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J. Biol. Chem., Vol. 280, Issue 23, 22406-22417, June 10, 2005

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A Hairpin-like Structure within an AU-rich mRNA-destabilizing Element Regulates trans-Factor Binding Selectivity and mRNA Decay Kinetics^*

Elizabeth J. Fialcowitz, Brandy Y. Brewer, Bridget P. Keenan, and Gerald M. Wilson¶

From the Department of Biochemistry and Molecular Biology and Center for Fluorescence Spectroscopy and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

In mammals, rapid mRNA turnover directed by AU-rich elements (AREs) is mediated by selective association of cellular ARE-binding proteins. These trans-acting factors display overlapping RNA substrate specificities and may act to either stabilize or destabilize targeted transcripts; however, the mechanistic features of AREs that promote preferential binding of one trans-factor over another are not well understood. Here, we describe a hairpin-like structure adopted by the ARE from tumor necrosis factor (TNF) mRNA that modulates its affinity for selected ARE-binding proteins. In particular, association of the mRNA-destabilizing factor p37^AUF1 was strongly inhibited by adoption of the higher order ARE structure, whereas binding of the inducible heat shock protein Hsp70 was less severely compromised. By contrast, association of the mRNA-stabilizing protein HuR was only minimally affected by changes in ARE folding. Consistent with the inverse relationship between p37^AUF1 binding affinity and the stability of ARE folding, mutations that stabilized the ARE hairpin also inhibited its ability to direct rapid mRNA turnover in transfected cells. Finally, phylogenetic analyses and structural modeling indicate that TNF mRNA sequences flanking the ARE are highly conserved and may stabilize the hairpin fold in vivo. Taken together, these data suggest that local higher order structures involving AREs may function as potent regulators of mRNA turnover in mammalian cells by modulating trans-factor binding selectivity.

Received for publication, January 18, 2005 , and in revised form, March 30, 2005.

^* This work was supported by NCI, National Institutes of Health Grant R01 CA102428 and a Scientist Development Grant from the American Heart Association (to G. M. W.). Additional support for the Center for Fluorescence Spectroscopy was provided by The National Center for Research Resources, National Institutes of Health Grant P41 RR08119. 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 Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201. Tel.: 410-706-8904; Fax: 410-706-8297; E-mail: gwils001{at}umaryland.edu.

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