OBJECTIVE Colon cancer cells express reduced levels of protein kinase C (PKC). This study examines the regulation of PKC isozymes in normal colonic epithelium, as a basis for understanding the significance of alterations in this enzyme system in colon carcinogenesis. METHODS The expression and localization of PKC isozymes in mouse and rat colonocytes at different developmental stages were determined using a combined morphological and biochemical approach. PKC alpha expression was compared in colonic adenocarcinomas and adjacent normal mucosa by immunoblot analysis. RESULTS Mouse and rat colonocytes express PKC alpha, beta II, delta, epsilon, and zeta. Relatively low levels of these isozymes were detected in proliferating cells of the crypt base, predominantly in the cytosolic compartment. Coincident with colonocyte growth arrest/differentiation, PKC isozyme expression markedly increased in both the cytosolic and, more significantly, in the membrane/cytoskeletal fraction. Colonic tumors express reduced levels of PKC alpha, an isozyme that has been implicated in negative control of intestinal cell growth. CONCLUSIONS These findings are supportive of a role for certain PKC isozyme(s) in signaling pathways mediating postmitotic events in colonocytes in situ, and suggest that diminished activity of these pathway(s) may contribute to the alterations in growth control/differentiation associated with colonic neoplasia.