HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 27, 25470-25477, July 8, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/27/25470    most recent M502320200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sakakibara, K. Articles by Liu, B. Search for Related Content PubMed PubMed Citation Articles by Sakakibara, K. Articles by Liu, B. Social Bookmarking                      What's this?

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over in Vascular Smooth Muscle Cells^*

Kenji Sakakibara, Kenji Kubota, Berhane Worku, Evan J. Ryer, Jeffrey P. Miller, Andrew Koff, K. Craig Kent, and Bo Liu¶

From the Department of Surgery, Division of Vascular Surgery, Weill Medical College of Cornell University, New York, New York 10021 and the Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

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 turnover, 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.

Received for publication, March 2, 2005 , and in revised form, April 25, 2005.

^* This work was supported by NHLBI, National Institutes of Health, Grant HL-68673 (to K. C. K. and B. L.), National Institute of Health Training Grant T32 CA68971-07 (to E. J. R.), and an Atorvastatin research award (to B. L.) sponsored by Pfizer Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Surgery, Weill Medical College of Cornell University, 1300 York Ave., Rm. P707, New York, NY 10021. Tel.: 212-746-2440; Fax: 212-746-5812; E-mail: bol2001{at}med.cornell.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Morita, T. Suzuki, T. Nakamura, K. Yokoyama, T. Miyasaka, and T. Yamamoto Depletion of Mammalian CCR4b Deadenylase Triggers Elevation of the p27Kip1 mRNA Level and Impairs Cell Growth Mol. Cell. Biol., July 1, 2007; 27(13): 4980 - 4990. [Abstract] [Full Text] [PDF]

				K. Kamiya, K. Sakakibara, E. J. Ryer, R. P. Hom, E. B. Leof, K. C. Kent, and B. Liu Phosphorylation of the Cyclic AMP Response Element Binding Protein Mediates Transforming Growth Factor {beta}-Induced Downregulation of Cyclin A in Vascular Smooth Muscle Cells Mol. Cell. Biol., May 1, 2007; 27(9): 3489 - 3498. [Abstract] [Full Text] [PDF]

				I. Timmerbeul, C. M. Garrett-Engele, U. Kossatz, X. Chen, E. Firpo, V. Grunwald, K. Kamino, L. Wilkens, U. Lehmann, J. Buer, et al. Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer PNAS, September 19, 2006; 103(38): 14009 - 14014. [Abstract] [Full Text] [PDF]

				E. J. Ryer, K. Sakakibara, C. Wang, D. Sarkar, P. B. Fisher, P. L. Faries, K. C. Kent, and B. Liu Protein Kinase C Delta Induces Apoptosis of Vascular Smooth Muscle Cells through Induction of the Tumor Suppressor p53 by Both p38-dependent and p38-independent Mechanisms J. Biol. Chem., October 21, 2005; 280(42): 35310 - 35317. [Abstract] [Full Text] [PDF]