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Vol. 13, No. 4, pp. 412-423, February 15, 1999
1 Laboratory of Molecular Genetics, Tsukuba Life Science
Center, RIKEN, Tsukuba, Ibaraki 305-0074, Japan; 2 National
Institute of Bioscience and Human Technology, Agency of Industrial
Science and Technology, Tsukuba, Ibaraki 305-0046, Japan;
3 Chugai Research Institute for Molecular Medicine, Niihari,
Ibaraki 300-4101, Japan; 4 Department of Cancer Biology,
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
44195 USA; 5 Iatron Laboratories Inc., Tako, Katori, Chiba
289-2247, Japan; 6 CREST (Core Research for Evolutional
Science and Technology), Japan Science and Technology Corporation (JST)
The N-CoR/SMRT complex containing mSin3 and histone
deacetylase (HDAC) mediates transcriptional repression by nuclear
hormone receptors and Mad. The proteins encoded by the ski
proto-oncogene family directly bind to N-CoR/SMRT and
mSin3A, and forms a complex with HDAC. c-Ski and its related gene
product Sno are required for transcriptional repression by Mad and
thyroid hormone receptor (TR
). The oncogenic form, v-Ski, which
lacks the mSin3A-binding domain, acts in a dominant-negative fashion,
and abrogates transcriptional repression by Mad and TR. In
ski-deficient mouse embryos, the ornithine decarboxylase gene,
whose expression is normally repressed by Mad-Max, is expressed
ectopically. These results show that Ski is a component of the HDAC
complex and that Ski is required for the transcriptional repression
mediated by this complex. The involvement of c-Ski in the HDAC complex
indicates that the function of the HDAC complex is important for oncogenesis.
[Key Words: Ski; N-CoR/SMRT corepressor; mSin3; Mad; histone deacetylase complex]
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