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¹ Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
² Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Kita-15 jou, Nishi-7-chome, Kita-ku, Sapporo 060-8638, Japan
³ Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4529 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
⁴ Ludwig Institute for Cancer Research, Biomedical Centre, Box 595, SE-751 24, Uppsala, Sweden
⁵ Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
⁶ Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Smad proteins are intracellular signalling mediators of transforming growth factor-ß (TGF-ß) superfamily. In the nucleus, activated Smad complexes regulate transcriptional responses of the target genes in cooperation with transcriptional coactivators and corepressors. To identify new components of transcriptional complexes containing Smad proteins, we purified DNA-binding proteins from human breast cancer MCF-7 cell nuclear extract using a Smad-binding DNA element as bait, and identified a coactivator GCN5 as a direct partner of activated Smad complexes. GCN5 is structurally similar to PCAF, which was previously identified as a coactivator for receptor-regulated Smads (R-Smads) for TGF-ß signalling pathways. GCN5 functions like PCAF, in that it binds to TGF-ß-specific R-Smads, and enhances transcriptional activity induced by TGF-ß. In addition, GCN5, but not PCAF, interacts with R-Smads for bone morphogenetic protein (BMP) signalling pathways, and enhances BMP-induced transcriptional activity, suggesting that GCN5 and PCAF have distinct physiological functions in vivo. Moreover, silencing of the GCN5 gene by RNA interference results in repression of transcriptional activities induced by TGF-ß. In conclusion we identified GCN5 as a Smad-binding transcriptional coactivator which positively regulates both TGF-ß and BMP signalling pathways.

^* Correspondence: E-mail: miyazono-ind{at}umin.ac.jp

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