, washed, cleaved with RNase and exposed to a sensitive emulsion for autoradiography. The samples may be stained with hematoxylin to demonstrate the histological composition of the sample, and dark field imaging with a suitable light filter shows the developed emulsion. Non-radioactive labels such as digoxigenin may also be used.

(304) Alternatively, mRNA expression can be detected on a DNA array, chip or a microarray. Labeled nucleic acids of a test sample obtained from a subject may be hybridized to a solid surface comprising biomarker DNA. Positive hybridization signal is obtained with the sample containing biomarker transcripts. Methods of preparing DNA arrays and their use are well-known in the art (see, e.g., U.S. Pat. Nos. 6,618,6796; 6,379,897; 6,664,377; 6,451,536; 548,257; U.S. 20030157485 and Schena et al. (1995) Science 20, 467-470; Gerhold et al. (1999) Trends In Biochem. Sci. 24, 168-173; and Lennon et al. (2000) Drug Discovery Today 5, 59-65, which are herein incorporated by reference in their entirety). Serial Analysis of Gene Expression (SAGE) can also be performed (See for example U.S. Patent Application 20030215858).

(305) To monitor mRNA levels, for example, mRNA is extracted from the biological sample to be tested, reverse transcribed, and fluorescently-labeled cDNA probes are generated. The microarrays capable of hybridizing to marker cDNA are then probed with the labeled cDNA probes, the slides scanned and fluorescence intensity measured. This intensity correlates with the hybridization intensity and expression levels.

(306) Types of probes that can be used in the methods described herein include cDNA, riboprobes, synthetic oligonucleotides and genomic probes. The type of probe used will generally be dictated by the particular situation, such as riboprobes for in situ hybridization, and cDNA for Northern blotting, for example. In one embodiment, the probe is directed to nucleotide regions unique to the RNA. The probes may be as short as is required to differentially recognize marker mRNA transcripts, and may be as short as, for example, 15 bases; however, probes of at least 17, 18, 19 or 20 or more bases can be used. In one embodiment, the primers and probes hybridize specifically under stringent conditions to a DNA fragment having the nucleotide sequence corresponding to the marker. As herein used, the term stringent conditions means hybridization will occur only if there is at least 95% identity in nucleotide sequences. In another embodiment, hybridization under stringent conditions occurs when there is at least 97% identity between the sequences.

(307) The form of labeling of the probes may be any that is appropriate, such as the use of radioisotopes, for example, .sup.32P and .sup.35S. Labeling with radioisotopes may be achieved, whether the probe is synthesized chemically or biologically, by the use of suitably labeled bases.

(308) In one embodiment, the biological sample contains polypeptide molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject.

(309) In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting marker polypeptide, mRNA, genomic DNA, or fragments thereof, such that the presence of the marker polypeptide, mRNA, genomic DNA, or fragments thereof, is detected in the biological sample, and comparing the presence of the marker polypeptide, mRNA, genomic DNA, or fragments thereof, in the control sample with the presence of the marker polypeptide, mRNA, genomic DNA, or fragments thereof in the test sample.

(310) 3. Methods for Detection of Biomarker Protein Expression

(311) The activity or level of a biomarker protein can be detected and/or quantified by detecting or quantifying the expressed polypeptide. The polypeptide can be detected and quantified by any of a number of means well-known to those of skill in the art. Aberrant levels of polypeptide expression of the polypeptides encoded by a biomarker nucleic acid and functionally similar homologs thereof, including a fragment or genetic alteration thereof (e.g., in regulatory or promoter regions thereof) are associated with the likelihood of response of a condition that would benefit from modulating an immune response to modulators of IRE1-XBP1 pathway. Any method known in the art for detecting polypeptides can be used. Such methods include, but are not limited to, immunodiffusion, immunoelectrophoresis, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, Western blotting, binder-ligand assays, immunohistochemical techniques, agglutination, complement assays, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like (e.g., Basic and Clinical Immunology, Sites and Terr, eds., Appleton and Lange, Norwalk, Conn. pp 217-262, 1991 which is incorporated by reference). Preferred are binder-ligand immunoassay methods including reacting antibodies with an epitope or epitopes and competitively displacing a labeled polypeptide or derivative thereof.

(312) For example, ELISA and RIA procedures may be conducted such that a desired biomarker protein standard is labeled (with a radioisotope such as .sup.125I or .sup.35S, or an assayable enzyme, such as horseradish peroxidase or alkaline phosphatase), and, together with the unlabeled sample, brought into contact with the corresponding antibody, whereon a second antibody is used to bind the first, and radioactivity or the immobilized enzyme assayed (competitive assay). Alternatively, the biomarker protein in the sample is allowed to react with the corresponding immobilized antibody, radioisotope- or enzyme-labeled anti-biomarker protein antibody is allowed to react with the system, and radioactivity or the enzyme assayed (ELISA-sandwich assay). Other conventional methods may also be employed as suitable.

(313) The above techniques may be conducted essentially as a one-step or two-step assay. A one-step assay involves contacting antigen with immobilized antibody and, without washing, contacting the mixture with labeled antibody. A two-step assay involves washing before contacting, the mixture with labeled antibody. Other conventional methods may also be employed as suitable.

(314) In one embodiment, a method for measuring biomarker protein levels comprises the steps of: contacting a biological specimen with an antibody or variant (e.g., fragment) thereof which selectively binds the biomarker protein, and detecting whether said antibody or variant thereof is bound to said sample and thereby measuring the levels of the biomarker protein.

(315) Enzymatic and radiolabeling of biomarker protein and/or the antibodies may be effected by conventional means. Such means will generally include covalent linking of the enzyme to the antigen or the antibody in question, such as by glutaraldehyde, specifically so as not to adversely affect the activity of the enzyme, by which is meant that the enzyme must still be capable of interacting with its substrate, although it is not necessary for all of the enzyme to be active, provided that enough remains active to permit the assay to be effected. Indeed, some techniques for binding enzyme are non-specific (such as using formaldehyde), and will only yield a proportion of active enzyme.

(316) It is usually desirable to immobilize one component of the assay system on a support, thereby allowing other components of the system to be brought into contact with the component and readily removed without laborious and time-consuming labor. It is possible for a second phase to be immobilized away from the first, but one phase is usually sufficient.

(317) It is possible to immobilize the enzyme itself on a support, but if solid-phase enzyme is required, then this is generally best achieved by binding to antibody and affixing the antibody to a support, models and systems for which are well-known in the art. Simple polyethylene may provide a suitable support.

(318) Enzymes employable for labeling are not particularly limited, but may be selected from the members of the oxidase group, for example. These catalyze production of hydrogen peroxide by reaction with their substrates, and glucose oxidase is often used for its good stability, ease of availability and cheapness, as well as the ready availability of its substrate (glucose). Activity of the oxidase may be assayed by measuring the concentration of hydrogen peroxide formed after reaction of the enzyme-labeled antibody with the substrate under controlled conditions well-known in the art.

(319) Other techniques may be used to detect biomarker protein according to a practitioner's preference based upon the present disclosure. One such technique is Western blotting (Towbin et at., Proc. Nat. Acad. Sci. 76:4350 (1979)), wherein a suitably treated sample is run on an SDS-PAGE gel before being transferred to a solid support, such as a nitrocellulose filter. Anti-biomarker protein antibodies (unlabeled) are then brought into contact with the support and assayed by a secondary immunological reagent, such as labeled protein A or anti-immunoglobulin (suitable labels including .sup.125I, horseradish peroxidase and alkaline phosphatase). Chromatographic detection may also be used.

(320) Immunohistochemistry may be used to detect expression of biomarker protein, e.g., in a biopsy sample. A suitable antibody is brought into contact with, for example, a thin layer of cells, washed, and then contacted with a second, labeled antibody. Labeling may be by fluorescent markers, enzymes, such as peroxidase, avidin, or radiolabeling. The assay is scored visually, using microscopy.

(321) Anti-biomarker protein antibodies, such as intrabodies, may also be used for imaging purposes, for example, to detect the presence of biomarker protein in cells and tissues of a subject. Suitable labels include radioisotopes, iodine (.sup.125I, .sup.121I) carbon (.sup.14C), sulphur (.sup.35S), tritium (.sup.3H), indium (.sup.112In), and technetium (.sup.99mTc), fluorescent labels, such as fluorescein and rhodamine, and biotin.

(322) For in vivo imaging purposes, antibodies are not detectable, as such, from outside the body, and so must be labeled, or otherwise modified, to permit detection. Markers for this purpose may be any that do not substantially interfere with the antibody binding, but which allow external detection. Suitable markers may include those that may be detected by X-radiography, NMR or MRI. For X-radiographic techniques, suitable markers include any radioisotope that emits detectable radiation but that is not overtly harmful to the subject, such as barium or cesium, for example. Suitable markers for NMR and MRI generally include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by suitable labeling of nutrients for the relevant hybridoma, for example.

(323) The size of the subject, and the imaging system used, will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of technetium-99. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain biomarker protein. The labeled antibody or antibody fragment can then be detected using known techniques.

(324) Antibodies that may be used to detect biomarker protein include any antibody, whether natural or synthetic, full length or a fragment thereof, monoclonal or polyclonal, that binds sufficiently strongly and specifically to the biomarker protein to be detected. An antibody may have a K.sub.d of at most about 10.sup.6M, 10.sup.7M, 10.sup.8M, 10.sup.9M, 10.sup.10M, 10.sup.11M, 10.sup.12M. The phrase specifically binds refers to binding of, for example, an antibody to an epitope or antigen or antigenic determinant in such a manner that binding can be displaced or competed with a second preparation of identical or similar epitope, antigen or antigenic determinant. An antibody may bind preferentially to the biomarker protein relative to other proteins, such as related proteins.

(325) Antibodies are commercially available or may be prepared according to methods known in the art.

(326) Antibodies and derivatives thereof that may be used encompass polyclonal or monoclonal antibodies, chimeric, human, humanized, primatized (CDR-grafted), veneered or single-chain antibodies as well as functional fragments, i.e., biomarker protein binding fragments, of antibodies. For example, antibody fragments capable of binding to a biomarker protein or portions thereof, including, but not limited to, Fv, Fab, Fab and F(ab) 2 fragments can be used. Such fragments can be produced by enzymatic cleavage or by recombinant techniques. For example, papain or pepsin cleavage can generate Fab or F(ab) 2 fragments, respectively. Other proteases with the requisite substrate specificity can also be used to generate Fab or F(ab) 2 fragments. Antibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a chimeric gene encoding a F(ab) 2 heavy chain portion can be designed to include DNA sequences encoding the CH, domain and hinge region of the heavy chain.

(327) Synthetic and engineered antibodies are described in, e.g., Cabilly et al., U.S. Pat. No. 4,816,567 Cabilly et al., European Patent No. 0,125,023 B1; Boss et al., U.S. Pat. No. 4,816,397; Boss et al., European Patent No. 0,120,694 B1; Neuberger, M. S. et al., WO 86/01533; Neuberger, M. S. et al., European Patent No. 0,194,276 B1; Winter, U.S. Pat. No. 5,225,539; Winter, European Patent No. 0,239,400 B1; Queen et al., European Patent No. 0451216 B1; and Padlan, E. A. et al., EP 0519596 A1. See also, Newman, R. et al., BioTechnology, 10: 1455-1460 (1992), regarding primatized antibody, and Ladner et al., U.S. Pat. No. 4,946,778 and Bird, R. E. et al., Science, 242: 423-426 (1988)) regarding single-chain antibodies. Antibodies produced from a library, e.g., phage display library, may also be used.

(328) In some embodiments, agents that specifically bind to a biomarker protein other than antibodies are used, such as peptides. Peptides that specifically bind to a biomarker protein can be identified by any means known in the art. For example, specific peptide binders of a biomarker protein can be screened for using peptide phage display libraries.

(329) 4. Methods for Detection of Biomarker Structural Alterations

(330) The following illustrative methods can be used to identify the presence of a structural alteration in a biomarker nucleic acid and/or biomarker polypeptide molecule in order to, for example, identify one or more biomarkers listed in Table 1, or other biomarkers used in the immunotherapies described herein.

(331) In certain embodiments, detection of the alteration involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al. (1988) Science 241:1077-1080; and Nakazawa et al. (1994) Proc. Natl. Acad. Sci. USA 91:360-364), the latter of which can be particularly useful for detecting point mutations in a biomarker nucleic acid such as a biomarker gene (see Abravaya et al. (1995) Nucleic Acids Res. 23:675-682). This method can include the steps of collecting a sample of cells from a subject, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to a biomarker gene under conditions such that hybridization and amplification of the biomarker gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

(332) Alternative amplification methods include: self-sustained sequence replication (Guatelli, J. C. et al. (1990) Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al. (1989) Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi, P. M. et al. (1988) Bio-Technology 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well-known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

(333) In an alternative embodiment, mutations in a biomarker nucleic acid from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, for example, U.S. Pat. No. 5,498,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

(334) In other embodiments, genetic mutations in biomarker nucleic acid can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing hundreds or thousands of oligonucleotide probes (Cronin, M. T. et al. (1996) Hum. Mutat. 7:244-255; Kozal, M. J. et al. (1996) Nat. Med. 2:753-759). For example, biomarker genetic mutations can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin et al. (1996) supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential, overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene. Such biomarker genetic mutations can be identified in a variety of contexts, including, for example, germline and somatic mutations.

(335) In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence a biomarker gene and detect mutations by comparing the sequence of the sample biomarker with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxam and Gilbert (1977) Proc. Natl. Acad. Sci. USA 74:560 or Sanger (1977) Proc. Natl. Acad Sci. USA 74:5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (Naeve (1995) Biotechniques 19:448-53), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen et al. (1996) Adv. Chromatogr. 36:127-162; and Griffin et al. (1993) Appl. Biochem. Biotechnol. 38:147-159).

(336) Other methods for detecting mutations in a biomarker gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes (Myers et al. (1985) Science 230:1242). In general, the art technique of mismatch cleavage starts by providing heteroduplexes formed by hybridizing (labeled) RNA or DNA containing the wild-type biomarker sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent which cleaves single-stranded regions of the duplex such as which will exist due to base pair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with SI nuclease to enzymatically digest the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, for example, Cotton et al. (1988) Proc. Natl. Acad. Sci. USA 85:4397 and Saleeba et al. (1992) Methods Enzymol. 217:286-295. In a preferred embodiment, the control DNA or RNA can be labeled for detection.

(337) In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called DNA mismatch repair enzymes) in defined systems for detecting and mapping point mutations in biomarker cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis 15:1657-1662). According to an exemplary embodiment, a probe based on a biomarker sequence, e.g., a wild-type biomarker treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like (e.g., U.S. Pat. No. 5,459,039.)

(338) In other embodiments, alterations in electrophoretic mobility can be used to identify mutations in biomarker genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc Natl. Acad. Sci USA 86:2766; see also Cotton (1993) Mutat. Res. 285:125-144 and Hayashi (1992) Genet. Anal. Tech. Appl. 9:73-79). Single-stranded DNA fragments of sample and control biomarker nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In a preferred embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet. 7:5).

(339) In yet another embodiment the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al. (1985) Nature 313:495). When DGGE is used as the method of analysis, DNA will be modified to ensure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys. Chem. 265:12753).

(340) Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163; Saiki et al. (1989) Proc. Natl. Acad. Sci. USA 86:6230). Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

(341) Alternatively, allele specific amplification technology which depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3 end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech 11:238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al. (1992) Mol. Cell Probes 6:1). It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification (Barany (1991) Proc. Natl. Acad. Sci USA 88:189). In such cases, ligation will occur only if there is a perfect match at the 3 end of the 5 sequence making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

III. Subjects

(342) In one embodiment, the subject for whom a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate TGF-Smad/p63 signaling pathway is administered, or whose predicted likelihood of efficacy of the cancer vaccine for treating a cancer is determined, is a mammal (e.g., rat, primate, non-human mammal, domestic animal, such as a dog, cat, cow, horse, and the like), and is preferably a human. In another embodiment, the subject is an animal model of cancer. For example, the animal model can be an orthotopic xenograft animal model of a human-derived cancer or allograft of syngeneic cancer models.

(343) In another embodiment of the methods of the present invention, the subject has not undergone treatment, such as chemotherapy, radiation therapy, targeted therapy, and/or immunotherapies. In still another embodiment, the subject has undergone treatment, such as chemotherapy, radiation therapy, targeted therapy, and/or immunotherapies. In yet another embodiment, the subject is previously has the cancer and/or in remission for the cancer.

(344) In certain embodiments, the subject has had surgery to remove cancerous or precancerous tissue. In other embodiments, the cancerous tissue has not been removed, e.g., the cancerous tissue may be located in an inoperable region of the body, such as in a tissue that is essential for life, or in a region where a surgical procedure would cause considerable risk of harm to the patient.

(345) The methods of the present invention can be used to determine the responsiveness to the cancer vaccine for treating a cancer.

IV. Methods of Treatment

(346) The present invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a cancer. The cancer may be a solid or hematological cancer. In one embodiment, the cancer is the same cancer type with the same genetic mutations as the cancer vaccine. In another embodiment, the cancer is a different cancer type from the cancer vaccine but has the same genetic mutations (e.g., co-loss of p53 and PTEN). In still another embodiment, the cancer is the same cancer type as the cancer vaccine with different genetic mutations. In yet another embodiment, the cancer is a different cancer type the cancer vaccine with different genetic mutations. For example, the cancer may be a PPA tumor (a very aggressive breast cancer characterized by triple loss of p53, PTEN, and p110), C260 tumor (a high grade serous ovarian cancer drived by p53/PTEN co-loss and high Myc expression), D658 (a Kras mutated recurrent breast cancer cell model generated from a PIK3CA.sup.H1047R GEMM of breast cancer), or d333 (a glioblastoma tumor model derived from p53 and PTEN co-loss GEMM).

(347) a. Prophylactic Methods

(348) In one aspect, the present invention provides a method for preventing a subject afflicted with cancer, by administering to the subject a therapeutically effective amount of a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Smad/p63 signaling pathway. Administration of a prophylactic agent (e.g., the cancer vaccine described herein) can occur prior to the manifestation of symptoms characteristic of cancer, such that a cancer is prevented or, alternatively, delayed in its progression. In certain embodiments, administration of the prophylactic agent (e.g., the cancer vaccine described herein) protects the subject from recurrent cancer.

(349) b. Therapeutic Methods

(350) Another aspect of the present invention pertains to methods treating a subject afflicted with cancer, by administering to the subject a therapeutically effective amount of a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Smad/p63 signaling pathway.

(351) As described below and in some embodiments, a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Smad/p63 signaling pathway, is administered to a subject. Thus, the cancer cells will have an immunocompatibility relationship to the subject host and any such relationship is contemplated for use according to the present invention. For example, the cancer cells can be syngeneic. The term syngeneic can refer to the state of deriving from, originating in, or being members of the same species that are genetically identical, particularly with respect to antigens or immunological reactions. These include identical twins having matching MHC types. Thus, a syngeneic transplant refers to transfer of cells from a donor to a recipient who is genetically identical to the donor or is sufficiently immunologically compatible as to allow for transplantation without an undesired adverse immunogenic response (e.g., such as one that would work against interpretation of immunological screen results described herein).

(352) A syngeneic transplant can be autologous if the transferred cells are obtained from and transplanted to the same subject. An autologous transplant refers to the harvesting and reinfusion or transplant of a subject's own cells or organs. Exclusive or supplemental use of autologous cells may eliminate or reduce many adverse effects of administration of the cells back to the host, particular graft versus host reaction.

(353) A syngeneic transplant can be matched allogeneic if the transferred cells are obtained from and transplanted to different members of the same species yet have sufficiently matched major histocompatibility complex (MHC) antigens to avoid an adverse immunogenic response. Determining the degree of MHC mismatch may be accomplished according to standard tests known and used in the art. For instance, there are at least six major categories of MHC genes in humans, identified as being important in transplant biology. HLA-A, HLA-B, HLA-C encode the HLA class I proteins while HLA-DR, HLA-DQ, and HLA-DP encode the HLA class II proteins. Genes within each of these groups are highly polymorphic, as reflected in the numerous HLA alleles or variants found in the human population, and differences in these groups between individuals is associated with the strength of the immune response against transplanted cells. Standard methods for determining the degree of MHC match examine alleles within HLA-B and HLA-DR, or HLA-A, HLA-B and HLA-DR groups. Thus, tests may be made of at least 4, and even 5 or 6 MHC antigens within the two or three HLA groups, respectively. In serological MEC tests, antibodies directed against each HLA antigen type are reacted with cells from one subject (e.g., donor) to determine the presence or absence of certain MHC antigens that react with the antibodies. This is compared to the reactivity profile of the other subject (e.g., recipient). Reaction of the antibody with an MHC antigen is typically determined by incubating the antibody with cells, and then adding complement to induce cell lysis (i.e., lymphocytotoxicity testing). The reaction is examined and graded according to the amount of cells lysed in the reaction (see, for example, Mickelson and Petersdorf (1999) Hematopoietic Cell Transplantation, Thomas, E. D. et al. eds., pg 28-37, Blackwell Scientific, Malden, Mass.). Other cell-based assays include flow cytometry using labeled antibodies or enzyme linked immunoassays (ELISA). Molecular methods for determining MHC type are well-known and generally employ synthetic probes and/or primers to detect specific gene sequences that encode the HLA protein. Synthetic oligonucleotides may be used as hybridization probes to detect restriction fragment length polymorphisms associated with particular HLA types (Vaughn (2002) Method. Mol. Biol. MHC Protocol. 210:45-60). Alternatively, primers may be used for amplifying the HLA sequences (e.g., by polymerase chain reaction or ligation chain reaction), the products of which may be further examined by direct DNA sequencing, restriction fragment polymorphism analysis (RFLP), or hybridization with a series of sequence specific oligonucleotide primers (SSOP) (Petersdorf et al. (1998) Blood 92:3515-3520; Morishima et al. (2002) Blood 99:4200-4206; and Middleton and Williams (2002) Method. Mol. Biol. MHC Protocol. 210:67-112).

(354) A syngeneic transplant can be congenic if the transferred cells and cells of the subject differ in defined loci, such as a single locus, typically by inbreeding. The term congenic refers to deriving from, originating in, or being members of the same species, where the members are genetically identical except for a small genetic region, typically a single genetic locus (i.e., a single gene). A congenic transplant refers to transfer of cells or organs from a donor to a recipient, where the recipient is genetically identical to the donor except for a single genetic locus. For example, CD45 exists in several allelic forms and congenic mouse lines exist in which the mouse lines differ with respect to whether the CD45.1 or CD45.2 allelic versions are expressed.

(355) By contrast, mismatched allogeneic refers to deriving from, originating in, or being members of the same species having non-identical major histocompatibility complex (MHC) antigens (i.e., proteins) as typically determined by standard assays used in the art, such as serological or molecular analysis of a defined number of MHC antigens, sufficient to elicit adverse immunogenic responses. A partial mismatch refers to partial match of the MHC antigens tested between members, typically between a donor and recipient. For instance, a half mismatch refers to 50% of the MHC antigens tested as showing different MHC antigen type between two members. A full or complete mismatch refers to all MHC antigens tested as being different between two members.

(356) Similarly, in contrast, xenogeneic refers to deriving from, originating in, or being members of different species, e.g., human and rodent, human and swine, human and chimpanzee, etc. A xenogeneic transplant refers to transfer of cells or organs from a donor to a recipient where the recipient is a species different from that of the donor.

(357) In addition, cancer cells can be obtained from a single source or a plurality of sources (e.g., a single subject or a plurality of subjects). A plurality refers to at least two (e.g., more than one). In still another embodiment, the non-human mammal is a mouse. The animals from which cell types of interest are obtained may be adult, newborn (e.g., less than 48 hours old), immature, or in utero. Cell types of interest may be primary cancer cells, cancer stem cells, established cancer cell lines, immortalized primary cancer cells, and the like. In certain embodiments, the immune systems of host subjects can be engineered or otherwise elected to be immunological compatible with transplanted cancer cells. For example, in one embodiment, the subject may be humanized in order to be compatible with human cancer cells. The term immune-system humanized refers to an animal, such as a mouse, comprising human HSC lineage cells and human acquired and innate immune cells, survive without being rejected from the host animal, thereby allowing human hematopoiesis and both acquired and innate immunity to be reconstituted in the host animal. Acquired immune cells include T cells and B cells. Innate immune cells include macrophages, granulocytes (basophils, eosinophils, neutrophils), DCs, NK cells and mast cells. Representative, non-limiting examples include SCID-hu, Hu-PBL-SCID, Hu-SRC-SCID, NSG (NOD-SCID IL2r-gamma(null) lack an innate immune system, B cells, T cells, and cytokine signaling), NOG (NOD-SCID IL2r-gamma(truncated)), BRG (BALB/c-Rag2(null)IL2r-gamma(null)), and H2dRG (Stock-H2d-Rag2(null)IL2r-gamma(null)) mice (see, for example, Shultz et al. (2007) Nat. Rev. Immunol. 7:118; Pearson et al. (2008) Curr. Protocol. Immunol. 15:21; Brehm et al (2010) Clin. Immunol. 135:84-98; McCune et al. (1988) Science 241:1632-1639, U.S. Pat. No. 7,960,175, and U.S. Pat. Publ. 2006/0161996), as well as related null mutants of immune-related genes like Rag1 (lack B and T cells), Rag2 (lack B and T cells), TCR alpha (lack T cells), perforin (cD8+ T cells lack cytotoxic function), FoxP3 (lack functional CD4+ T regulatory cells), IL2rg, or Prfl, as well as mutants or knockouts of PD-1, PD-L1, Tim3, and/or 2B4, allow for efficient engraftment of human immune cells in and/or provide compartment-specific models of immunocompromised animals like mice (see, for example, PCT Publ. WO2013/062134). In addition, NSG-CD34+ (NOD-SCID IL2r-gamma(null) CD34+) humanized mice are useful for studying human gene and tumor activity in animal models like mice.

(358) As used herein, obtained from a biological material source means any conventional method of harvesting or partitioning a source of biological material from a donor. For example, biological material may obtained from a solid tumor, a blood sample, such as a peripheral or cord blood sample, or harvested from another body fluid, such as bone marrow or amniotic fluid. Methods for obtaining such samples are well-known to the artisan. In the present invention, the samples may be fresh (i.e., obtained from a donor without freezing). Moreover, the samples may be further manipulated to remove extraneous or unwanted components prior to expansion. The samples may also be obtained from a preserved stock. For example, in the case of cell lines or fluids, such as peripheral or cord blood, the samples may be withdrawn from a cryogenically or otherwise preserved bank of such cell lines or fluid. Such samples may be obtained from any suitable donor.

(359) The obtained populations of cells may be used directly or frozen for use at a later date. A variety of mediums and protocols for cryopreservation are known in the art. Generally, the freezing medium will comprise DMSO from about 5-10%, 10-90% serum albumin, and 50-90% culture medium. Other additives useful for preserving cells include, by way of example and not limitation, disaccharides such as trehalose (Scheinkonig et al. (2004) Bone Marrow Transplant. 34:531-536), or a plasma volume expander, such as hetastarch (i.e., hydroxyethyl starch). In some embodiments, isotonic buffer solutions, such as phosphate-buffered saline, may be used. An exemplary cryopreservative composition has cell-culture medium with 4% HSA, 7.5% dimethyl sulfoxide (DMSO), and 2% hetastarch. Other compositions and methods for cryopreservation are well-known and described in the art (see, e.g., Broxmeyer et al. (2003) Proc. Natl. Acad. Sci. U.S.A. 100:645-650). Cells are preserved at a final temperature of less than about 135 C.

(360) c. Combination Therapy

(361) The cancer vaccine can be administered in combination therapy with, e.g., chemotherapeutic agents, hormones, antiangiogens, radiolabelled, compounds, or with surgery, cryotherapy, and/or radiotherapy. The preceding treatment methods can be administered in conjunction with other forms of conventional therapy (e.g., standard-of-care treatments for cancer well-known to the skilled artisan), either consecutively with, pre- or post-conventional therapy. For example, the cancer vaccine can be administered with a therapeutically effective dose of chemotherapeutic agent. In another embodiment, the cancer vaccine is administered in conjunction with chemotherapy to enhance the activity and efficacy of the chemotherapeutic agent. The Physicians' Desk Reference (PDR) discloses dosages of chemotherapeutic agents that have been used in the treatment of various cancers. The dosing regimen and dosages of these aforementioned chemotherapeutic drugs that are therapeutically effective will depend on the particular cancer being treated, the extent of the disease and other factors familiar to the physician of skill in the art, and can be determined by the physician.

(362) The cancer vaccine can also be administered in combination with targeted therapy, e.g., immunotherapy. The term targeted therapy refers to administration of agents that selectively interact with a chosen biomolecule to thereby treat cancer. For example, targeted therapy regarding the inhibition of immune checkpoint inhibitor is useful in combination with the methods of the present invention. The term immune checkpoint inhibitor means a group of molecules on the cell surface of CD4+ and/or CD8+ T cells that fine-tune immune responses by down-modulating or inhibiting an anti-tumor immune response. Immune checkpoint proteins are well-known in the art and include, without limitation, CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, 2B4, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KM family receptors, TIM-1, TIM-3, TIM-4, LAG-3, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, and A2aR (see, for example, WO 2012/177624). Inhibition of one or more immune checkpoint inhibitors can block or otherwise neutralize inhibitory signaling to thereby upregulate an immune response in order to more efficaciously treat cancer. In some embodiments, the cancer vaccine is administered in combination with one or more inhibitors of immune checkpoints, such as PD1, PD-L1, and/or CD47 inhibitors.

(363) Immunotherapy is one form of targeted therapy that may comprise, for example, the use of additional cancer vaccines and/or sensitized antigen presenting cells. For example, an oncolytic virus is a virus that is able to infect and lyse cancer cells, while leaving normal cells unharmed, making them potentially useful in cancer therapy. Replication of oncolytic viruses both facilitates tumor cell destruction and also produces dose amplification at the tumor site. They may also act as vectors for anticancer genes, allowing them to be specifically delivered to the tumor site. The immunotherapy can involve passive immunity for short-term protection of a host, achieved by the administration of pre-formed antibody directed against a cancer antigen or disease antigen (e.g., administration of a monoclonal antibody, optionally linked to a chemotherapeutic agent or toxin, to a tumor antigen). For example, anti-VEGF and mTOR inhibitors are known to be effective in treating renal cell carcinoma. Immunotherapy can also focus on using the cytotoxic lymphocyte-recognized epitopes of cancer cell lines. Alternatively, antisense polynucleotides, ribozymes, RNA interference molecules, triple helix polynucleotides and the like, can be used to selectively modulate biomolecules that are linked to the initiation, progression, and/or pathology of a tumor or cancer.

(364) The term untargeted therapy refers to administration of agents that do not selectively interact with a chosen biomolecule yet treat cancer. Representative examples of untargeted therapies include, without limitation, chemotherapy, gene therapy, and radiation therapy.

(365) In one embodiment, chemotherapy is used. Chemotherapy includes the administration of a chemotherapeutic agent. Such a chemotherapeutic agent may be, but is not limited to, those selected from among the following groups of compounds: platinum compounds, cytotoxic antibiotics, antimetabolities, anti-mitotic agents, alkylating agents, arsenic compounds, DNA topoisomerase inhibitors, taxanes, nucleoside analogues, plant alkaloids, and toxins; and synthetic derivatives thereof. Exemplary compounds include, but are not limited to, alkylating agents: cisplatin, treosulfan, and trofosfamide; plant alkaloids: vinblastine, paclitaxel, docetaxol; DNA topoisomerase inhibitors: teniposide, crisnatol, and mitomycin; anti-folates: methotrexate, mycophenolic acid, and hydroxyurea; pyrimidine analogs: 5-fluorouracil, doxifluridine, and cytosine arabinoside; purine analogs: mercaptopurine and thioguanine; DNA antimetabolites: 2-deoxy-5-fluorouridine, aphidicolin glycinate, and pyrazoloimidazole; and antimitotic agents: halichondrin, colchicine, and rhizoxin. Compositions comprising one or more chemotherapeutic agents (e.g., FLAG, CHOP) may also be used. FLAG comprises fludarabine, cytosine arabinoside (Ara-C) and G-CSF. CHOP comprises cyclophosphamide, vincristine, doxorubicin, and prednisone. The foregoing examples of chemotherapeutic agents are illustrative, and are not intended to be limiting.

(366) In another embodiment, radiation therapy is used. The radiation used in radiation therapy can be ionizing radiation. Radiation therapy can also be gamma rays, X-rays, or proton beams. Examples of radiation therapy include, but are not limited to, external-beam radiation therapy, interstitial implantation of radioisotopes (I-125, palladium, iridium), radioisotopes such as strontium-89, thoracic radiation therapy, intraperitoneal P-32 radiation therapy, and/or total abdominal and pelvic radiation therapy. For a general overview of radiation therapy, see Hellman, Chapter 16: Principles of Cancer Management: Radiation Therapy, 6th edition, 2001, DeVita et al., eds., J. B. Lippencott Company, Philadelphia. The radiation therapy can be administered as external beam radiation or teletherapy wherein the radiation is directed from a remote source. The radiation treatment can also be administered as internal therapy or brachytherapy wherein a radioactive source is placed inside the body close to cancer cells or a tumor mass. Also encompassed is the use of photodynamic therapy comprising the administration of photosensitizers, such as hematoporphyrin and its derivatives, Vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, demethoxy-hypocrellin A; and 2BA-2-DMHA.

(367) In another embodiment, hormone therapy is used. Hormonal therapeutic treatments can comprise, for example, hormonal agonists, hormonal antagonists (e.g., flutamide, bicalutamide, tamoxifen, raloxifene, leuprolide acetate (LUPRON), LH-RH antagonists), inhibitors of hormone biosynthesis and processing, and steroids (e.g., dexamethasone, retinoids, deltoids, betamethasone, cortisol, cortisone, prednisone, dehydrotestosterone, glucocorticoids, mineralocorticoids, estrogen, testosterone, progestins), vitamin A derivatives (e.g., all-trans retinoic acid (ATRA)); vitamin D3 analogs; antigestagens (e.g., mifepristone, onapristone), or antiandrogens (e.g., cyproterone acetate).

(368) In another embodiment, hyperthermia, a procedure in which body tissue is exposed to high temperatures (up to 106 F.) is used. Heat may help shrink tumors by damaging cells or depriving them of substances they need to live. Hyperthermia therapy can be local, regional, and whole-body hyperthermia, using external and internal heating devices. Hyperthermia is almost always used with other forms of therapy (e.g., radiation therapy, chemotherapy, and biological therapy) to try to increase their effectiveness. Local hyperthermia refers to heat that is applied to a very small area, such as a tumor. The area may be heated externally with high-frequency waves aimed at a tumor from a device outside the body. To achieve internal heating, one of several types of sterile probes may be used, including thin, heated wor hollow tubes filled with warm water; implanted microwave antennae; and radiofrequency electrodes. In regional hyperthermia, an organ or a limb is heated. Magnets and devices that produce high energy are placed over the region to be heated. In another approach, called perfusion, some of the patient's blood is removed, heated, and then pumped (perfused) into the region that is to be heated internally. Whole-body heating is used to treat metastatic cancer that has spread throughout the body. It can be accomplished using warm-water blankets, hot wax, inductive coils (like those in electric blankets), or thermal chambers (similar to large incubators). Hyperthermia does not cause any marked increase in radiation side effects or complications. Heat applied directly to the skin, however, can cause discomfort or even significant local pain in about half the patients treated. It can also cause blisters, which generally heal rapidly.

(369) In still another embodiment, photodynamic therapy (also called PDT, photoradiation therapy, phototherapy, or photochemotherapy) is used for the treatment of some types of cancer. It is based on the discovery that certain chemicals known as photosensitizing agents can kill one-celled organisms when the organisms are exposed to a particular type of light. PDT destroys cancer cells through the use of a fixed-frequency laser light in combination with a photosensitizing agent. In PDT, the photosensitizing agent is injected into the bloodstream and absorbed by cells all over the body. The agent remains in cancer cells for a longer time than it does in normal cells. When the treated cancer cells are exposed to laser light, the photosensitizing agent absorbs the light and produces an active form of oxygen that destroys the treated cancer cells. Light exposure must be timed carefully so that it occurs when most of the photosensitizing agent has left healthy cells but is still present in the cancer cells. The laser light used in PDT can be directed through a fiber-optic (a very thin glass strand). The fiber-optic is placed close to the cancer to deliver the proper amount of light. The fiber-optic can be directed through a bronchoscope into the lungs for the treatment of lung cancer or through an endoscope into the esophagus for the treatment of esophageal cancer. An advantage of PDT is that it causes minimal damage to healthy tissue. However, because the laser light currently in use cannot pass through more than about 3 centimeters of tissue (a little more than one and an eighth inch), PDT is mainly used to treat tumors on or just under the skin or on the lining of internal organs. Photodynamic therapy makes the skin and eyes sensitive to light for 6 weeks or more after treatment. Patients are advised to avoid direct sunlight and bright indoor light for at least 6 weeks. If patients must go outdoors, they need to wear protective clothing, including sunglasses. Other temporary side effects of PDT are related to the treatment of specific areas and can include coughing, trouble swallowing, abdominal pain, and painful breathing or shortness of breath. In December 1995, the U.S. Food and Drug Administration (FDA) approved a photosensitizing agent called porfimer sodium, or Photofrin, to relieve symptoms of esophageal cancer that is causing an obstruction and for esophageal cancer that cannot be satisfactorily treated with lasers alone. In January 1998, the FDA approved porfimer sodium for the treatment of early non-small cell lung cancer in patients for whom the usual treatments for lung cancer are not appropriate. The National Cancer Institute and other institutions are supporting clinical trials (research studies) to evaluate the use of photodynamic therapy for several types of cancer, including cancers of the bladder, brain, larynx, and oral cavity.

(370) In yet another embodiment, laser therapy is used to harness high-intensity light to destroy cancer cells. This technique is often used to relieve symptoms of cancer such as bleeding or obstruction, especially when the cancer cannot be cured by other treatments. It may also be used to treat cancer by shrinking or destroying tumors. The term laser stands for light amplification by stimulated emission of radiation. Ordinary light, such as that from a light bulb, has many wavelengths and spreads in all directions. Laser light, on the other hand, has a specific wavelength and is focused in a narrow beam. This type of high-intensity light contains a lot of energy. Lasers are very powerful and may be used to cut through steel or to shape diamonds. Lasers also can be used for very precise surgical work, such as repairing a damaged retina in the eye or cutting through tissue (in place of a scalpel). Although there are several different kinds of lasers, only three kinds have gained wide use in medicine: Carbon dioxide (CO.sub.2) laserThis type of laser can remove thin layers from the skin's surface without penetrating the deeper layers. This technique is particularly useful in treating tumors that have not spread deep into the skin and certain precancerous conditions. As an alternative to traditional scalpel surgery, the CO.sub.2 laser is also able to cut the skin. The laser is used in this way to remove skin cancers. Neodymium:yttrium-aluminum-garnet (Nd:YAG) laserLight from this laser can penetrate deeper into tissue than light from the other types of lasers, and it can cause blood to clot quickly. It can be carried through optical fibers to less accessible parts of the body. This type of laser is sometimes used to treat throat cancers. Argon laserThis laser can pass through only superficial layers of tissue and is therefore useful in dermatology and in eye surgery. It also is used with light-sensitive dyes to treat tumors in a procedure known as photodynamic therapy (PDT). Lasers have several advantages over standard surgical tools, including: Lasers are more precise than scalpels. Tissue near an incision is protected, since there is little contact with surrounding skin or other tissue. The heat produced by lasers sterilizes the surgery site, thus reducing the risk of infection. Less operating time may be needed because the precision of the laser allows for a smaller incision. Healing time is often shortened; since laser heat seals blood vessels, there is less bleeding, swelling, or scarring. Laser surgery may be less complicated. For example, with fiber optics, laser light can be directed to parts of the body without making a large incision. More procedures may be done on an outpatient basis. Lasers can be used in two ways to treat cancer: by shrinking or destroying a tumor with heat, or by activating a chemicalknown as a photosensitizing agentthat destroys cancer cells. In PDT, a photosensitizing agent is retained in cancer cells and can be stimulated by light to cause a reaction that kills cancer cells. CO.sub.2 and Nd:YAG lasers are used to shrink or destroy tumors. They may be used with endoscopes, tubes that allow physicians to see into certain areas of the body, such as the bladder. The light from some lasers can be transmitted through a flexible endoscope fitted with fiber optics. This allows physicians to see and work in parts of the body that could not otherwise be reached except by surgery and therefore allows very precise aiming of the laser beam. Lasers also may be used with low-power microscopes, giving the doctor a clear view of the site being treated. Used with other instruments, laser systems can produce a cutting area as small as 200 microns in diameterless than the width of a very fine thread. Lasers are used to treat many types of cancer. Laser surgery is a standard treatment for certain stages of glottis (vocal cord), cervical, skin, lung, vaginal, vulvar, and penile cancers. In addition to its use to destroy the cancer, laser surgery is also used to help relieve symptoms caused by cancer (palliative care). For example, lasers may be used to shrink or destroy a tumor that is blocking a patient's trachea (windpipe), making it easier to breathe. It is also sometimes used for palliation in colorectal and anal cancer. Laser-induced interstitial thermotherapy (LITT) is one of the most recent developments in laser therapy. LITT uses the same idea as a cancer treatment called hyperthermia; that heat may help shrink tumors by damaging cells or depriving them of substances they need to live. In this treatment, lasers are directed to interstitial areas (areas between organs) in the body. The laser light then raises the temperature of the tumor, which damages or destroys cancer cells.

(371) The immunotherapy and/or cancer therapy may be administered before, after, or concurrently with the cancer vaccine described herein. The duration and/or dose of treatment with the cancer vaccine may vary according to the particular cancer vaccine, or the particular combinatory therapy. An appropriate treatment time for a particular cancer therapeutic agent will be appreciated by the skilled artisan. The invention contemplates the continued assessment of optimal treatment schedules for each cancer therapeutic agent, where the phenotype of the cancer of the subject as determined by the methods of the invention is a factor in determining optimal treatment doses and schedules.

V. Clinical Efficacy

(372) Clinical efficacy can be measured by any method known in the art. For example, the response to an cancer therapy (e.g., a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Samd/p63 signaling pathway), relates to any response of the cancer, e.g., a tumor, to the therapy, preferably to a change in tumor mass and/or volume after initiation of neoadjuvant or adjuvant chemotherapy. Tumor response may be assessed in a neoadjuvant or adjuvant situation where the size of a tumor after systemic intervention can be compared to the initial size and dimensions as measured by CT, PET, mammogram, ultrasound or palpation and the cellularity of a tumor can be estimated histologically and compared to the cellularity of a tumor biopsy taken before initiation of treatment. Response may also be assessed by caliper measurement or pathological examination of the tumor after biopsy or surgical resection. Response may be recorded in a quantitative fashion like percentage change in tumor volume or cellularity or using a semi-quantitative scoring system such as residual cancer burden (Symmans et al. (2007) J. Clin. Oncol. 25:4414-4422) or Miller-Payne score (Ogston et al. (2003) Breast (Edinburgh, Scotland) 12:320-327) in a qualitative fashion like pathological complete response (pCR), clinical complete remission (cCR), clinical partial remission (cPR), clinical stable disease (cSD), clinical progressive disease (cPD) or other qualitative criteria. Assessment of tumor response may be performed early after the onset of neoadjuvant or adjuvant therapy, e.g., after a few hours, days, weeks or preferably after a few months. A typical endpoint for response assessment is upon termination of neoadjuvant chemotherapy or upon surgical removal of residual tumor cells and/or the tumor bed.

(373) In some embodiments, clinical efficacy of the therapeutic treatments described herein may be determined by measuring the clinical benefit rate (CBR). The clinical benefit rate is measured by determining the sum of the percentage of patients who are in complete remission (CR), the number of patients who are in partial remission (PR) and the number of patients having stable disease (SD) at a time point at least 6 months out from the end of therapy. The shorthand for this formula is CBR=CR+PR+SD over 6 months. In some embodiments, the CBR for a particular cancer vaccine therapeutic regimen is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or more.

(374) Additional criteria for evaluating the response to cancer therapy (e.g., a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Samd/p63 signaling pathway) are related to survival, which includes all of the following: survival until mortality, also known as overall survival (wherein said mortality may be either irrespective of cause or tumor related); recurrence-free survival (wherein the term recurrence shall include both localized and distant recurrence); metastasis free survival; disease free survival (wherein the term disease shall include cancer and diseases associated therewith). The length of said survival may be calculated by reference to a defined start point (e.g., time of diagnosis or start of treatment) and end point (e.g., death, recurrence or metastasis). In addition, criteria for efficacy of treatment can be expanded to include response to chemotherapy, probability of survival, probability of metastasis within a given time period, and probability of tumor recurrence.

(375) For example, in order to determine appropriate threshold values, a particular agent encompassed by the present invention can be administered to a population of subjects and the outcome can be correlated to biomarker measurements that were determined prior to administration of any cancer therapy (e.g., a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Samd/p63 signaling pathway). The outcome measurement may be pathologic response to therapy given in the neoadjuvant setting. Alternatively, outcome measures, such as overall survival and disease-free survival can be monitored over a period of time for subjects following cancer therapy (e.g., a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Samd/p63 signaling pathway) for whom biomarker measurement values are known. In certain embodiments, the same doses of the agent are administered to each subject. In related embodiments, the doses administered are standard doses known in the art for the agent. The period of time for which subjects are monitored can vary. For example, subjects may be monitored for at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, or 60 months. Biomarker measurement threshold values that correlate to outcome of a cancer therapy (e.g., a cancer vaccine comprising cancer cells, wherein the cancer cells are (1) PTEN-deficient, (2) p53-deficient, and (3) modified to activate the TGF-Samd/p63 signaling pathway) can be determined using methods such as those described in the Examples section.

VI. Pharmaceutical Compositions and Administration

(376) For cancer vaccine of present invention, cancer cells can be administered at 1, 10, 1000, 10,000, 0.110.sup.6, 0.210.sup.6, 0.310.sup.6, 0.410.sup.6, 0.510.sup.6, 0.610.sup.6, 0.710.sup.6, 0.810.sup.6, 0.910.sup.6, 1.010.sup.6, 5.010.sup.6, 1.010.sup.7, 5.010.sup.7, 1.010.sup.8, 5.010.sup.8, 1.010.sup.9 or more, or any range in between or any value in between, cells per kilogram of subject body weight. The number of cells transplanted may be adjusted based on the desired level of engraftment in a given amount of time. Generally, 110.sup.5 to about 110.sup.9 cells/kg of body weight, from about 110.sup.6 to about 110.sup.8 cells/kg of body weight, or about 110.sup.7 cells/kg of body weight, or more cells, as necessary, may be transplanted. In some embodiment, transplantation of at least about 100, 1000, 10,000, 0.110.sup.6, 0.510.sup.6, 1.010.sup.6, 2.010.sup.6, 3.010.sup.6, 4.010.sup.6, or 5.010.sup.6 total cells relative to an average size mouse is effective.

(377) Cancer vaccine can be administered in any suitable route as described herein, such as by infusion. Cancer vaccine can also be administered before, concurrently with, or after, other anti-cancer agents.

(378) Administration can be accomplished using methods generally known in the art. Agents, including cells, may be introduced to the desired site by direct injection, or by any other means used in the art including, but are not limited to, intravascular, intracerebral, parenteral, intraperitoneal, intravenous, epidural, intraspinal, intrasternal, intra-articular, intra-synovial, intrathecal, intra-arterial, intracardiac, or intramuscular administration. For example, subjects of interest may be engrafted with the transplanted cells by various routes. Such routes include, but are not limited to, intravenous administration, subcutaneous administration, administration to a specific tissue (e.g., focal transplantation), injection into the femur bone marrow cavity, injection into the spleen, administration under the renal capsule of fetal liver, and the like. In certain embodiment, the cancer vaccine of the present invention is injected to the subject intratumorally or subcutaneously. Cells may be administered in one infusion, or through successive infusions over a defined time period sufficient to generate a desired effect. Exemplary methods for transplantation, engraftment assessment, and marker phenotyping analysis of transplanted cells are well-known in the art (see, for example, Pearson et al. (2008) Curr. Protoc. Immunol. 81:15.21.1-15.21.21; Ito et al. (2002) Blood 100:3175-3182; Traggiai et al. (2004) Science 304:104-107; Ishikawa et al. Blood (2005) 106:1565-1573; Shultz et al. (2005) J. Immunol. 174:6477-6489; and Holyoake et al. (1999) Exp. Hematol. 27:1418-1427).

(379) Two or more cell types can be combined and administered, such as cancer vaccine and adoptive cell transfer of stem cells, cancer vaccine and other cell-based vaccines, and the like. For example adoptive cell-based immunotherapies can be combined with the cancer vaccine of the present invention. Well-known adoptive cell-based immunotherapeutic modalities, including, without limitation, irradiated autologous or allogeneic tumor cells, tumor lysates or apoptotic tumor cells, antigen-presenting cell-based immunotherapy, dendritic cell-based immunotherapy, adoptive T cell transfer, adoptive CAR T cell therapy, autologous immune enhancement therapy (AIET), cancer vaccines, and/or antigen presenting cells. Such cell-based immunotherapies can be further modified to express one or more gene products to further modulate immune responses, such as expressing cytokines like GM-CSF, and/or to express tumor-associated antigen (TAA) antigens, such as Mage-1, gp-100, and the like. The ratio of cancer cells in the cancer vaccine described herein to other cell types can be 1:1, but can modulated in any amount desired (e.g., 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1, or greater).

(380) Engraftment of transplanted cells may be assessed by any of various methods, such as, but not limited to, tumor volume, cytokine levels, time of administration, flow cytometric analysis of cells of interest obtained from the subject at one or more time points following transplantation, and the like. For example, a time-based analysis of waiting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 days or can signal the time for tumor harvesting. Any such metrics are variables that can be adjusted according to well-known parameters in order to determine the effect of the variable on a response to anti-cancer immunotherapy. In addition, the transplanted cells can be co-transplanted with other agents, such as cytokines, extracellular matrices, cell culture supports, and the like.

(381) In addition, anti-cancer agents (e.g., TGF superfamily proteins, agents that increase the copy number, amount, and/or activity of at least one biomarker listed in Table 1, and/or immune checkpoint inhibitors) of the present invention can be administered to subjects or otherwise applied outside of a subject body in a biologically compatible form suitable for pharmaceutical administration. By biologically compatible form suitable for administration in vivo is meant a form to be administered in which any toxic effects are outweighed by the therapeutic effects. Administration of an anti-cancer agent as described herein can be in any pharmacological form including a therapeutically active amount of an agent alone or in combination with a pharmaceutically acceptable carrier. The phrase therapeutically-effective amount as used herein means that amount of an agent that is effective for producing some desired therapeutic effect, e.g., cancer treatment, at a reasonable benefit/risk ratio.

(382) Administration of a therapeutically active amount of the therapeutic composition of the present invention is defined as an amount effective, at dosages and for periods of time necessary, to achieve the desired result. For example, a therapeutically active amount of an agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of peptide to elicit a desired response in the individual. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses can be administered daily or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation.

(383) A combination dosage form or simultaneous administration of single agents can result in effective amounts of each desired modulatory agent present in the patient at the same time.

(384) The therapeutic agents described herein can be administered in a convenient manner such as by injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, or rectal administration. Depending on the route of administration, the active compound can be coated in a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the compound. For example, for administration of agents, by other than parenteral administration, it may be desirable to coat the agent with, or co-administer the agent with, a material to prevent its inactivation.

(385) An agent can be administered to an individual in an appropriate carrier, diluent or adjuvant, co-administered with enzyme inhibitors or in an appropriate carrier such as liposomes. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Adjuvant is used in its broadest sense and includes any immune stimulating compound such as interferon. Adjuvants contemplated herein include resorcinols, non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether. Enzyme inhibitors include pancreatic trypsin inhibitor, diisopropylfluorophosphate (DEEP) and trasylol. Liposomes include water-in-oil-in-water emulsions as well as conventional liposomes (Sterna et al. (1984) J. Neuroimmunol. 7:27).

(386) The agent may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

(387) Pharmaceutical compositions of agents suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the composition will preferably be sterile and must be fluid to the extent that easy syringeability exists. It will preferably be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

(388) Sterile injectable solutions can be prepared by incorporating an agent of the invention in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the agent plus any additional desired ingredient from a previously sterile-filtered solution thereof.

(389) When the agent is suitably protected, as described above, the protein can be orally administered, for example, with an inert diluent or an assimilable edible carrier. As used herein pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well-known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the therapeutic compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

(390) It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by, and directly dependent on, (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

VII. Kits

(391) The present invention also encompasses kits. For example, the kit can comprise PTEN and p53-deficient cancer cells modified as described herein, TGF superfamily proteins, agents that increase the copy number, amount, and/or activity of at least one biomarker listed in Table 1, immune checkpoint inhibitors, and combinations thereof, packaged in a suitable container and can further comprise instructions for using such reagents. The kit may also contain other components, such as administration tools packaged in a separate container.

(392) Other embodiments of the present invention are described in the following Examples. The present invention is further illustrated by the following examples which should not be construed as further limiting. The contents of all references, patents and published patent applications cited throughout this application, as well as the Figures, are incorporated herein by reference.

EXAMPLES

Example 1: Materials and Methods for Examples 2-7

(393) a. Cell Culture

(394) PP and PP.sub.T breast cancer cells were cultured in DMEM/F12 (3:1) media supplemented with 10% fetal bovine serum (FBS), 25 ng/ml hydrocortisone, 5 g/ml insulin, 8.5 ng/ml cholera toxin, 0.125 ng/ml epidermal growth factor (EGF), 5 M Y-27632 Rock1 inhibitor, penicillin (100 U/mL), and streptomycin (100 mg/mL). For PP.sub.T cells, 4 ng/ml TGF1 was freshly added into the media every three days. Cells were incubated at 37 C. in a humidified atmosphere under 5% CO.sub.2. NMuMG, HMEC, MCF10A, ZR-75-1, MDA-MB-453, MDA-MB-231, MCF7, BT549, HCC1954 and HCC70 cells were purchased from American Type Culture Collection (ATCC) and were cultured according to vendor's instructions.

(395) b. Antibodies and Reagents

(396) TGF1 (#GF111) was purchased from Millipore (Billerica, MA, USA). FITC anti-mouse CD45 (30-F11), PE/Dazzle 594 anti-mouse CD3 (145-2C11), APC/Cy7 anti-mouse CD4 (RM4-5), Alexa Fluor 700 anti-mouse CD8 (53-6.7), APC anti-mouse TNF (MP6-XT22), PE anti-mouse IFN (XMG1.2), PE/Cy7 anti-mouse CD11c (N418), APC/Cy7 anti-mouse I-A/I-E (M5/114.15.2), PerCP/Cy5 anti-mouse CD103 (2E7), PE anti-mouse CD80 (16-10A1), FITC anti-human CD45 (H130), Alexa Fluor 700 anti-human CD11C (Bu15), PerCP/Cy5 anti-human CD80 (2D10), Pacific Blue anti-human CD86 (IT2.2), and anti-human APC CD103 (Ber-ACT8) were purchased from Biolegend (San Diego, CA, USA). Smad2 (D43B4) rabbit monoclonal antibody (#5339), phospho-Smad2 (Ser465/467; 138D4) rabbit monoclonal antibody, Lamin A/C (4C11) mouse monoclonal antibody, and p63 (D9L7L) rabbit monoclonal antibody (#39692) were purchased from Cell Signaling Technology. Anti-Vinculin antibody (#V9131) was bought from Sigma Aldrich.

(397) c. Real-Time PCR

(398) Real-time PCR was performed using SYBR Select Master Mix on an Applied Biosystems 7300 Fast Real-Time PCR system according to manufacturer's instructions. In brief, incubation cycles were as follows: 95 C. for 10 min, then 95 C. for 15 s, 60 C. for 1 min. Amplification was completed by 40 cycles and melting curves were measured. Primers used for real-time PCR assay are shown in Table. 3.

(399) TABLE-US-00004 TABLE3 mAx1-F ATGGCCGACATTGCCAGTG(SEQIDNO:191) mAx1-R CGGTAGTAATCCCCGTTGTAGA(SEQIDNO:192) mBatf3-F CAGAGCCCCAAGGACGATG(SEQIDNO:193) mBatf3-R GCACAAAGTTCATAGGACACAGC(SEQIDNO:194) mCcl2-F TTAAAAACCTGGATCGGAACCAA(SEQIDNO:195) mCcl2-R GCATTAGCTTCAGATTTACGGGT(SEQIDNO:196) mCcl7-F GCTGCTTTCAGCATCCAAGTG(SEQIDNO:197) mCcl7-R CCAGGGACACCGACTACTG(SEQIDNO:198) mCcl8-F CTGGGCCAGATAAGGCTCC(SEQIDNO:199) mCCL8-F CTGGGCCAGATAAGGCTCC(SEQIDNO:199) mCcl8-R CATGGGGCACTGGATATTGTT(SEQIDNO:200) mCCL8-R CATGGGGCACTGGATATTGTT(SEQIDNO:200) mCCR7-F TGTACGAGTCGGTGTGCTTC(SEQIDNO:201) mCCR7-R GGTAGGTATCCGTCATGGTCTTG(SEQIDNO:202) mCD14-F CTCTGTCCTTAAAGCGGCTTAC(SEQIDNO:203) mCD14-R GTTGCGGAGGTTCAAGATGTT(SEQIDNO:204) mCD200-F CTCTCCACCTACAGCCTGATT(SEQIDNO:205) mCD200-R AGAACATCGTAAGGATGCAGTTG(SEQIDNO:206) mCD207-F CCGAAGCGCACTTCACAGT(SEQIDNO:207) mCD207-R GCAGATACAGAGAGGTTTCCTCA(SEQIDNO:208) mCD4-F TCCTAGCTGTCACTCAAGGGA(SEQIDNO:209) mCD4-R TCAGAGAACTTCCAGGTGAAGA(SEQIDNO:210) mCD40-F TGTCATCTGTGAAAAGGTGGTC(SEQIDNO:211) mCD40-R ACTGGAGCAGCGGTGTTATG(SEQIDNO:212) mCD45-F CAGAAACGCCTAAGCCTAGTTG(SEQIDNO:213) mCD45-R ATGCAGGATCAGGTTTAGATGC(SEQIDNO:214) mCD74-F AGTGCGACGAGAACGGTAAC(SEQIDNO:215) mCD74-R CGTTGGGGAACACACACCA(SEQIDNO:216) mCD8-F CCGTTGACCCGCTTTCTGT(SEQIDNO:217) mCD8-R CGGCGTCCATTTTCTTTGGAA(SEQIDNO:218) mCd80-F ACCCCCAACATAACTGAGTCT(SEQIDNO:219) mCd80-R TTCCAACCAAGAGAAGCGAGG(SEQIDNO:220) mCD86-F CTGGACTCTACGACTTCACAATG(SEQIDNO:221) mCD86-R AGTTGGCGATCACTGACAGTT(SEQIDNO:222) mCD8a-F CCGTTGACCCGCTTTCTGT(SEQIDNO:217) mCD8a-R CGGCGTCCATTTTCTTTGGAA(SEQIDNO:218) mCeacam1-F TTCCCTGGGGAGGACTACTG(SEQIDNO:225) mCeacam1-R TGTATGCTTGCCCCGTGAAAT(SEQIDNO:226) mClec9a-F GAAGTGCCAATCCCCTAGCAA(SEQIDNO:227) mClec9a-R CAGTCACTACCTGAATGGAGAGA(SEQIDNO:228) mCtsb-F TCCTTGATCCTTCTTTCTTGCC(SEQIDNO:229) mCtsb-F TCCTTGATCCTTCTTTCTTGCC(SEQIDNO:229) mCtsb-R ACAGTGCCACACAGCTTCTTC(SEQIDNO:230) mCtsb-R ACAGTGCCACACAGCTTCTTC(SEQIDNO:230) mCts1-F ATCAAACCTTTAGTGCAGAGTGG(SEQIDNO:231) mCts1-F ATCAAACCTTTAGTGCAGAGTGG(SEQIDNO:231) mCts1-R CTGTATTCCCCGTTGTGTAGC(SEQIDNO:232) mCts1-R CTGTATTCCCCGTTGTGTAGC(SEQIDNO:232) mCXCL10-F CCAAGTGCTGCCGTCATTTTC(SEQIDNO:233) mCXCL10-R GGCTCGCAGGGATGATTTCAA(SEQIDNO:234) mCXCR3-F TACCTTGAGGTTAGTGAACGTCA(SEQIDNO:235) mCXCR3-R CGCTCTCGTTTTCCCCATAATC(SEQIDNO:236) mFyn-F ACCTCCATCCCGAACTACAAC(SEQIDNO:237) mFyn-R CGCCACAAACAGTGTCACTC(SEQIDNO:238) mGas6-F TGCTGGCTTCCGAGTCTTC(SEQIDNO:239) mGas6-R CGGGGTCGTTCTCGAACAC(SEQIDNO:240) mH2-Ab1-F AGCCCCATCACTGTGGAGT(SEQIDNO:241) mH2-Ab1-R GATGCCGCTCAACATCTTGC(SEQIDNO:242) mH2-D1-F CCCTGACCTGGCAGTTGAATG(SEQIDNO:243) mH2-D1-R AGCTCCAATGATGGCCATAGC(SEQIDNO:244) mHspa1b-F GAGATCGACTCTCTGTTCGAGG(SEQIDNO:245) mHspa1b-R GCCCGTTGAAGAAGTCCTG(SEQIDNO:246) mIcos-F ATGAAGCCGTACTTCTGCCAT(SEQIDNO:247) mIcos-R CGCATTTTTAACTGCTGGACAG(SEQIDNO:248) mIfnb1-F CAGCTCCAAGAAAGGACGAAC(SEQIDNO:249) mIfnb1-R GGCAGTGTAACTCTTCTGCAT(SEQIDNO:250) mIfng-F ATGAACGCTACACACTGCATC(SEQIDNO:251) mIfng-R CCATCCTTTTGCCAGTTCCTC(SEQIDNO:252) mIL12b-F TGGTTTGCCATCGTTTTGCTG(SEQIDNO:253) mIL12b-R ACAGGTGAGGTTCACTGTTTCT(SEQIDNO:254) mIL18-F GTGAACCCCAGACCAGACTG(SEQIDNO:255) mIL18-R CCTGGAACACGTTTCTGAAAGA(SEQIDNO:256) mIL1b-F GAAATGCCACCTTTTGACAGTG(SEQIDNO:257) mIL1b-R TGGATGCTCTCATCAGGACAG(SEQIDNO:258) mIL2ra-F AACCATAGTACCCAGTTGTCGG(SEQIDNO:259) mIL2ra-R TCCTAAGCAACGCATATAGACCA(SEQIDNO:260) mIL2rb-F TGGAGCCTGTCCCTCTACG(SEQIDNO:261) mIL2rb-R TCCACATGCAAGAGACATTGG(SEQIDNO:262) mIL6st-F CCGTGTGGTTACATCTACCCT(SEQIDNO:263) mIL6st-R CGTGGTTCTGTTGATGACAGTG(SEQIDNO:264) mIrf1-F ATGCCAATCACTCGAATGCG(SEQIDNO:265) mIrf1-R TTGTATCGGCCTGTGTGAATG(SEQIDNO:266) mIrf4-F TCCGACAGTGGTTGATCGAC(SEQIDNO:267) mIrf4-R CCTCACGATTGTAGTCCTGCTT(SEQIDNO:268) mIrf8-F CGGGGCTGATCTGGGAAAAT(SEQIDNO:269) mIrf8-R CACAGCGTAACCTCGTCTTC(SEQIDNO:270) mItga6-F TGCAGAGGGCGAACAGAAC(SEQIDNO:271) mItga6-R GCACACGTCACCACTTTGC(SEQIDNO:272) mItgae-F CCTGTGCAGCATGTAAAAGAATG(SEQIDNO:273) mItgae-R CAAGGATCGGCAGTTCAGATAC(SEQIDNO:274) mItgam-F ATGGACGCTGATGGCAATACC(SEQIDNO:275) mItgam-R TCCCCATTCACGTCTCCCA(SEQIDNO:276) mK1rc1-F GCCCCTGCAAAGATACCGAA(SEQIDNO:277) mK1rc1-R TCTGTGGGTTCTAGTCATTGAGG(SEQIDNO:278) mLamp1-F CAGCACTCTTTGAGGTGAAAAAC(SEQIDNO:279) mLamp1-R ACGATCTGAGAACCATTCGCA(SEQIDNO:280) mLifr-F TACGTCGGCAGACTCGATATT(SEQIDNO:281) mLifr-R TGGGCGTATCTCTCTCTCCTT(SEQIDNO:282) mMalt1-F CACAGAACTGAGCGACTTCCT(SEQIDNO:283) mMalt1-R CAGCCAACACTGCCTTGGA(SEQIDNO:284) mNotch2-F GAGAAAAACCGCTGTCAGAATGG(SEQIDNO:285) mNotch2-R GGTGGAGTATTGGCAGTCCTC(SEQIDNO:286) mPik3cd-F GTAAACGACTTCCGCACTAAGA(SEQIDNO:287) mPik3cd-R GCTGACACGCAATAAGCCG(SEQIDNO:288) mRelb-F CCGTACCTGGTCATCACAGAG(SEQIDNO:289) mRelb-R CAGTCTCGAAGCTCGATGGC(SEQIDNO:290) mSirpa-F CCACGGGGAAGGAACTGAAG(SEQIDNO:291) mSirpa-R ACGTATTCTCCTGCGAAACTGTA(SEQIDNO:292) mTap1-F GGACTTGCCTTGTTCCGAGAG(SEQIDNO:293) mTAp1-R GCTGCCACATAACTGATAGCGA(SEQIDNO:294) mTapbp-F ACAAGGCCCCCAGAGTGT(SEQIDNO:295) mTapbp-R GGAAGAAGTGGGATGCAAGA(SEQIDNO:296) mTlr1-F TGAGGGTCCTGATAATGTCCTAC(SEQIDNO:297) mTlr1-R AGAGGTCCAAATGCTTGAGGC(SEQIDNO:298) mTlr3-F GTGAGATACAACGTAGCTGACTG(SEQIDNO:299) mTlr3-R TCCTGCATCCAAGATAGCAAGT(SEQIDNO:300) mTlr6-F TGAGCCAAGACAGAAAACCCA(SEQIDNO:301) mTlr6-R GGGACATGAGTAAGGTTCCTGTT(SEQIDNO:302) mTnf-F CCCTCACACTCAGATCATCTTCT(SEQIDNO:303) mTnf-R GCTACGACGTGGGCTACAG(SEQIDNO:304) mTnfaip3-F GAACAGCGATCAGGCCAGG(SEQIDNO:305) mTnfaip3-R GGACAGTTGGGTGTCTCACATT(SEQIDNO:306) mXcr1-F CTCAGCCTTGTGGGTAACAGC(SEQIDNO:307) mXcr1-R ACAGGCAGTAGACAGGAGAAC(SEQIDNO:308) mZeb2-F ATTGCACATCAGACTTTGAGGAA(SEQIDNO:309) mZeb2-R ATAATGGCCGTGTCGCTTCG(SEQIDNO:310)
d. Flow Cytometry Analysis

(400) To obtain single cell suspensions, tumors were first disrupted by mechanical dissociation and then digested in dissociation buffer (1 collagenase/hyaluronidase [#07912, Stem Cell Technologies] in DMEM, 10 mM HEPES, 5% FBS, 100 ng/mL DNase I [#07900, Stem Cell Technologies], and penicillin-streptomycin [#14140122, Thermo Fisher]) for 1 hour at 37 C. Spleens and lymph nodes were first dissociated by passing through 70- and 40-m cell strainers. Blood was collected by retro-orbital bleeding with EDTA microcaps (#47729-742, VWR) and microtainer (#0266933, Thermo Fisher), and blood cells were separated by centrifugation. For all tissues, red blood cells were lysed with ammonium chloride (4 volumes of 0.8% NH.sub.4Cl 0.1 mM EDTA [#07850, Stem Cell Technologies] plus 1 volume PBS). Single cell suspensions were then blocked with anti-CD16/32 (93, Biolegend) and stained with appropriate cell surface antibodies. For intracellular staining, cells were fixed and permeabilized using fixation and permeabilization wash buffers (#421002 and #4208801, Biolegend) according to manufacturer's instructions. Gating strategies can be found in the Supplementary Methods section.

(401) e. Animal Experiments

(402) Six-to-eight-week-old female nude, SCID and wild type FVB mice were purchased from Taconic Biosciences. For PP and PP.sub.T cell tumor formation assays, 110.sup.6 cells were injected into the third fat pads in 50% matrigel. For tumor transplantation assays, 110.sup.5 collagenase-digested PP tumor cells were injected into the third fat pads in 10% matrigel. For vaccination assays, 110.sup.6PP.sub.T cells were injected subcutaneously in 10% matrigel. After one month, PP cells or tumors were injected into the third fat pads of immunized mice. For in vivo depletion assays, mice were injected intravenously with Ultra-LEAF purified anti-CD3 (200 g/mouse, 145-2C11, Biolegend), anti-CD4 (200 g/mouse, GK1.5, Biolegend), anti-CD8 (200 g/mouse, 53-6.7, Biolegend), or anti-IgG (200 g/mouse, HTK888, Biolegend) one week before tumor challenge and weekly thereafter. All mouse experiments were performed in accordance with federal laws for animal protection and permission from the local veterinary office, and in compliance with the guidelines approved by the Institutional Animal Care and Use Committee of Dana-Farber Cancer Institute and Harvard Medical School.

(403) f. Mouse Transcriptome Methodology and Analysis

(404) An Ion AmpliSeq Custom Panel containing 4,604 cancer- and immune-associated genes (designed by Thermo Fisher using Ion AmpliSeq Designer) was used for the studies as described previously (Goel et al. (2017) Nature 548:471-475). 10 ng total RNA was used to prepare the cDNA library for each sample. Libraries were multiplexed and amplified using an Ion OneTouch 2 System, and sequenced on an Ion Torrent Proton system (Thermo Fisher). Count data was generated by Thermo Fisher's Torrent Suite and AmpliSeq RNA analysis plugin. For gene ontology enrichment and KEGG pathway analysis, genes with a mean fold change (PP.sub.T vs PP) greater than two or lesser than 0.4 were utilized. Gene Ontology enrichment and KEGG pathway analysis were carried out using Cytoscape Software and STRING plugin.

(405) g. In Vitro Immature DC Differentiation and Activation

(406) Mouse bone marrow monocytes were isolated with EasySep Mouse Monocyte Isolation Kit (#19861, StemCell Technologies) from wild type female FVB mice according to vendor's instructions. Enriched monocytes were cultured in RPMI 1640 medium with 20 ng/ml mouse recombinant GM-CSF (Stem Cell Technologies, #78017), 10 ng/ml mouse recombinant IL-4 (Stem Cell Technologies, #78047), and 10% FBS for one week. Immature DCs were then incubated with indicated cells at a 1:1 ratio for 24 hours. Human bone marrow was purchased from ALLCELLS (#ABM001, MA). Monocytes were isolated with EasySep Human Monocyte Isolation Kit (#19359, StemCell) according to vendor's instruction. Monocytes were then cultured in RPMI 1640 medium with 10% FBS, 20 ng/ml human recombinant GM-CSF (#78190, Stem Cell) and 10 ng/ml human recombinant IL-4 (#78045, StemCell) for one week. DC function was determined by flow cytometry 24 hours after incubation with human breast cancer cell lines at a 1:1 ratio.

(407) h. Mixed Lymphocyte Reaction Assay

(408) Spleens collected from wild type female FVB mice were mechanically dissociated by passing through 70 m cell strainers. Nave CD3+ T cells were then isolated with EasySep Mouse Pan-Nave T Cell Isolation Kit (Stem Cell Technologies, #19848) according to manufacturer's instructions. Purified T cells were co-cultured with tumor cells at a 10:1 ratio in presence or absence of immature DCs. After co-culturing overnight, cells were harvested and T cell activation was determined by flow cytometry.

(409) i. Nuclear and Cytoplasmic Protein Extraction, Co-Immunoprecipitation, and Western Blotting

(410) Cells were lysed with cytoplasmic extract (CE) buffer (10 mM HEPES (pH 7.6), 50 mM KCl, 0.05% NP40, and phosphatase and protease inhibitors in 1PBS) for 5 minutes on ice. Cell lysates were centrifuged at 2,300 g for 5 min and supernatants were collected as the cytoplasmic fraction. After three washes with CE buffer, the precipitate was lysed by sonication in nuclear extraction buffer (20 mM HEPES pH 7.6, 100 mM KCl, 5% glycerol, 0.5% NP40, phosphatase and protease inhibitors in 1PBS). Cell lysates were centrifuged at 13,400 g for 5 min and supernatants were collected as the nuclear fraction. For co-immunoprecipitation assays, cell extracts were adjusted to 20 mM HEPES (pH 7.6), 0.1% NP40, 50 mM KCl, 5% glycerol and 2.5 mM MgCl.sub.2, and incubated with an appropriate primary antibody or IgG overnight at 4 C. Protein A/G magnetic beads were added into the mixture and incubated for 2 hours. After three washes with binding buffer, beads were re-suspended in 1 western blotting loading buffer and denatured at 95 C. for 10 min. Western blot analysis was performed as previously described (Tang et al. (2015) Nat. Commun. 6:8230).

(411) j. Statistical Analysis

(412) Quantitative data were expressed as meansSEM. Statistical significance was determined by t-test for comparison of two groups and ANOVA with post-hoc analysis for three or more groups. A P-value of <0.05 was considered statistically significant.

Example 2: TGF-Treated Tumor Cells Induce T Cell Dependent Antitumor Immunity

(413) Transforming growth factor beta (TGF) is a pluripotent cytokine that plays critical roles in regulating embryo development, cell metabolism, tumor progression, and immune system homeostasis (David and Massague (2018) Nat. Rev. Mol. Cell. Biol. 19:419-435). Upon binding to its receptors on plasma membrane, TGF, regulates the expressions of its downstream genes in Smad-dependent and independent manners (FIG. 16).

(414) Loss of tumor suppressor p53 or PTEN is among the most frequent events in human cancer (Lawrence et al. (2014) Nature 505:495-501). The majority of advanced epithelial tumors, including triple-negative breast cancer (TNBC), exhibit loss of both p53 and PTEN (Cancer Genome Atlas Network (2012) Nature 490:61-70). A syngeneic genetically-engineered mouse model (GEMM) of TNBC derived from concurrent ablation of p53 (encoded by Trp53 in mice) and Pten (termed PP) in female FVB mice carrying K14-Cre; Trp53.sup.L/L; Pten.sup.L/L, was generated (Berrueta et al. (2018) Sci. Rep. 8:7864). To investigate the interaction of tumor cells harboring activated TGF signaling with the immune system, primary PP tumor cells were treated with TGF in vitro for a prolonged time (e.g., one month), and were subsequently allografted to FVB female mice. These TGF-treated PP cells (termed PP.sub.T) were confirmed to have activated TGF signaling with significant induction of epithelial-to-mesenchymal transition (EMT; FIG. 1B). Unexpectedly, while orthotopic injection of PP cells into wild type FVB mice resulted in tumor formation with full penetration, PP.sub.T cells completely failed to form tumors in FVB recipients despite their EMT phenotype, which is usually associated with more aggressive tumors (FIG. 1C). However, both PP and PP.sub.T cells were able to grow in immune-compromised mouse hosts lacking adaptive immunity, including athymic nude and severe combined immunodeficient (SCID) mice, although the growth rate of PP.sub.T tumors was slower than that of PP tumors (FIGS. 2A and 2B).

(415) To further assess whether T cells are required for immune rejection of PP.sub.T cells, CD3+ T cells were depleted via injection of an antibody against CD3 in recipient FVB mice transplanted with PP.sub.T cells. In this case, in contrast to absolute no growth of PP.sub.T cells in FVB mice with proficient T cells, PP.sub.T cells were able to form tumors with 100% penetrance upon depletion of T cells (FIGS. 3A and 3B). Tumor tissue, spleens and blood were harvested from host mice six days after transplantation of PP or PP.sub.T tumor cells, and T cells were analyzed by flow cytometry (FIG. 3C). Both the abundance of CD4+ and CD8+ T cell levels, as well as TNF and INF production, were significantly increased in the tumors and blood of PP.sub.T-transplanted mice compared to PP-bearing mice (FIGS. 3D-3I). Together, these results indicate that activated TGF signaling in tumor cells triggers cytotoxic T cell-mediated antitumor immunity.

Example 3: DC Plays an Essential Role in Mediating TGF-Induced Antitumor Immunity

(416) In parallel, transcriptome analysis was performed across a panel of 4,604 cancer- and immune-related genes on PP and PP.sub.T tumor tissue isolated from recipient mice six days after engrafting. Notably, expression of genes with gene ontology (GO) terms related to activation of multiple immune pathways was greatly up-regulated in PP.sub.T tumors compared to PP tumors (FIG. 4A). Significant up-regulation of genes encoding cytokines, cytokine receptors, and T cell costimulatory molecules was further confirmed by real time quantitative PCR (FIG. 4B). Moreover, expression of genes encoding components of both class I and class II major histocompatibility complex (MHC), such as H2-D1, H2-Ab1 and Cd74, was significantly up-regulated in PP.sub.T tumor sites compared to PP tumors (FIG. 4B). These data further confirm that PP.sub.T cells were able to elicit a robust immune response in the tumor microenvironment.

(417) Interestingly, Cd74 (also known as HLA class II histocompatibility antigen gamma chain) was at the top of up-regulated immune-related networks in PP.sub.T tumor tissues (FIG. 4C). Flow cytometry analysis determined that neither PP nor PP.sub.T tumor cells express MHC class II molecules (FIGS. 5A and 5B), indicating that antigen-presenting cells (APCs), and dendritic cells (DCs) in particular, are likely involved in PP.sub.T tumor-induced immune response in the host animals. Indeed, PP.sub.T tumors had a significantly higher number of tumor-infiltrating DCs than PP tumors (FIG. 4D). Further analysis revealed that PP.sub.T tumor-associated DCs also have increased levels of CD80, a costimulatory molecule necessary for T cell activation, CD103, a critical molecule for priming tumor-specific CD8+ T cells and trafficking of effector T cells, and MHC-II antigen-presenting machinery (Eisenbarth (2019) Nat. Rev. Immunol. 19:89-103; Worbs et al. (2017) Nat. Rev. Immunol. 17:30-48) (FIG. 4E). These observations indicate that tumor-associated DCs play an important role in mediating antitumor immunity against TGF-treated tumor cells.

(418) To delineate how PP.sub.T tumor cells elicit antitumor immunity when they are introduced into immune competent host animals, co-culture experiments of PP or PP.sub.T tumor cells with DCs or T cells in vitro were performed. Co-culture of bone marrow-derived DCs (BMDCs) obtained from nave mice with tumor cells revealed that PP.sub.T cells, but not PP, were able to activate BMDCs (FIGS. 4F and 4G). A similar co-culture of T cells isolated from the spleen of nave FVB mice with tumor cells showed that T cells were not activated when they were co-cultured with either PP or PP.sub.T cells (FIGS. 5C and 5D). However, in the presence of DCs, both CD4+ and CD8+ T cells were activated by co-culturing with PP.sub.T cells, but not with PP cells (FIGS. 4H and 4I). These results indicate that PP.sub.T cells trigger activation of DCs to mount an adaptive immune response, which in turn primes T cells to target PP.sub.T tumor cells (FIG. 17).

Example 4: TGF Stimulates Antitumor Immunity Through the TGF-Smad/p63 Signaling Axis

(419) The molecular mechanisms by which prolonged treatment of tumor cells with TGF could enhance immunogenicity to the extent observed in PP.sub.T cells were next determined. Since Smad proteins are specific transcriptional effectors of TGF signaling (Xu et al. (2016) Cold Spring Harb. Perspect. Biol. 8: a022087; Budi et al. (2017) Trends Cell Biol. 27:658-672; Cantelli et al. (2017) Semin. Cancer Biol. 42:60-69), the expression levels of Smads and Smad-related transcription factors in PP.sub.T cells were analyzed by transcriptome profiling. Notably, the expression level of p63 (encoded by Trp63 in mice) was highest among the Smad-associated transcriptional networks (FIG. 6A). The transcription factor p63 is a member of the p53 family, which has been reported to either suppress or promote tumor progression depending on the cellular context (Bergholz and Xiao (2012) Cancer Microenviron. 5:311-322; Adorno et al. (2009) Cell 137:87-98; Memmi et al. (2015) Proc. Natl. Acad. Sci. U.S.A. 112:3499-3504; Chen et al. (2018) Cell Mol. Life Sci. 75:965-973; Yoh et al. (2016) Proc. Natl. Acad. Sci. U S. A. 113:E6107-E6116). To determine the role of p63 in PP.sub.T cells, p63 was depleted via short hairpin RNA (shRNA) and p63-knockdown PP.sub.T cells were transplanted into FVB mice. Remarkably, while PP.sub.T cells expressing a control shRNA failed to form tumors, PP.sub.T cells expressing shTrp63-1 and undetectable p63 protein levels quickly formed tumors with full penetrance (FIG. 6B). PP.sub.T cells expressing shTrp63-2 with still detectable p63 formed tumors with a longer latency and reduced penetrance (70%) than that of cells expressing shTrp63-1 (FIG. 6B). Moreover, PP.sub.T cells expressing either shTrp63-1 or shTrp63-2 lost the capacity to activate BMDCs in co-culture systems (FIG. 6C). These results indicate that p63 plays a critical role in mediating enhanced immunogenicity and immune sensitization induced by TGF treatment, which then results in failure to evade immune attack and loss of tumorigenicity.

(420) Intriguingly, both PP and PP.sub.T cells express an abundant amount of p63 (FIG. 7A). To investigate why and how p63 plays a different role in PP and PP.sub.T cells, immunofluorescence analysis was performed to detect the cellular localization of p63 and Smad2. Results showed that while p63 was in the nucleus in both PP and PP.sub.T cells, Smad2 was restricted to the cytoplasmic compartment in PP cells, but localized to both the cytoplasm and nucleus in PP.sub.T cells (FIG. 7B). The cellular localization of p63 and Smad2 was validated by cellular fractionation (FIG. 7C), and their association in the nucleus of PP.sub.T cells was confirmed by co-immunoprecipitation (FIG. 7D). These data indicate that p63 can act as a co-factor of the nuclear Smads to target specific sets of genes for transcriptional regulation upon TGF treatment.

(421) To determine transcriptional programs co-regulated by p63 and Smad2, transcriptome analysis of PP.sub.T cells with shRNA-mediated silencing of p63 or Smad2 expression was performed. Approximately 70% of altered genes in PP.sub.T cells expressing shTrp63 or shSmad2 were regulated in common by p63 and Smad2 (FIGS. 8A and 8B). Notably, while multiple major oncogenic signaling pathways were up-regulated in both shTrp63- and shSmad2-expressing PP.sub.T cells, many immune regulatory pathways were down-regulated (FIGS. 8C and 8D).

Example 5: TGF-Smad/p63 Signaling Activation Reprogramed Human Tumor Cells to Activate DCs in a Similar Fashion

(422) To determine whether TGF-Smad/p63 pathway was also important in the interaction of human tumor cells with the immune system, a panel of breast cancer cell lines was screened and it was found that most of these cell lines do not express p63. Only HCC1954 and the two non-cancer cell lines screened express p63 at levels detectable by western blotting (FIG. 9A). HCC1954 and MCF7 cells were treated with TGF and co-cultured with human DCs (FIG. 9B). Consistent with previous results, only HCC1954 cells, but not MCF7, were able to induce DC activation upon TGF-treatment (FIGS. 9C-9E). These data indicate that the TGF-Smad/p63 signaling activation can also reprogram human tumor cells to activate DCs in a similar fashion. More importantly, breast cancer patients with a higher level of the TP63/Smad-based gene expression signature had much better survival outcome than those patients with a lower level of TP63/Smad-based gene signature (FIG. 9F).

Example 6: PP.SUB.T .Cells have Therapeutic Effect on Blocking the Growth of their Parental PP Tumor Cells

(423) It was determined whether the enhanced immune response elicited by PP.sub.T cells can extend its cytotoxic effects towards non-TGF-treated parental PP tumor cells, which can lead to important therapeutic implications for cancer treatment. Remarkably, co-injection of PP.sub.T cells with PP tumor cells into FVB mice completely abrogated growth of PP tumors (FIGS. 10A and 10B). The results indicated that PP.sub.T induced antitumor immunities against its parental PP tumor cells.

Example 7: PP.SUB.T .Cells have Potent Vaccine Activity Against Parental PP Tumor Cells Through Induction of Memory T Cell Responses

(424) To gain a further understanding on the antitumor immunity of PP.sub.T cells, it was determined whether PP.sub.T cells can induce tumor specific memory T cell responses. T cells harvested from the spleen and lymph nodes of PP.sub.T-bearing mice at 1, 2 and 6 weeks after injection of PP.sub.T cells were analyzed, and it was found that both populations of CD4+ central memory (T.sub.CM) and effector memory (T.sub.EM) T cell were increased (FIGS. 11A and 11B) Increased long-term splenic CD8+ T.sub.CM and T.sub.EM cells were also observed in these mice after PP.sub.T cell injection (FIGS. 11C and 11D).

(425) It was next determined whether PP.sub.T cells can prevent the growth of parental PP cells in the primary site as well as in a distal tissue, i.e., the lung. Remarkably, PP tumor cells or tumor fragments were entirely rejected when they were introduced into the mammary fat pads of FVB mice that had been previously immunized with PP.sub.T cells (FIGS. 12A-12E). In addition, PP cells were introduced into PP.sub.T-immunized mice via tail vein injection to mimic metastatic tumor cells in the circulation. While control mice developed substantial metastatic burden in the lungs when analyzed four weeks after injection, PP.sub.T-immunized mice were completely clear of tumor lesions (FIGS. 12F and 12G).

(426) It was further shown that the tumor infiltrating CD4+ and CD8+ T cells were significantly increased in the PP tumor cells injection sites in mice immunized with PP.sub.T cells (FIGS. 13A and 13B). Both the CD4+ and CD8+ effector memory T cells as well as central memory T cells were also substantially increased in these sites in immunized mice (FIGS. 13C and 13D).

Example 8: The Vaccine Effect of PP.SUB.T .Cells was not Dampened by a Sub-Lethal Dose of Irradiation

(427) In order to prevent further cell division, PP.sub.T tumor cells were treated with a sub-lethal dose of irradiation (100 Gy), and it was determined whether irradiation can impair the potency of the vaccine effect of the PP.sub.T tumor cells. As shown in FIGS. 14A-14C, mice immunized with irradiated PP.sub.T cells were fully protected from tumor development when PP tumor fragments were transplanted (FIGS. 14A-14C). In contrast, PP tumor fragments were quickly grafted and grew in non-immunized mice (FIGS. 14A-14C). In parallel, PP tumor cells were also treated with the same dose of irradiation and injected them into one flank of mice, and 4 weeks later, these mice were transplanted with PP tumor fragments into the other side of flank. Irradiated PP tumor cells fail to grow in vivo, confirming that the irradiation prevented the further proliferation of PP tumor cells in vivo. Interestingly, pre-injection of irradiated PP tumor cells were able to delay the growth of transplanted PP tumor fragments and extend the survival, but, in a limited manner (FIGS. 14A-14C).

Example 9: PP.SUB.T .can be an Effective Allogeneic Vaccine Against Other Tumor Types

(428) The autologous tumor cell vaccines are greatly limited by the availability of tumor tissues. Therefore, it's also important to determine if PP.sub.T can also be used as an allogeneic tumor vaccine against other tumors with similar genetic background but different tumor types, or the same tumor type with different genetic mutations. The results showed that PP.sub.T vaccination completely rejected growth of PPA tumor (a very aggressive breast cancer cell characterized by triple loss of p53, PTEN, and p110alpha; FIGS. 15A and 15B). Notably, 9/10 of C260 tumor transplants (a high-grade serious ovarian cancer model driven by p53/PTEN co-loss and high Myc expression) were rejected in PP.sub.T immunized mice and 1/10 C260 eventual grew in a much delayed time (FIGS. 15C and 15D). Moreover, PP.sub.T vaccination significantly delayed the tumor latency of D658 (a Kras-mutated recurrent breast cancer cell model generated from a PIK3CA.sup.H1047R GEMM of breast cancer) and d333 (a glioblastoma tumor model derived from p53 and PTEN co-loss GEMM) and markedly extended the survivals of these mice (FIGS. 15E to 15H). The data indicated that PP.sub.T can be used not only as a highly effective allogeneic vaccine against other epithelial tumors with the same genetic changes, i.e., loss of p53 and PTEN, but also as a biologic which is active against different types of cancers with different cancer mutations. The data described herein support a tumor-cell based vaccine (T. Vax) platform (FIG. 18).

INCORPORATION BY REFERENCE

(429) All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

(430) Also incorporated by reference in their entirety are any polynucleotide and polypeptide sequences which reference an accession number correlating to an entry in a public database, such as those maintained by The Institute for Genomic Research (TIGR) on the world wide web at tigr.org and/or the National Center for Biotechnology Information (NCBI) on the World Wide Web at ncbi.nlm.nih.gov.

EQUIVALENTS

(431) Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.