Evidence of a role for protein kinase C in epidermal growth factor-induced prostaglandin E2 synthesis in amnion cells.
Human amnion cells synthesize and release prostaglandin E2 in response to epidermal growth factor. The protein kinase C activator, phorbol 12-myristate, 13-acetate also stimulates amnion cell prostaglandin E2 synthesis. We used a human amnion cell line (WISH) to conduct in vitro experiments to investigate a potential role of protein kinase C in the signal transduction pathway leading to epidermal growth factor-induced prostaglandin E2 production. Pretreatment of cultured amnion cells with a low, nonstimulating dose of phorbol 12-myristate, 13-acetate potentiated the action of epidermal growth factor in causing prostaglandin E2 production as measured by radioimmunoassay. The protein kinase C-selective inhibitor staurosporine inhibited epidermal growth factor-induced prostaglandin E2 production, further suggesting a role for protein kinase C in epidermal growth factor action. Experiments were conducted in which amnion cells were rendered protein kinase C-deficient by chronic exposure to phorbol ester, which has been shown to down-regulate the enzyme. In these cells, epidermal growth factor caused prostaglandin E2 synthesis at levels comparable to native (non-protein kinase C-deficient) cells. We conclude that protein kinase C plays a more modulatory than direct role in the epidermal growth factor signal transduction cascade that leads to prostaglandin E2 production by amnion cells. We propose a bifurcating transduction scheme in which, under conditions of protein kinase C inactivation, epidermal growth factor alone causes prostaglandin E2 synthesis. When protein kinase C is activated by as yet unknown endogenous substances, the epidermal growth factor responsiveness of the amnion cells is greatly enhanced. This pathway could have important implications in a feed-forward mechanism regulating the level of prostaglandin E2 production during the onset of labor.
Kniss
D A
DA
Department of Obstetrics and Gynecology, (Division of Maternal-Fetal Medicine), Ohio State University College of Medicine, Columbus 43210.
Mershon
J
J
Su
H C
HC
Sonek
J
J
Fertel
R H
RH
Waxman
M
M
Iams
J D
JD
Gabbe
S G
SG
D000470:Alkaloids / Q000494:pharmacology; D000650:Amnion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D015232:Dinoprostone / Q000096:biosynthesis*; D015536:Down-Regulation; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D006801:Humans; D011247:Pregnancy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D019311:Staurosporine; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate