Transforming growth factor beta 1 augments mitogen-induced prostaglandin synthesis and expression of the TIS10/prostaglandin synthase 2 gene both in Swiss 3T3 cells and in murine embryo fibroblasts.
Transforming growth factor-beta (TGF-beta), a potent cytokine, modulates a wide variety of biological responses. Among its actions, TGF-beta can augment prostaglandin synthesis in several cell types. Although TGF-beta alone has no effect on prostaglandin production in Swiss 3T3 cells, we find that TGF-beta augments the ability of tetradecanoyl phorbol acetate (TPA) or serum to stimulate PGE2 production. The TIS10 gene is a primary response gene encoding a second form of prostaglandin synthase (PGS), the rate-limiting enzyme in the biosynthesis of prostaglandins, thromboxanes, and prostacyclins from arachidonic acid. TIS10/PGS-2 expression is induced by mitogens in Swiss 3T3 cells. TGF-beta also augments mitogen-induced synthesis and accumulation of TIS10/PGS-2 protein and induction of TIS10/PGS-2 message in Swiss 3T3 cells. In contrast, TGF-beta has little or no effect on the level of PGS-1 (EC1.14.99.1) message, either alone or in concert with TPA or serum. TGF-beta concentrations in the range of 0.01-0.10 ng/ml (0.4-4.0 pM) maximally enhance mitogen induction of TIS10/PGS-2 message. TPA-induced accumulation of unspliced TIS10/PGS-2 transcript is augmented by TGF-beta, suggesting that this cytokine exerts its effect on expression of the TIS10/PGS-2 gene by transcriptional regulation. TGF-beta also augments TPA-induced prostaglandin production, TIS10/PGS-2 antigen accumulation, and TIS10/PGS-2 message induction in primary cultures of mouse embryo fibroblasts. Dexamethasone attenuates TGF-beta enhancement of all these mitogen-induced responses: PGE2 accumulation, appearance of TIS10/PGS-2 protein and message, and accumulation of TIS10/PGS-2 unprocessed transcript.
Gilbert
R S
RS
Laboratory of Structural Biology and Molecular Medicine, UCLA School of Medicine 90024.
Reddy
S T
ST
Kujubu
D A
DA
Xie
W
W
Luner
S
S
Herschman
H R
HR
D016475:3T3 Cells / Q000201:enzymology*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011453:Prostaglandins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012709:Serum Albumin / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D008934:Mitogens; D011453:Prostaglandins; D012333:RNA, Messenger; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate