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Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15 Ink4B transcription in response to TGF‐β
Author(s) -
Feng XinHua,
Lin Xia,
Derynck Rik
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.19.5178
Subject(s) - biology , smad2 protein , transforming growth factor beta , transcription factor , smad , tgf beta signaling pathway , sp1 transcription factor , microbiology and biotechnology , cancer research , r smad , transforming growth factor , promoter , endoglin , gene , genetics , gene expression , stem cell , cd34
Transforming growth factor‐β (TGF‐β) arrests growth of epithelial cells by inducing the transcription of p15 Ink4B , a cyclin‐dependent kinase inhibitor. In this study, we demonstrate that p15 Ink4B induction was mediated by a TGF‐β‐induced complex of Smad2, Smad3, Smad4 and Sp1. Mutations in the Sp1‐ or Smad‐binding sequences decreased or abolished the TGF‐β responsiveness of the p15 Ink4B promoter. Interference with, or deficiency in, Smad2, Smad3 or Smad4 functions also reduced or abolished the TGF‐β‐dependent p15 Ink4B induction, whereas the absence of Sp1 reduced the basal and TGF‐β‐induced p15 Ink4B transcription. In the nucleoprotein complex, Smad2 interacted through its C‐domain with Sp1 and enhanced the DNA binding and transcriptional activity of Sp1. Smad3 interacted indirectly with Sp1 through its association with Smad2 and/or Smad4, and bound directly to the p15 Ink4B promoter. Finally, Smad4 interacted through its N‐domain with Sp1. Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15 Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF‐β