Protein kinase C beta;II regulates its own expression in rat intestinal epithelial cells and the colonic epithelium in vivo

Protein kinase C βII (PKCβII) is induced early during colon carcinogenesis. Transgenic mice expressing elevated PKCβII in the colonic epithelium (transgenic PKCβII mice) exhibit hyperproliferation and enhanced colon carcinogenesis. Here we demonstrate that nullizygous PKCβ (PKCβKO) mice are highly resistant to azoxymethane (AOM)-induced preneoplastic lesions, aberrant crypt foci. However, reexpression of PKCβII in the colon of PKCβKO mice by transgenesis restores susceptibility to AOM-induced colon carcinogenesis. Expression of human PKCβII in rat intestinal epithelial (RIE) cells induces expression of endogenous rat PKCβII mRNA and protein. Induction of PKCβII is dependent upon catalytically active PKCβII and does not appear to involve changes in alternative splicing of the PKCβ gene. Two human PKCβ promoter constructs are activated by expression of PKCβ in RIE cells. Both PKCβ promoter activity and PKCβ mRNA levels are inhibited by the MEK1 and -2 inhibitor U0126, but not the Cox-2 inhibitor celecoxib in RIE/PKCβII cells. PKCβ promoter activity correlates directly with expression of endogenous PKCβ mRNA and protein in HT29 and HCT116 human colon cancer cell lines. PKCβ promoter activity and PKCβII mRNA expression in HCT116 cells are inhibited by the selective PKCβ inhibitor LY317615 and by U0126, demonstrating autoregulation of PKCβII expression. Transgenic PKCβII mice exhibit specific induction of endogenous PKCβII, but not its splice variant PKCβII, in the colonic epithelium in vivo. Taken together, our results demonstrate that 1) expression of PKCβII in the colonic epithelium is both necessary and sufficient to confer susceptibility to AOM-induced colon carcinogenesis in transgenic mice, 2) PKCβII regulates its own expression in RIE and human colon cancer cells in vitro and in the colonic epithelium in vivo, and 3) PKCβII autoregulation is mediated through a MEK-dependent signaling pathway in RIE/PKCβII and HCT116 colon cancer cells.