DIFFERENTIAL MODULATION OF HUMAN FIBROBLAST AND KERATINOCYTE GROWTH BY THE PROTEIN-KINASE-C INHIBITOR GF 109203X

Protein kinase C (PKC) is known to be involved in cellular proliferati on and differentiation. In this work, we have investigated the effects of a novel PKC inhibitor, GF 109203X, on normal human fibroblast and keratinocyte growth. GF 109203X selectively inhibited PKC activity ext racted from either fibroblasts (IC50 = 0.01 mu M) or keratinocytes (IC 50 = 0.4 mu M). The inhibitory effects of GF 109203X on total PKC acti vity and Ca2+-independent PKC activity were similar. Nevertheless, in keratinocytes Ca2+-independent PKC activity represented 95% of total P KC activity, whereas in fibroblasts it corresponded to only 32% of tot al PKC activity. GF 109903X also inhibited a cellular function related to PKC activity in living fibroblasts and keratinocytes; it blocked t he inhibitory effect of 12-O-tetradecanoyiphorbol-13-acetate on I-125- epidermal growth factor binding. GF 109203X inhibited fibroblast growt h, in terms of tritiated thymidine incorporation and cell counts, in a dose-dependent manner. We also observed that GF 109203X at 1 mu M inh ibited serum stimulation of expression of mRNA for c-fos and c-jun, wh ich are usually involved in cellular proliferation. These results sugg est that PKC stimulates fibroblast growth. In contrast, GF 109203X sti mulated keratinocyte growth. We also observed that GF 109203X inhibite d c-fos and c-jun mRNA expression in these cells. In fact, in keratino cytes these proto-oncogenes would be involved in the cellular differen tiation process rather than in cellular proliferation. This suggests t hat the inhibition of PKC favors keratinocyte proliferation probably b y inhibiting their differentiation. Thus, using GF 109203X, we show th at PKC is involved differently in human fibroblast and keratinocyte gr owth.