Differential inhibition by staurosporine of phorbol ester, bryostatin and okadaic acid effects on mouse skin.
The tumor promoters 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a strong activator of protein kinase C (PKC) and okadaic acid, which is ineffective in this respect, induce a rapidly developing ('early') edema of the mouse ear. Bryostatin, another potent activator of PKC, is unable to induce an 'early' edema but causes a more delayed development of edema at a time when most of the PKC is down-regulated. The PKC inhibitor staurosporine neither inhibits the early TPA- nor the late bryostatin-induced edema, but suppresses the okadaic acid-induced edema very effectively. TPA as well as bryostatin, but not okadaic acid cause a down-regulation of PKC, which is not inhibited by staurosporine. The calmodulin antagonist cyclosporine A, which does not suppress PKC activity, very effectively inhibits the TPA-induced edema and down regulation of PKC. Hence we conclude that protein phosphorylation catalyzed by staurosporine-suppressable PKC is not involved in the induction of edema and PKC down-regulation by TPA but that a calmodulin dependent process may play a critical role in these and other TPA effects in mouse skin.
Gschwendt
M
M
German Cancer Research Center, Heidelberg.
Kittstein
W
W
Lindner
D
D
Marks
F
F
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D054713:Bryostatins; D016572:Cyclosporine / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced; D004988:Ethers, Cyclic / Q000633:toxicity*; D005260:Female; D007783:Lactones / Q000633:toxicity*; D018942:Macrolides; D051379:Mice; D019319:Okadaic Acid; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012867:Skin / Q000187:drug effects*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D000470:Alkaloids; D054713:Bryostatins; D004988:Ethers, Cyclic; D007783:Lactones; D018942:Macrolides; D019319:Okadaic Acid; C046785:bryostatin 1; D016572:Cyclosporine; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate