Nitric oxide down-regulates caveolin-3 levels through the interaction with myogenin, its transcription factor.
Certain patients suffering from chronic diseases such as AIDS or cancer experience a constant cellular secretion of tumor necrosis factor alpha 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.
Martínez-Moreno
Mónica
M
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
Martínez-Ruiz
Antonio
A
Alvarez-Barrientos
Alberto
A
Gavilanes
Francisco
F
Lamas
Santiago
S
Rodríguez-Crespo
Ignacio
I
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002100:Cachexia / Q000378:metabolism; D051244:Caveolin 3 / Q000096:biosynthesis*; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D018008:Myogenin / Q000096:biosynthesis*; D009569:Nitric Oxide / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D051244:Caveolin 3; D018008:Myogenin; D014157:Transcription Factors; D009569:Nitric Oxide