INDUCTION OF THE C-JUN PROTOONCOGENE BY A PROTEIN KINASE-C-DEPENDENT MECHANISM DURING EXPOSURE OF HUMAN EPIDERMAL-KERATINOCYTES TO ETHANOL

The present work demonstrates that ethanol induces expression of the c-jun proto-oncogene in human keratinocytes. Increased c-jun mRNA levels were detectable at 1 hr of exposure to 1% ethanol and at 24 hr remained above that in control keratinocytes. An increase in c-jun expression was also detectable at ethanol concentrations of 0. 1 and 0.5%. Similar findings were obtained for the related jun-B and c-fos early response genes. The results also demonstrate that ethanol exposure is associated with increases in protein kinase C activity in both the cytosol and membrane fractions. This increase was detectable at 5 min and maximal at 30-60 min. The finding that induction of c-jun expression by ethanol was inhibited by the isoquinolinesulfonamide derivative H7, but not by HA1004, suggested that this effect is mediated by protein kinase C. Furthermore, down-regulation of protein kinase C by prolonged exposure to 12-O-tetradecanoylphorbol-13-acetate was associated with a block in ethanol-induced c-jun expression. We also demonstrated that ethanol exposure is associated with rapid (5-30 min) increases in intracellular levels of diradylglycerol. Taken together, these findings demonstrate that the exposure of keratinocytes to ethanol results in the activation of protein kinase C and c-jun expression.