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J. Biol. Chem., Vol. 282, Issue 45, 32699-32709, November 9, 2007

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Platelet-derived Growth Factor-induced Stabilization of Cyclooxygenase 2 mRNA in Rat Smooth Muscle Cells Requires the c-Src Family of Protein-tyrosine Kinases^*

Kaiming Xu¹, Chad M. Kitchen, Hui-Kuo G. Shu, and Thomas J. Murphy

From the Departments of Pharmacology and Radiation Oncology, Emory University, Atlanta, Georgia 30322

Cyclooxygenases (COXs) are crucial rate-limiting enzymes required for the biosynthesis of prostaglandins. COX-2 is an inducible isoform of this enzyme, which is believed to play important roles in the development of atherosclerotic vascular disease. We found that COX-2 expression rapidly increases in response to various signaling events, including activation of the platelet-derived growth factor (PDGF) pathway. Activation of PDGF receptor (PDGFR) in rat aortic vascular smooth muscle cells leads to c-Src-dependent stabilization of COX-2 mRNA requiring an AU-rich region within the 3'-untranslated region of this transcript. This regulation correlates with tyrosine phosphorylation of the RNA-associated protein, CUG-binding protein 2 (CUGBP2), which appears to enhance its interaction with COX-2 mRNA. Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA. We further show that silencing of CUGBP2 with specific small interference RNAs significantly reduces PDGF-dependent induction of COX-2 at both mRNA and protein levels. Furthermore, forced expression of CUGBP2 or constitutively active c-Src leads to stabilization of co-expressed COX-2 mRNA. Finally, in vitro RNA decay assay demonstrates that CUGBP2 is functionally required for the stabilization of COX-2 mRNA. Therefore, our data suggest that tyrosine phosphorylation of CUGBP2 is an important underlying mechanism for the ability of PDGFR/c-Src signaling to control the stability of COX-2 mRNA.

Received for publication, June 27, 2007 , and in revised form, September 11, 2007.

^* This work was supported by NHLBI, National Institutes of Health Grant HL56107 (to T. J. M.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-778-2148; Fax: 404-778-5520; E-mail: kxu{at}emory.edu.

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