Phorbol esters inhibit fibroblast growth factor-2-stimulated fibroblast proliferation by a p38 MAP kinase dependent pathway

Treatment of fibroblasts with the phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA), specifically inhibits fibroblast growth factor-2 (FGF-2) induced proliferation. TPA treatment has little or no effect on FGF receptor activation but specifically inhibits the activation of p38 MAPK but not other downstream signaling pathways implicated in cell proliferation. p38 MAPK was recently shown to be required for the FGF-2-stimulated proliferation of fibroblasts. The effect of TPA on both p38 MAPK activation and cell proliferation can be reversed by treatment with the PKC inhibitor Go6983. The TPA-mediated inhibition of p38 MAPK activation requires phosphatase activity and is at least partially mediated by ERKs since it is reduced by treatment with the MEK inhibitor PD98059. In contrast, the FGF-2-stimulated differentiation of PC12 cells, which express the same FGF receptor as Swiss 3T3 fibroblasts, is not affected by TPA treatment, consistent with a lack of involvement of p38 MAPK activity in this process. These data indicate that the effects of TPA treatment on cellular function are not only cell type but also stimulus specific and are dependent upon the distinct pathways activated downstream of each stimulus.