c-myc Is a Downstream Target of the Smad Pathway210

• Published in: The Journal of biological chemistry 2002-01, Vol.277 (1), p.854-861
• Main Authors: Yagi, Ken, Furuhashi, Masao, Aoki, Hiromasa, Goto, Daisuke, Kuwano, Hiroyuki, Sugamura, Kazuo, Miyazono, Kohei, Kato, Mitsuyasu
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M104170200

c-Myc is one of the most potent regulators of cell cycle progression in higher eukaryotes. Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. This element is a complex of the TGF-β1 inhibitory element (TIE) originally identified in the transin/stromelysin promoter and an E2F site responsible for transcriptional activation of the c-myc promoter. Smad3 and E2F-4 directly bound to the element (TIE/E2F), and substitution of two nucleotides in TIE/E2F impaired binding of both Smad3 and E2F-4 as well as serum-induced activation and TGF-β-induced suppression of the c-mycpromoter activity. Smads bound TIE/E2F within 1 h after stimulation with TGF-β, before the suppression of c-myc transcription, whereas binding of p130 to TIE/E2F became augmented later than 12 h. TGF-β signaling did not compete with E2F-4 for binding to TIE/E2F, but reduced p300 co-immunoprecipitating with E2F-4. Therefore, TGF-β signaling may suppress c-myc promoter activity by dissociating p300 from E2F-4.