Involvement of protein kinase C activation in ornithine decarboxylase gene expression in primary culture of newborn mouse epidermal cells and in skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.

The role of protein kinase C in ornithine decarboxylase (ODC; EC 4.1.1.17) gene expression in primary culture of newborn mouse epidermal cells (MEC) from BALB/c mice and in skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) in female CD-1 mice was determined. A time course and the dose-response curves of ODC induction paralleled that of ODC mRNA induction by TPA in MEC. TPA treatment did not elicit any change in the size of ODC mRNA. The magnitude of ODC induction was proportional to the amount of ODC mRNA increased by TPA. TPA (2 X 10(-7) M) failed to induce ODC activity in MEC plated in Ca2+-deprived medium; TPA induction of ODC could be resumed upon Ca2+ restoration in the medium. 1-Oleoyl-2-acetylglycerol, a membrane-permeable diacylglycerol which activates protein kinase C, induced at the same rate both ODC activity and the amount of ODC mRNA in MEC. Phospholipase C, which releases diacylglycerol from membrane phospholipids, also induced ODC activity; 0.02 units of phospholipase C per ml led to about a 50-fold increase in ODC activity at 6 h after treatment. Phospholipase A2 was ineffective. Phospholipase C-induced ODC activity correlated with an increased level of ODC mRNA. Furthermore, palmitoylcarnitine, an inhibitor of protein kinase C, inhibited epidermal ODC induction and the increased level of ODC mRNA by TPA. Also, palmitoylcarnitine inhibited skin tumor promotion by TPA; application of 3 mumol of palmitoylcarnitine in conjunction with each promotional treatment with 10 nmol of TPA to the initiated skin of female CD-1 mice inhibited tumor formation. Taken together, we conclude that activation of protein kinase C may be an early event in ODC gene transcription and skin tumor promotion by TPA.