B-Catenin and K-ras Synergize to Form Wilm's Tumor with Concurrent p53 Pathways Modulation
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Humans can develop pediatric kidney tumors called Wilm's tumors. If one identifies the specific genes that cause Wilm's tumor, or that concomitantly change expression levels in the tumor tissue, then diagnosis and eventually drug targets for therapy are expedited. Characterizing genetic determinants in the mouse model can help actualize these future therapies. When the genes Kras and βCatenin are overexpressed in a mouse, it develops a renal tumor histologically identical to a human Wilm's tumor. Microarray analysis on mouse tumor tissue showed modulated expression levels of gene targets in the p53 tumor suppressor pathway. Immunohistochemistry stained mice tissue specifically for p53. In tissue with Kras and βcatenin overexpression, p53 staining is positive surrounding the tumor. RT qPCR measured levels of gene expression of p53 pathway associated genes. Combination mutants βCatenin and Kras were compared with controls. This PCR array analysis identified genes, such as cJun, Traf1, and Dapk1, that had significant expression changes in the combination mutant when compared to either mutant individually. The expression is modulated in a nonadditive fashion in Kras + βcatenin mutant tissues, which can explain the phenotype of Wilm's tumor in only double mutant mice. These genes individually represent targets for therapy in the future, and together represent an identifying fingerprint for diagnosis and prediction.