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 β1 (TGF-β1). 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-β1 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-β1 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 D1 protein, and enhanced the protein expression of p27kip1. TGF-β1 had no effect on the expression of c-myc or p27kip1 and weakly attenuated the expression of cyclin D1. These findings support the conclusion that the suppression of VSMC mitogenesis by cAMP and TGF-β1 is independent of ERK inhibition. Anti-mitogenic effects of cAMP might be primarily mediated by events in late G1.
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Research Article|
August 24 1999
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
Rosario COSPEDAL;
Rosario COSPEDAL
1Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
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Melvin LOBO;
Melvin LOBO
1Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
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Ian ZACHARY
Ian ZACHARY
1
1Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, U.K.
1To whom correspondence should be addressed (i.zachary@ucl.ac.uk).
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Publisher: Portland Press Ltd
Received:
January 15 1999
Revision Received:
May 24 1999
Accepted:
June 21 1999
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1999
1999
Biochem J (1999) 342 (2): 407–414.
Article history
Received:
January 15 1999
Revision Received:
May 24 1999
Accepted:
June 21 1999
Citation
Rosario COSPEDAL, Melvin LOBO, Ian ZACHARY; 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. Biochem J 1 September 1999; 342 (2): 407–414. doi: https://doi.org/10.1042/bj3420407
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