TY - JOUR
T1 - Smad4 as a transcription corepressor for estrogen receptor α
AU - Wu, Liyu
AU - Wu, Yalei
AU - Gathings, Bill
AU - Wan, Mei
AU - Li, Xuelin
AU - Grizzle, William
AU - Liu, Zhiyong
AU - Lu, Chongyuan
AU - Mao, Zhengkuan
AU - Cao, Xu
PY - 2003/4/25
Y1 - 2003/4/25
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M212332200
DO - 10.1074/jbc.M212332200
M3 - Article
C2 - 12576474
AN - SCOPUS:0038012730
SN - 0021-9258
VL - 278
SP - 15192
EP - 15200
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 17
ER -