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J. Biol. Chem., Vol. 280, Issue 27, 25361-25368, July 8, 2005

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The RNA-binding Protein HuR Binds to Acetylcholinesterase Transcripts and Regulates Their Expression in Differentiating Skeletal Muscle Cells^*

Julie Deschênes-Furry, Guy Bélanger¶, James Mwanjewe, John A. Lunde, Robin J. Parks||**, Nora Perrone-Bizzozero, and Bernard J. Jasmin**¶¶

From the Department of Cellular and Molecular Medicine and ^||Departments of Medicine and Biochemistry and Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, The University of Ottawa Centre for Neuromuscular Disease, Ottawa, Ontario KIH 8L6, Canada, ^**Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada, and Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131

During myogenic differentiation, acetylcholinesterase (AChE) transcript levels are known to increase dramatically. Although this increase can be attributed in part to increased transcriptional activity, posttranscriptional mechanisms have also been implicated in the high levels of AChE mRNA in myotubes. In this study, we observed that transfection of a luciferase reporter construct containing the full-length AChE 3'-untranslated region (UTR) resulted in significantly higher (5-fold) luciferase activity in differentiated myotubes versus myoblasts. RNA-electrophoretic mobility shift assays (REMSAs) performed with a full-length AChE 3'-UTR probe and the AU-rich element revealed that the intensity of RNA-binding protein complexes increased as myogenic differentiation proceeded. Using several complementary approaches including supershift REMSA, mRNA-binding protein pull-down assays, and immunoprecipitation followed by reverse transcription-PCR, we found that the mRNA-stabilizing protein HuR interacts directly with AChE transcripts. Stable overexpression of HuR in C2C12 cells increased the expression of endogenous AChE transcripts as well as that of the luciferase reporter construct containing the AChE 3'-UTR. In vitro stability assays performed with protein extracts from these cells versus controls resulted in a slower rate of AChE mRNA decay. The down-regulation of HuR expression mediated through small interfering RNA further confirmed the role of HuR in the regulation of AChE mRNA levels. Taken together, these studies demonstrate that HuR interacts with the AChE 3'-UTR to regulate posttranscriptionally the expression of AChE mRNA during myogenic differentiation.

Received for publication, September 22, 2004 , and in revised form, May 3, 2005.

^* This work was supported in part by grants from the Canadian Institutes of Health Research (CIHR) (to B. J. J. and R. J. P.) and by National Institutes of Health Grant NS-30255 (to N. P.-B.). 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.

^¶ Recipient of a fellowship from the Association Française contre les Myopathies.

A CIHR new investigator.

^¶¶ A CIHR investigator. To whom correspondence should be addressed: Dept. of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, Ontario K1H 8M5, Canada. Tel.: 613-562-5800 (ext. 8383); Fax: 613-562-5636; E-mail: jasmin{at}uottawa.ca.

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