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J. Biol. Chem., Vol. 282, Issue 11, 7950-7960, March 16, 2007

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Post-transcriptional Regulation of RNase-L Expression Is Mediated by the 3'-Untranslated Region of Its mRNA^*

Xiao-Ling Li^¶, Jesper B. Andersen, Heather J. Ezelle, Gerald M. Wilson^||, and Bret A. Hassel^¶1

From the University of Maryland, Departments of Microbiology and Immunology and ^||Biochemistry and Molecular Biology, Marlene and Stewart Greenebaum Cancer Center, ^¶Graduate Program in Molecular Medicine, Baltimore, Maryland 21201

RNase-L mediates critical cellular functions including antiviral, pro-apoptotic, and tumor suppressive activities; accordingly, its expression must be tightly regulated. Little is known about the control of RNASEL expression; therefore, we examined the potential regulatory role of a conserved 3'-untranslated region (3'-UTR) in its mRNA. The 3'-UTR mediated a potent decrease in the stability of RNase-L mRNA, and of a chimeric -globin-3'-UTR reporter mRNA. AU-rich elements (AREs) are cis-acting regulatory regions that modulate mRNA stability. Eight AREs were identified in the RNase-L 3'-UTR, and deletion analysis identified positive and negative regulatory regions associated with distinct AREs. In particular, AREs 7 and 8 served a strong positive regulatory function. HuR is an ARE-binding protein that stabilizes ARE-containing mRNAs, and a predicted HuR binding site was identified in the region comprising AREs 7 and 8. Co-transfection of HuR and RNase-L enhanced RNase-L expression and mRNA stability in a manner that was dependent on this 3'-UTR region. Immunoprecipitation demonstrated that RNase-L mRNA associates with a HuR containing complex in intact cells. Activation of endogenous HuR by cell stress, or during myoblast differentiation, increased RNase-L expression, suggesting that RNase-L mRNA is a physiologic target for HuR. HuR-dependent regulation of RNase-L enhanced its antiviral activity demonstrating the functional significance of this regulation. These findings identify a novel mechanism of RNase-L regulation mediated by its 3'-UTR.

Received for publication, August 18, 2006 , and in revised form, January 18, 2007.

^* 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.

The amino acid sequence of this protein can be accessed through NCBI Protein Database under NCBI accession number 801337.

¹ To whom correspondence should be addressed: 655 West Baltimore St., 9th floor BRB, Baltimore, MD 21201. Tel.: 410-328-2344; Fax: 410-328-6559; E-mail: bhassel{at}som.umaryland.edu.

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