Colon cancer is an important cause of cancer mortality. In the United States, over 150,000 people are newly diagnosed with this disease each year, and one-third of them will ultimately die from their disease. Abnormal regulation of p-catenin levels and function commonly occur during colon carcinogenesis. p-catenin is a multifunctional protein with known roles in enhancing proliferation, inhibiting intestinal cell differentiation and apoptosis, and regulating cell-cell adhesion, angiogenesis, and cell migration. Dysregulation of p-catenin can thus endow a cancer cell with many of the features necessary for colon carcinogenesis. The molecular mechanisms by which normal intestinal cells regulate p-catenin function, and by which cancer cells abrogate this regulation, are not understood. The homeodomain transcription factor Cdx2 is a well-studied regulator of intestine-specific gene expression. Its role in promoting intestinal cell differentiation and regulating proliferation is recognized but the mechanisms remain to be elucidated. Our research has specifically investigated these processes. We have found that Cdx2 inhibits p-catenin/TCF transcriptional activity. Moreover, cancer cells were relatively resistant to Cdx2's effect on p-catenin/TCF. In addition, we have developed a cell culture system to model Cdx2 induction of a polarized, columnar cell morphology in human colonocytes, a novel mechanism attributable to Cdx2. This effect requires a functional E-cadherin/p-catenin complex, and accompanying post- translational modifications of p-catenin. This proposal is directed towards characterizing Cdx2 mediated biological effects upon proliferation and cell-adhesion and will test the following overarching hypothesis: Cdx2 inhibits colonocvte proliferation and promotes morphologic maturation by modulating B-catenin transcriptional and cell-cell adhesion activity. This hypothesis will be pursued by the following inter-related Specific Aims: (1) To investigate the inhibition of p- catenin mediated proliferation by Cdx2, and the resistance to this inhibitory effect in colon cancer cells;and, (2) To characterize the molecular mechanisms for Cdx2-mediated cell-cell adhesion and columnar morphogenesis. This proposal therefore explores the novel roles for Cdx2 in regulating the interdependent processes of cell-cell adhesion, acquisition of a polarized and columnar morphology, and cell-proliferation within the colonocyte. Understanding these mechanisms will improve greatly our knowledge of the molecular events governing normal colonocyte biology, and simultaneously, provide new insights into the molecular pathogenesis of sporadic colon cancer. As a result, potential novel targeted therapeutics mayalso emerge.
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