c-Ski activates MyoD in the nucleus of myoblastic cells through suppression of histone deacetylases.
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-beta (TGF-beta). In the present study, we show that c-Ski activates the myogenin promoter independently of regulation of endogenous TGF-beta 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.
Kobayashi
Norihiko
N
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Goto
Kouichiro
K
Horiguchi
Kana
K
Nagata
Motoko
M
Kawata
Mikiko
M
Miyazawa
Keiji
K
Saitoh
Masao
M
Miyazono
Kohei
K
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018008:Myogenin / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C499605:Diablo protein, mouse; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D024101:Mitochondrial Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D011518:Proto-Oncogene Proteins; C512653:Ski protein, mouse; D016212:Transforming Growth Factor beta; D004247:DNA; D006655:Histone Deacetylases