2 CLOSELY-RELATED ISOFORMS OF PROTEIN-KINASE-C PRODUCE RECIPROCAL EFFECTS ON THE GROWTH OF RAT FIBROBLASTS - POSSIBLE MOLECULAR MECHANISMS

We have previously reported that two closely related protein kinase C (PKC) isoforms, PKC alpha and PKC beta I, had divergent effects on the growth and transformation of the same parental R6 rat embryo fibrobla st cell line (Housey, G. M., Johnson, M. D., Hsiao, W.-L. W., O'Brian, C. A., Murphey, J. P., Kirschmeier, P., and Weinstein, I. B. (1988) C ell 52, 343-354; Borner, C., Filipuzzi, I., Weinstein, I. B., and Imbe r, R. (1991) Nature 353, 78-80). Whereas cells that overexpress PKC be ta I lost anchorage dependence, grew to higher saturation densities, a nd generated small tumors when injected into nude mice, none of these properties were seen with cells that overexpress PKC alpha. In fact, t he latter cells grew even slower and to lower saturation densities as compared to control cells. Here we investigate possible molecular mech anisms underlying the reciprocal effects of PKC alpha and PKC beta I. Overexpression of both isoforms enhanced 12-O-tetradecanoyl phorbol-13 acetate-induced expression of the growth regulatory genes c-jun, c-my c, and collagenase and enhanced feedback inhibition of epidermal growt h factor receptor binding and cellular levels of diacylglycerol. Howev er, the cells overexpressing PKC beta I differed from those overexpres sing PKC alpha by displaying a decreased requirement for growth factor s and by the production of a mitogenic factor. Thus, the basis for enh anced growth and transformation of cells overexpressing PKC beta I may be the establishment of an autocrine growth factor loop. These findin gs may be relevant to the roles of specific isoforms of PKC in carcino genesis and tumor growth.