Differential regulation of extracellular signal-regulated protein kinases (ERKs) 1 and 2 by cAMP and dissociation of ERK inhibition from anti-mitogenic effects in rabbit vascular smooth muscle cells.
The inhibition of extracellular signal-regulated protein kinases (ERKs) is implicated in the negative regulation of vascular smooth muscle cell (VSMC) mitogenesis by cAMP-elevating agents and transforming growth factor beta(1) (TGF-beta(1)). These factors inhibited rabbit aortic VSMC mitogenesis induced by platelet-derived growth factor (PDGF)-BB by preventing the entry of cells into S-phase. cAMP-elevating agents partly inhibited the late phase (1-4 h) of activation of ERKs 1 and 2 induced by PDGF-BB without inhibiting the early phase of activity (5-15 min) and had no effect on activity induced by basic fibroblast growth factor (bFGF). In contrast, cAMP elevation caused a marked inhibition of early ERK activation induced by angiotensin II and thrombin. TGF-beta(1) had no inhibitory effect on ERK activation induced by PDGF-BB or bFGF. The inhibition of PDGF-BB-stimulated DNA synthesis by either forskolin/3-isobutyl-1-methylxanthine (IBMX) or TGF-beta(1) was not decreased when the agents were added up to 8 h after growth factor. In contrast, the selective ERK kinase inhibitor PD98059 was a weak inhibitor of DNA synthesis; a combination of PD98059 and forskolin/IBMX had an additive inhibitory effect on DNA synthesis. Forskolin/IBMX inhibited the growth factor-induced expression of c-myc mRNA and cyclin D(1) protein, and enhanced the protein expression of p27(kip1). TGF-beta(1) had no effect on the expression of c-myc or p27(kip1) and weakly attenuated the expression of cyclin D(1). These findings support the conclusion that the suppression of VSMC mitogenesis by cAMP and TGF-beta(1) is independent of ERK inhibition. Anti-mitogenic effects of cAMP might be primarily mediated by events in late G(1).
Cospedal
R
R
Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
Lobo
M
M
Zachary
I
I
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; D005576:Colforsin; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015056:1-Methyl-3-isobutylxanthine