The long-term goals of this application are (a) to define the function(s) of individual members of the protein kinase C (PKC) family of signal transduction molecules in regulation of intestinal epithelial self-renewal, and (b) to determine how alterations in PKC isozyme signaling pathways contribute to the development of intestinal disease. This renewal application draws on new information demonstrating that PKC/PKC a signaling triggers a coordinated program of cell cycle withdrawal in intestinal epithelial cells, that PKC alpha activity regulates survival pathways in this system, that desensitization of PKC a signaling appears to be an important component of intestinal carcinogenesis, and that loss of PKC/PKC a expression/activity promotes the growth of intestinal cells. Based on these findings, strategies are proposed in this application to test the hypothesis that PKC alpha is a key component of signaling pathways that regulate intestinal epithelial cell growth and cell survival, and that specific alterations in the activity/ expression of this molecule play a pivotal role in the development of intestinal neoplasia. Restoration of PKC a function may thus be of benefit for the prevention and/or therapy of intestinal tumors. To test this hypothesis, the following Specific Aims will be addressed: (1) To define the mechanisms involved in transcriptional induction of p21waf1/cip1 by PKC/PKC a signaling in intestinal epithelial cells and determine if p21waf1/cip1 regulatory pathways downstream of PKC alpha signaling are altered in neoplastic intestinal cells, (2) To determine the role of PKC a signaling in regulation of intestinal epithelial cell survival, (3) To define the molecular mechanisms underlying loss of PKC a expression during intestinal carcinogenesis, and (4) To explore the potential of differentiation agents with promising preventive and therapeutic activity in colon cancer (i.e., retinoids, vitamin D) to restore PKC alpha expression in neoplastic intestinal cells. These studies are expected to enhance our understanding of the signaling pathways that orchestrate the process of intestinal epithelial renewal and highlight the contribution of defects in PKC signaling to intestinal neoplasia.
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