Smad4 as a transcription corepressor for estrogen receptor alpha.
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-beta (TGF-beta) signaling pathway, functions as a transcription corepressor for human estrogen receptor alpha (ERalpha). Endogenous ERalpha 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 ERalpha form a complex when ERalpha 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 ERalpha 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-beta may regulate cell fate through Smad4-mediated cross-talk with estrogen.
Wu
Liyu
L
Department of Pathology, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama 35294, USA.
Wu
Yalei
Y
Gathings
Bill
B
Wan
Mei
M
Li
Xuelin
X
Grizzle
William
W
Liu
Zhiyong
Z
Lu
Chongyuan
C
Mao
Zhengkuan
Z
Cao
Xu
X
D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D005786:Gene Expression Regulation; D006801:Humans; D020239:Receptor Cross-Talk; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D020218:Response Elements; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology
D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D012097:Repressor Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta