TY - JOUR T1 - Endothelin-1-induced mitogenic responses of Chinese hamster ovary cells expressing human endothelinA: the role of a wortmannin-sensitive signaling pathway. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 447 LP - 457 VL - 49 IS - 3 AU - F Sugawara AU - H Ninomiya AU - Y Okamoto AU - S Miwa AU - O Mazda AU - Y Katsura AU - T Masaki Y1 - 1996/03/01 UR - http://molpharm.aspetjournals.org/content/49/3/447.abstract N2 - In the current study, endothelin-1 (ET-1) worked as a mitogen on Chinese hamster ovary cells stably expressing human endothelinA; when applied to serum-deprived cells, ET-1 caused dose-dependent increase in [3H]thymidine incorporation and cell proliferation. No synergism was observed between the effect of ET-1 and that of insulin-like growth factor-1/basic fibroblast growth factor. Both the inhibition of intracellular Ca2+ response by phospholipase C inhibitor U73122 and the down-regulation of protein kinase C (PKC) by pretreatment with phorbol 12-myristate-13-acetate (PMA) partially blocked the ET-1-induced mitogenic responses. Wortmannin, a phosphatidylinositol-3-kinase inhibitor, caused dose-dependent inhibition of the ET-1-induced mitogenic responses in both PMA-treated and -untreated cells. Wortmannin also inhibited ET-1-induced increase in phosphatidylinositol trisphosphate formation and activation of mitogen-activated protein kinase (MAPK), whereas it failed to inhibit PMA-induced activation of MAPK. In accordance with its effect on MAPK activation, wortmannin inhibited ET-1-induced activation of Raf-B, whereas it failed to inhibit the effect of PMA. These results suggested the role of a Ca2+/PKC-independent, wortmannin-sensitive signaling pathway that linked ETA and MAPK cascade in the mitogenic signaling activated by ETA. ER -