THE EPSILON ISOFORM OF PROTEIN-KINASE-C IS AN ONCOGENE WHEN OVEREXPRESSED IN RAT FIBROBLASTS

We have overproduced the Ca2+-independent protein kinase C isoform, nPKCepsilon, in Rat 6 embryo fibroblasts, and examined the effects of this novel isoform on cell growth and transformation. As compared to vector control cell lines expressing only the hygromycin resistance gene, the nPKCepsilon overproducing cell lines exhibited a 7-13-fold increase in Ca2+-independent enzyme activity. Detailed analysis of seven individual nPKCepsilon over-producing clones indicated that those clones that expressed very high activity displayed a number of disorders in growth control, including: formation of dense foci in monolayer culture, decreased doubling time, increased saturation density, decreased serum requirement, growth in soft agar, and tumor formation in nude mice. These findings are in contrast to previous studies from our laboratory indicating that stable expression of high levels of cPKCbeta1 produced only a partially transformed phenotype (Housey et al., 1988). Taken together, these results provide the first direct evidence that distinct isoforms of PKC can exert different effects on growth control and malignant transformation in the same cell type.