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1 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
2 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan
c-Ski, originally identified as an oncogene product, induces myogenic differentiation in nonmyogenic fibroblasts through transcriptional activation of muscle regulatory factors. Although c-Ski does not bind to DNA directly, it binds to DNA through interaction with Smad proteins and regulates signaling activities of transforming growth factor-ß (TGF-ß). In the present study, we show that c-Ski activates the myogenin promoter independently of regulation of endogenous TGF-ß signaling. Expression of myogenin is regulated by a transcription factor complex containing proteins of the MyoD family and the myocyte enhancer factor 2 (MEF2) family. c-Ski acts on the MyoD–MEF2 complex and modulates the activity of MyoD in myogenin promoter regulation. Interestingly, histone deacetylase (HDAC) inhibitors up-regulated basal activity of transcription from a MyoD-responsive reporter, although c-Ski failed to further augment this transcription in the presence of HDAC inhibitors. c-Ski is observed both in the cytoplasm and in the nucleus, but its nuclear localization is required for myogenic differentiation. We conclude that c-Ski induces myogenic differentiation through acting on MyoD and inhibiting HDAC activity in the nucleus of myogenic cells.
* Correspondence: E-mail: miyazono-ind{at}umin.ac.jp
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