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

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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.

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