Protein kinase C (PKC) plays a key role in colonic cell signal transduction, and this signaling pathway is significantly modulated by dietary fat composition. It is not known, however, if the dietary fat- induced changes in PKC are localized to proliferating or differentiated cells or are generalized to all colonocytes. Also unknown is whether or not dietary fat-induced changes in PKC ar the same in malignant transformed cells as in their normal counterparts. We will utilize the well- characterized and highly relevant rat model of colon carcinogenesis to investigate the role of PKC signal transduction in proliferating, differentiated, and malignant transformed colonic mucosa. Specifically, using a 2x2 factorial design (2 dietary fats, corn oil and fish oil) in dimethylhydrazine-treated or vehicle injected (control) animals, the proposed research will address the following specific aims; (1) To determine if dietary fat and carcinogen-induced changes i PKC isozyme expression are similar in proliferating versus differentiated cells; (2) To determine if dietary fat-induced changes in PKC activity and isozyme expression in cytosolic and membrane fractions are similar in malignant transformed cells as compared to both """"""""uninvolved"""""""" mucosa from the same animals, and """"""""normal"""""""" mucosa from vehicle-injected controls; and (3) To determine if membrane diglycerides, known lipid mediators of PKC, are modified to the same extent by dietary fat in tissue samples from colon tumors, """"""""uninvolved"""""""" mucosa from the same animals, and """"""""normal"""""""" mucosa from controls (vehicle-injected). The monitoring of PKC isozyme expression profiles during the transformation process allows for the characterization of dietary fat-induced changes at both the precancerous and cancerous stages. Elucidation of the ability of dietary fat to modulate colonic PKC activity and isozyme expression in relation to epithelial cytokinetics will support future studies of nutritional intervention designed to inhibit colon cancer.
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