Colon carcinogenesis is a complex, multi-step process involving progressive changes in intestinal epithelial cell proliferation, differentiation and programmed death. Our long-term goal is to understand the role of protein kinase C (PKC) isozymes in intestinal epithelial cell biology and colon carcinogenesis. Several lines of evidence suggest that the PKC betaII isozyme (PKC betaII) is involved in colon carcinogenesis. First, PKC betaII levels and activity are elevated in colon carcinomas compared to normal colonic epithelium. Second, PKC betaII is involved in colon carcinoma cell proliferation in vitro. Third, components of a high fat diet can potently stimulate intestinal epithelial cell PKC betaII activity and promote colon carcinogenesis. Based on these findings, and our preliminary studies, we hypothesize that PKC betaII is directly involved in colon carcinogenesis. To directly test this hypothesis, we developed transgenic mice that express elevated PKC betaII levels in the intestinal epithelium. In preliminary studies, these mice exhibit evidence of colonic epithelial hyperproliferation and an increased susceptibility to carcinogen-induced colon cancer. In this application we propose four specific aims to: 1) characterize three transgenic PKC betaII lines for transgene copy number, tissue distribution, expression level and activity of the PKC betaII transgene, and for changes in intestinal epithelial cytokinetics; 2) assess whether transgenic PKC betaII mice exhibit increased susceptibility to carcinogen-induced colon cancer; 3) determine whether a high fat diet enhances the susceptibility of transgenic PKC betaII mice to colon cancer; and 4) determine whether elevated PKC betaII expression synergizes with loss-of-function mutation of the APC tumor suppressor gene in promoting intestinal tumorigenesis in the APCmin mouse model. These studies will allow the first direct analysis of the role of PKC betaII in colon cancer in two relevant animal models of the human disease.
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