THE INVOLVEMENT OF PROTEIN-KINASE-C IN PROLIFERATION AND DIFFERENTIATION OF HUMAN KERATINOCYTES - AN INVESTIGATION USING INHIBITORS OF PROTEIN-KINASE-C

Protein kinase C, the major cellular receptor for tumour-promoting pho rbol esters, has been suggested as playing a key role in the regulatio n of proliferation and differentiation of epidermal cells. In the pres ent study, we investigated the effects of various well-characterized i nhibitors of protein kinase C on proliferation and differentiation of SV 40-transformed and normal human keratinocytes. The drugs were found to inhibit cell proliferation in a dose-dependent manner, displaying similar effects in both cell types and reflecting their potencies in i nhibiting purified protein kinase C. In contrast, keratinocyte differe ntiation induced by treatment with a calcium ionophore or spontaneousl y, i.e. by exposure of cells grown in the presence of low calcium conc entration (0.06 mM) to normal calcium concentration (1.6 mM), was not inhibited by the compounds tested. The potent protein kinase C inhibit or, staurosporine, was found even to enhance cell differentiation. The refore, the present study provides evidence that the classical protein kinase C pathway plays a critical role in the regulation of keratinoc yte proliferation rather than in calcium-induced differentiation.