Regulation of transforming growth factor-beta and bone morphogenetic protein signalling by transcriptional coactivator GCN5.
Smad proteins are intracellular signalling mediators of transforming growth factor-beta (TGF-beta) 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-beta signalling pathways. GCN5 functions like PCAF, in that it binds to TGF-beta-specific R-Smads, and enhances transcriptional activity induced by TGF-beta. 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-beta. In conclusion we identified GCN5 as a Smad-binding transcriptional coactivator which positively regulates both TGF-beta and BMP signalling pathways.
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.
Kaoru
K
Kahata
Makoto
M
Hayashi
Masahiro
M
Asaka
Ulf
U
Hellman
Hirochika
H
Kitagawa
Jun
J
Yanagisawa
Shigeaki
S
Kato
Takeshi
T
Imamura
Kohei
K
Miyazono
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism; D018797:Cell Cycle Proteins; D002457:Cell Extracts; D002460:Cell Line; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D051785:Smad Proteins; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D002457:Cell Extracts; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D017395:Plasminogen Activator Inhibitor 1; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C497790:SMAD3 protein, human; C501179:KAT2A protein, human