Smad4 as a transcription corepressor for estrogen receptor α

Academic Article


  • 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.
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    Digital Object Identifier (doi)

    Author List

  • Wu L; Wu Y; Gathings B; Wan M; Li X; Grizzle W; Liu Z; Lu C; Mao Z; Cao X
  • Start Page

  • 15192
  • End Page

  • 15200
  • Volume

  • 278
  • Issue

  • 17