HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 33, 22457-22463, August 15, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/33/22457    most recent M802803200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhang, L. Articles by Wilusz, C. J. PubMed PubMed Citation Articles by Zhang, L. Articles by Wilusz, C. J. Social Bookmarking                      What's this?

The RNA-binding Protein CUGBP1 Regulates Stability of Tumor Necrosis Factor mRNA in Muscle Cells

IMPLICATIONS FOR MYOTONIC DYSTROPHY^*

Libin Zhang, Jerome E. Lee¹, Jeffrey Wilusz, and Carol J. Wilusz²

From the Department of Microbiology, Immunology, and Pathology and the Cell and Molecular Biology Program, Colorado State University, Fort Collins, Colorado 80523

Type I myotonic dystrophy (DM1) is caused by a triplet repeat expansion in the 3'-untranslated region (UTR) of the dystrophia myotonia protein kinase (DMPK) gene. Pathogenesis is closely linked with production of a toxic RNA from the mutant allele, which interferes with function of several RNA-binding proteins, including CUGBP1. Here we show that expression of a mutant DMPK 3'-UTR containing 960 CUG repeats is sufficient to increase expression and stability of an mRNA encoding the potent proinflammatory cytokine, tumor necrosis factor (TNF). CUGBP1 specifically recognizes sequences within the TNF 3'-UTR that are dissimilar from its canonical UG-rich binding site. Depletion of CUGBP1 from mouse myoblasts results in increased abundance of TNF mRNA through stabilization of the transcript. Moreover, activation of the protein kinase C pathway by treatment with phorbol ester, which has been shown previously to result in CUGBP1 phosphorylation, also causes TNF mRNA stabilization. Our results suggest that the elevated serum TNF seen in DM1 patients may be derived from muscle where it is induced by expression of toxic DMPK RNA. Importantly, overexpression of this potent cytokine could contribute to the muscle wasting and insulin resistance that are characteristic of this debilitating disease.

Received for publication, April 11, 2008 , and in revised form, May 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM 072481 (to J. W.). This work was also supported by Muscular Dystrophy Association Award 4326 (to C. J. W.), and by Colorado State University College of Veterinary Medicine and Biomedical Sciences (to C. J. W.). 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Recipient of American Heart Association Predoctoral Fellowship 0810142Z.

² To whom correspondence should be addressed: Dept. of Microbiology, Immunology, and Pathology, 1682 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1682. Tel.: 970-491-4919; Fax: 970-491-4941; E-mail: cwilusz{at}colostate.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?