OKADAIC ACID INDUCES THE EXPRESSION OF BOTH EARLY AND SECONDARY RESPONSE GENES IN MOUSE KERATINOCYTES

Okadaic acid (OA), a potent mouse skin tumor promoter and inhibitor of the protein phosphatases 1 and 2A, was investigated for its effects on the expression of tumor-associated early and secondary response genes in mouse keratinocytes. Adult mice were treated topically with 12.5 nmol of OA, and the steady-state levels of various gene transcripts in the skin were determined at different times after treatment. The nuclear protooncogenes c-fos and c-jun are referred to as early response genes because the classical tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces their expression to maximal levels within 2 h after treatment. OA induced the expression of c-fos 2-72 h after treatment, with two peaks at 6 and 48 h. The steady-state level of expression of c-jun was relatively high in untreated skin, and OA induced a slight increase in its expression from 12 to 48 h after treatment. Transin and plasminogen-activator (PA) urokinase, whose induced expression peaks at least 4 h after TPA treatment, are referred to as secondary response genes. OA induced their expression more slowly than TPA. In mouse papilloma cell line 308, OA induced higher and more sustained steady-state levels of c-jun and c-fos than an equimolar dose of TPA. Transin and PA-urokinase were induced to similar levels by TPA and OA in 308 cells; however the induction of these genes by OA was slower than induction by TPA. The existence of different patterns of induced expression of early and secondary response genes by OA and TPA suggests that these tumor promoters affect gene expression in mouse keratinocytes through different pathways.