Possible involvement of protein kinase C and calcium ion in growth factor-induced expression of c-myc oncogene in Swiss 3T3 fibroblasts.

Abstract

The addition of platelet-derived growth factor and fibroblast growth factor to quiescent cultures of Swiss 3T3 fibroblasts rapidly induced protein kinase C activation and Ca2+ mobilization and afterwards markedly increased c-myc mRNA levels.1-Oleoyl-2-acetylglycerol, a membrane-permeable synthetic diacylglycerol, and 12-0-tetradecanoylphorbol 13-acetate, a tumor-promoting phorbol ester, stimulated protein kinase C activation without Ca2+ mobilization.Inversely, Ca2+ ionophores, A23187 and ionomycin, elicited Ca2+ mobilization without protein kinase C activation.Both protein kinase C-activating and Ca2+-mobilizing agents were able to increase c-myc mRNA levels in an additive manner.Prolonged treatment of the cells with phorbol 12,13-dibutyrate, another protein kinase Cactivating phorbol ester, led to the down-regulation and complete disappearance of protein kinase C. In these cells, 1-oleoyl-2-acetylglycerol and 12-0-tetradecanoylphorbol 13-acetate did not increase c-myc mRNA levels, but platelet-derived growth factor, fibroblast growth factor, and the Ca2+ ionophores, all of which still induced Ca2+ mobilization, stimulated the increase of c-myc mRNA levels.These results strongly suggest that both protein kinase C and Ca2+ may be involved in platelet-derived growth factoras well as fibroblast growth factor-induced expression of the cmyc oncogene in Swiss 3T3 cells.It has been demonstrated that the c-myc oncogene is rapidly activated after stimulation of mouse lymphocytes by concanavalin A and of BALB/c 3T3 fibroblasts by PDGF,' FGF, and TPA and in regenerating rat liver (1, 2).Moreover, it has been described that expression of the c-myc gene, which is