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

Citation
R. Cospedal et al., 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, 342, 1999, pp. 407-414
Citations number
53
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL JOURNAL
ISSN journal
02646021 → ACNP
Volume
342
Year of publication
1999
Part
2
Pages
407 - 414
Database
ISI
SICI code
0264-6021(19990901)342:<407:DROESP>2.0.ZU;2-Y
Abstract
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 ind uced 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 induc ed by basic fibroblast growth factor (bFGF). In contrast, cAMP elevation ca used a marked inhibition of early ERK activation induced by angiotensin II and thrombin. TGF-beta(1) had no inhibitory effect on ERK activation induce d by PDGF-BB or bFGF. The inhibition of PDGF-BB-stimulated DNA synthesis by either forskolin/3isobutyl-1-methylxanthine (IBMX) or TGF-beta(1) was not decreased when the agents were added up to 8 h after growth factor. In cont rast, the selective ERK kinase inhibitor PD98059 was a weak inhibitor of DN A synthesis; a combination of PD98059 and forskolin/IBMX had an additive in hibitory effect on DNA. synthesis. Forskolin/IBMX inhibited the growth fact or-induced expression of c-myc mRNA and cyclin D, protein, and enhanced the protein expression of p27(kip1). TGF-P, had no effect on the expression of c-myc or p27(kip1) and weakly attenuated the expression of cyclin D-1. The se findings support the conclusion that the suppression of VSMC mitogenesis by cAMP and TGF-beta(1) is independent of ERK inhibition. Anti-mitogenic e ffects of cAMP might be primarily mediated by events in late G(1).