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J. Biol. Chem., Vol. 279, Issue 47, 49298-49306, November 19, 2004

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Prostaglandin A₂-mediated Stabilization of p21 mRNA through an ERK-dependent Pathway Requiring the RNA-binding Protein HuR^*

Xiaoling Yang, Wengong Wang, Jinshui Fan, Ashish Lal, Dongmei Yang, Heping Cheng, and Myriam Gorospe¶

From the Laboratory of Cellular and Molecular Biology and the Laboratory of Cardiovascular Science, Intramural Research Program, NIA, National Institutes of Health, Baltimore, Maryland 21224

Treatment with the stress agent prostaglandin A₂ (PGA₂) induces expression of the cyclin-dependent kinase inhibitor p21. Here, we present evidence that p21 expression increases through PGA₂-triggered stabilization of the p21 mRNA and further show that these events require the mitogen-activated protein (MAP) kinase ERK. Binding experiments using either endogenous p21 mRNA or in vitro-labeled p21 transcripts revealed a specific PGA₂-dependent association of the p21 mRNA with the RNA-binding protein HuR. Interestingly, although inhibition of the ERK pathway did not prevent the PGA₂-triggered increase in cytoplasmic HuR, it did impair the formation of endogenous and in vitro [HuR-p21 mRNA] complexes and further prevented the PGA₂-mediated stabilization of the p21 mRNA, suggesting that ERK-mediated events were required for binding HuR to the p21 mRNA and preventing its decay. RNA interference-based knockdown of HuR abundance further served to demonstrate the contribution of HuR-mediated p21 mRNA stabilization toward enhancing p21 expression after PGA₂ treatment. Collectively, our results indicate that PGA₂ stabilizes the p21 mRNA through an ERK-independent increase in cytoplasmic HuR levels and an ERK-dependent association of HuR with the p21 mRNA.

Received for publication, July 6, 2004 , and in revised form, September 10, 2004.

^* 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: Box 12, Laboratory of Cellular and Molecular Biology, NIA, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825; Tel.: 410-558-8443; Fax: 410-558-8386; E-mail: myriam-gorospe{at}nih.gov.

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