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J. Biol. Chem., Vol. 282, Issue 32, 23044-23054, August 10, 2007

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Nitric Oxide Down-regulates Caveolin-3 Levels through the Interaction with Myogenin, Its Transcription Factor^*

Mónica Martínez-Moreno, Antonio Martínez-Ruiz^¶, Alberto Álvarez-Barrientos^¶, Francisco Gavilanes, Santiago Lamas, and Ignacio Rodríguez-Crespo¹

From the Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain, the Instituto "Reina Sofía" de Investigaciones Nefrológicas, Centro de Investigaciones Biológicas, Ramiro de Maeztu, 9, 28040 Madrid, Spain, and the ^¶Fundación Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, Melchor Fernández Almagro, 3, 28040 Madrid, Spain

Certain patients suffering from chronic diseases such as AIDS or cancer experience a constant cellular secretion of tumor necrosis factor and other pro-inflammatory cytokines that results in a continuous release of nitric oxide (·NO) to the bloodstream. One immediate consequence of the deleterious action of ·NO is weight loss and the progressive destruction of muscular mass in a process known as cachexia. We have previously reported that caveolin-3, a specific marker of muscle cells, becomes down-regulated by the action of ·NO on muscular myotubes. We describe herein that the changes observed in caveolin-3 levels are due to the alteration of the DNA binding activity of the muscular transcription factor myogenin. In the presence of ·NO, the binding of transcription factors from cell nuclear extracts of muscular tissues to the E boxes present in the caveolin-3 promoter become substantially reduced. When we purified recombinant myogenin and treated it with ·NO donors, we could detect its S-nitrosylation by three independent methods, suggesting that very likely one of the cysteine residues of the molecule is being modified. Given the role of myogenin as a regulatory protein that determines the level of multiple muscle genes expressed during late myogenesis, our results might represent a novel mode of regulation of muscle development under conditions of nitric oxide-mediated toxicity.

Received for publication, November 20, 2006 , and in revised form, April 20, 2007.

^* This work was supported by Dirección General de Investigación Científica y Técnica Grants BFU 2006-13033, BFU 2006-05395, CP03-0025, and SAF2006-02410. 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.

¹ To whom correspondence should be addressed. Tel.: 34-91-394-4258; Fax: 34-91-394-4159; E-mail: nacho{at}bbm1.ucm.es.

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