Smad4 as a transcription corepressor for estrogen receptor α

Liyu Wu, Yalei Wu, Bill Gathings, Mei Wan, Xuelin Li, William Grizzle, Zhiyong Liu, Chongyuan Lu, Zhengkuan Mao, Xu Cao

Research output: Contribution to journalArticlepeer-review

Abstract

Antiestrogen compounds exhibit a variety of different effects in different tissues and are widely used for the treatment of osteoporosis, breast cancer, and other diseases. Upon examining the molecular mechanisms, we found that Smad4, a common signal transducer in the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) signaling pathway, functions as a transcription corepressor for human estrogen receptor α (ERα). Endogenous ERα was co-immunoprecipitated with Smad4, and the interaction was induced by antiestrogen ligands such as tamoxifen, raloxifene, and droloxifen, which was confirmed in chromatin immunoprecipitation assays. Smad4 and ERα form a complex when ERα binds to the estrogen-responsive element within the estrogen target gene promoter. Importantly, the expression of Smad4 inhibits both antiestrogen-induced luciferase activity and estrogen downstream target gene transcription in breast cancer cells. Mapping of the interaction domains indicates that the activation function 1 (AF1) domain of ERα is essential for its interaction with Smad4, while the MH1 domain and linker region of Smad4 are essential for the interaction. Our findings represent a novel mechanism that TGF-β may regulate cell fate through Smad4-mediated crosstalk with estrogen.

Original languageEnglish (US)
Pages (from-to)15192-15200
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number17
DOIs
StatePublished - Apr 25 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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