WORTMANNIN HAS OPPOSITE EFFECTS ON PHORBOL ESTER-INDUCED DNA-SYNTHESIS AND PHOSPHATIDYLCHOLINE HYDROLYSIS

The tumor promoter phorbol 12-myristate 13-acetate (PMA) and hormonal activators of protein kinase C (PKC) commonly stimulate phospholipase D (PLD)-mediated formation of phosphatidic acid from phosphatidylcholi ne (PtdCho) in fibroblasts and other cell types, On the basis that pho sphatidic acid is a mitogen, PLD is often considered to have a major r ole in the regulation of cell growth by PKC activators, However, we fo und that in NIH 3T3 fibroblasts wortmannin, an inhibitor of phosphatid ylinositol 3-kinase (PI3K), strongly inhibited DNA synthesis induced b y 100 nM PMA, while it actually enhanced PMA-stimulated PtdCho hydroly sis. These results indicate that stimulation of PLD activity is either not required or not sufficient for the mitogenic action of PMA.