c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads.
Smads are intracellular signaling mediators of the transforming growth factor-beta (TGF-beta) superfamily that regulates a wide variety of biological processes. Among them, Smads 2 and 3 are activated specifically by TGF-beta. We identified c-Ski as a Smad2 interacting protein. c-Ski is the cellular homologue of the v-ski oncogene product and has been shown to repress transcription by recruiting histone deacetylase (HDAC). Smad2/3 interacts with c-Ski through its C-terminal MH2 domain in a TGF-beta-dependent manner. c-Ski contains two distinct Smad-binding sites with different binding properties. c-Ski strongly inhibits transactivation of various reporter genes by TGF-beta. c-Ski is incorporated in the Smad DNA binding complex, interferes with the interaction of Smad3 with a transcriptional co-activator, p300, and in turn recruits HDAC. c-Ski is thus a transcriptional co-repressor that links Smads to HDAC in TGF-beta signaling.
Akiyoshi
S
S
Department of Biochemistry, The Cancer Institute of Japanese Foundation for Cancer Research, Research for the Future Program, Japan Society for Promotion of Science, 1-37-1, Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.
Inoue
H
H
Hanai
J
J
Kusanagi
K
K
Nemoto
N
N
Miyazono
K
K
Kawabata
M
M
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D015151:Immunoblotting; D008907:Mink; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases