Agonist-dependent repression mediated by mutant estrogen receptor alpha that lacks the activation function 2 core domain.
Nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) form heterogeneous complexes with various histone deacetylases (HDACs). In this report, we found that ER alpha-Delta AF2, a mutant estrogen receptor alpha (ER alpha) deleted for the C-terminal activation function 2 (AF2) core domain, directs estradiol (E(2))-dependent repression and impairs E(2)-induced transactivation by wild type ER alpha. This repression required coexpressed BRG1 in SW-13 cells that lack BRG1, the ATPase constituent of the chromatin-remodeling SWI.SNF complex, and was abolished by HDAC inhibitor trichostatin A. We further demonstrated that ER alpha-Delta AF2 constitutively associates with SMRT but binds DNA in an E(2)-dependent manner in vivo. These results suggest that ER alpha-Delta AF2 and similar mutant receptors recently found associated with certain tumors may actively perturb the normal E(2) signaling via SWI/SNF, N-CoR/SMRT, and HDAC.
Jung
D J
DJ
Center for Ligand and Transcription, Pohang University of Science and Technology, Pohang 790-784, Korea.
Lee
S K
SK
Lee
J W
JW
D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D017353:Gene Deletion; D020868:Gene Silencing / Q000502:physiology*; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured; D000099186:Histone Deacetylase 3
D004247:DNA; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D004958:Estradiol; D047628:Estrogen Receptor alpha; D006655:Histone Deacetylases; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; C084108:SMARCA4 protein, human