MITOGENIC SIGNALING BY PROSTAGLANDINS IN CHEMICALLY TRANSFORMED MOUSE FIBROBLASTS - COMPARISON WITH PHORBOL ESTERS AND INSULIN

A In the quiescent mouse BP-A31 fibroblasts, prostaglandin F2alpha (PGF2alpha) induces the expression of cell cycle-related genes c-fos, c-jun, and c-myc, and after a delay of approximately 12 h the entry into the phase of DNA replication. A weaker mitogenic effect was produced by certain other PGs (F1alpha > D2), whereas the effects of PGs E and I were marginal or absent. The mitogenic effects of PGF2alpha as well as of 12-O-tetradecanoyl phorbol 13-acetate (TPA; activator of protein kinase C) but not those of insulin (acting via the insulin-like growth factor 1 receptor) were abolished by a low concentration (7.5 nM) of staurosporin (inhibitor of protein kinase C), Moreover, long-time (24 h) preincubation with phorbol dibutyrate reduced the mitogenic effects of a subsequent exposure either TPA or PGF2alpha. These observations favor the involvement of protein kinase C in the PGF2alpha-dependent intracellular signal transduction. However, simultaneous stimulation of the quiescent cells with saturating concentrations of PGF2alpha and TPA had a greater mitogenic effect than either drug alone, both in cells with and without down-regulation of protein kinase C, indicating that the protein kinase C-dependent signaling does not entirely account for the mito-genic activity of PGF2alpha.