PDGF-BB regulates p27 expression through ERK-dependent RNA turn-over in vascular smooth muscle cells Journal Article
| Authors: | Sakakibara, K.; Kubota, K.; Worku, B.; Ryer, E. J.; Miller, J. P.; Koff, A.; Kent, K C.; Liu, B. |
| Article Title: | PDGF-BB regulates p27 expression through ERK-dependent RNA turn-over in vascular smooth muscle cells |
| Abstract: | Cyclin-dependent kinase inhibitor p27, a critical determinant for cell cycle progression, is an important regulation target of mitogenic signals during arterial injury. In this study, we show in rat aortic smooth muscle cells that PDGF-BB down-regulated p27 protein and mRNA in an ERK-dependent mechanism. Inhibition of ERK, but not other subtypes of the mitogen-activated protein kinase family, prevented the reduction of p27 protein and mRNA. Conversely, direct activation of ERK via adenovirus-mediated expression of a constitutively active form of MEK led to a reduction of p27 protein and mRNA, further supporting the central role of ERK in regulation of p27 expression. Rapamycin, which potently inhibited PDGF-induced activation of p70 S6 kinase as well as proliferation of smooth muscle cells, did not alter the expression of p27. To delineate the molecular mechanism underlying the p27 down-regulation, we examined the effect of PDGF-BB on p27 promoter activity as well as mRNA stability. Stimulation with PDGF-BB significantly shortened the half-life of p27 mRNA without affecting its promoter activity. To further understand the PDGF-stimulated p27 mRNA turn-over, we inserted the 5′- and/or 3′- untranslated regions of p27 cDNA into a non-PDGF-responsive luciferase gene. Only those chimeric genes that contained the 3′-untranslated region responded to PDGF-BB with reduced expression. Moreover, inhibition of ERK completely prevented the effect of PDGF on the chimera expression. In summary, our data suggest that p27 is down-regulated by PDGF-BB in vascular smooth muscle cells through an ERK-dependent posttranscriptional mechanism. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | mitogen activated protein kinase; s6 kinase; controlled study; promoter region; nonhuman; protein function; cell proliferation; mitosis; proteins; animal cell; animals; cell cycle proteins; cells, cultured; cell cycle; smooth muscle fiber; enzyme inhibition; proteasome endopeptidase complex; genes; map kinase signaling system; down-regulation; enzyme activation; chimera; molecular mechanics; rna; gene expression regulation; protein processing; messenger rna; rna, messenger; 5' untranslated region; protein p27; cyclin-dependent kinase inhibitor p27; tumor suppressor proteins; rat; platelet-derived growth factor; anticoagulants; extracellular signal-regulated map kinases; computer simulation; down regulation; rats; 3' untranslated region; rna stability; adenovirus vector; gene insertion; cyclin dependent kinase inhibitor; rapamycin; enzymes; enzyme mechanism; complementary dna; artery injury; adenoviridae; 3' untranslated regions; gene activity; muscle; muscle, smooth, vascular; rna degradation; cells; vascular smooth muscle; aorta; viruses; kinase inhibitors; promoter regions (genetics); ribosomal protein s6 kinases, 70-kda; adenoviruses; mitogenic signals; muscle cells; platelet derived growth factor bb |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 280 |
| Issue: | 27 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2005-07-08 |
| Start Page: | 25470 |
| End Page: | 25477 |
| Language: | English |
| DOI: | 10.1074/jbc.M502320200 |
| PUBMED: | 15894805 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 26" - "Export Date: 24 October 2012" - "CODEN: JBCHA" - "Source: Scopus" |
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