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The Corepressors Silencing Mediator of Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Are Involved in Agonist- and Antagonist-Regulated Transcription by Androgen Receptor

 Ho-Geun Yoon  ;  Jiemin Wong 
 MOLECULAR ENDOCRINOLOGY , Vol.20(5) : 1048-1060, 2006 
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Acetylation ; Androgen Receptor Antagonists ; Androgens ; Cell Line, Tumor ; DNA-Binding Proteins/antagonists & inhibitors ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism* ; Enhancer Elements, Genetic ; Gene Expression Regulation* ; Histones/metabolism ; Homeodomain Proteins/genetics ; Humans ; Male ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism* ; Nuclear Receptor Co-Repressor 1 ; Nuclear Receptor Co-Repressor 2 ; Prostate-Specific Antigen/genetics ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism* ; RNA Interference ; RNA, Small Interfering/genetics ; RNA, Small Interfering/pharmacology ; Receptors, Androgen/metabolism* ; Repressor Proteins/antagonists & inhibitors ; Repressor Proteins/genetics ; Repressor Proteins/metabolism* ; Transcription Factors/genetics ; Transcription, Genetic ; beta 2-Microglobulin/genetics
We have investigated the role of corepressors SMRT (silencing mediator of retinoid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) in transcriptional regulation by androgen receptor (AR) in the LNCaP prostate cancer cell line. Using specific small interference RNAs to knock down SMRT and/or N-CoR in LNCaP cells, we found that SMRT and N-CoR not only mediate antagonist-dependent inhibition of AR activation but also have a widespread role in suppressing agonist-dependent activation of several AR target genes we have tested, including PSA (prostate-specific antigen), TSC22 (TSC22 domain family member 1), NKX3–1 (NK3 transcription factor locus 1), and B2M(β-2-microglobulin). By sequencing analysis followed by analysis of physical association by chromatin immunoprecipitation assay, we mapped the putative androgen response elements in the NKX3–1 and B2M. Consistent with a role in both antagonist- and agonist-regulated transcription by AR, chromatin immunoprecipitation analysis revealed that both SMRT and N-CoR were recruited by AR to these genes in the presence of either flutamide or R1881. Knocking down SMRT and N-CoR enhanced the recruitment of the coactivators steroid receptor coactivator 1 and p300 by agonist-bound AR and led to increased hyperacetylation of histone H3 and H4, suggesting that the corepressors actively compete with coactivators for binding to agonist-bound AR. Taken together, our data indicate that SMRT and N-CoR corepressors are involved in transcriptional regulation by both agonist- and antagonist-bound AR and regulate the magnitude of hormone response, at least in part, by competing with coactivators.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
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