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, nP KCepsilon, in Rat 6 embryo fibroblasts, and examined the effects of th is novel isoform on cell growth and transformation. As compared to vec tor control cell lines expressing only the hygromycin resistance gene, the nPKCepsilon overproducing cell lines exhibited a 7-13-fold increa se in Ca2+-independent enzyme activity. Detailed analysis of seven ind ividual nPKCepsilon over-producing clones indicated that those clones that expressed very high activity displayed a number of disorders in g rowth control, including: formation of dense foci in monolayer culture , decreased doubling time, increased saturation density, decreased ser um requirement, growth in soft agar, and tumor formation in nude mice. These findings are in contrast to previous studies from our laborator y indicating that stable expression of high levels of cPKCbeta1 produc ed only a partially transformed phenotype (Housey et al., 1988). Taken together, these results provide the first direct evidence that distin ct isoforms of PKC can exert different effects on growth control and m alignant transformation in the same cell type.