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J. Biol. Chem., Vol. 280, Issue 7, 5750-5763, February 18, 2005

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Fragile X-related Protein FXR1P Regulates Proinflammatory Cytokine Tumor Necrosis Factor Expression at the Post-transcriptional Level^*

James Garnon, Claude Lachance, Sergio Di Marco, Zdenek Hel, Dominique Marion, Maria C. Ruiz, Marianna M. Newkirk, Edouard W. Khandjian, and Danuta Radzioch¶

From the McGill University Health Centre, McGill University, Department of Experimental Medicine, Montreal, Quebec H3G 1A4, Canada and Unité de Recherche en Génétique Humaine et Moléculaire, Hôpital Saint François d'Assise and Département de biologie médicale, Faculté de médecine, Université Laval, Quebec G1L 3L5, Canada

Tumor necrosis factor (TNF) is regulated post-transcriptionally by the AU-rich element (ARE) within the 3'-untranslated region of its mRNA. This regulation modulates translational efficacy and mRNA stability. By using a cRNA probe containing the TNF ARE sequence, we screened a macrophage protein expression library and identified FXR1P. Macrophages that we generated from FXR1 knock-out mice had enhanced TNF protein production compared with wild type macrophages following activation. Expression of several other proteins that are regulated by ARE sequences was also affected by FXR1P deficiency. A GFP-ARE reporter that has green fluorescent protein (GFP) expression under control of the 3'-untranslated region of TNF mRNA had enhanced expression in transfected macrophages deficient in FXR1P. Finally, we found that the ablation of FXR1P led to a dramatically enhanced association of the TNF mRNA with polyribosomes demonstrating the important role of FXR1P in the post-transcriptional regulation of TNF expression. Our data suggest that release of this repression by FXR1P occurs during lipopolysaccharide-induced macrophage activation. Finally, complementation of the knock-out macrophages with recombinant FXR1P resulted in decreased TNF protein production, supporting our findings that FXR1P operates as a repressor of TNF translation.

Received for publication, February 23, 2004 , and in revised form, November 17, 2004.

^* This work was supported by Canadian Institute of Health Research Grant 6033 (to D. R.), National Sciences and Engineering Research Council of Canada Grants 6844 (to D. R.) and 106026 (to E. W. K.), CCFF Grant 216714 (to D. R.), a doctoral research award from the Canadian Institute of Health Research (to J. G. and S. D.), and Chercheurs-Nationaux Scholarship by Fonds de la Recherche en Sante du Quebec (to D. R.). 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: Depts. of Experimental Medicine and Human Genetics, McGill University, 1650 Cedar Ave., L11–218, Montreal, Quebec H3G 1A4, Canada. Tel.: 514-934-1934 (ext. 44517); Fax: 514-934-8260; E-mail: danuta.radzioch{at}muhc.mcgill.ca.

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