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Title: Estrogen receptor alpha represses transcription of early target genes via p300 and CtBP1.

Authors: Stossi, Fabio; Madak-Erdogan, Zeynep; Katzenellenbogen, Benita S

Published In Mol Cell Biol, (2009 Apr)

Abstract: The regulation of gene expression by nuclear receptors controls the phenotypic properties and diverse biologies of target cells. In breast cancer cells, estrogen receptor alpha (ERalpha) is a master regulator of transcriptional stimulation and repression, yet the mechanisms by which agonist-bound ERalpha elicits repression are poorly understood. We analyzed early estrogen-repressed genes and found that ERalpha is recruited to ERalpha binding sites of these genes, albeit more transiently and less efficiently than for estrogen-stimulated genes. Of multiple cofactors studied, only p300 was recruited to ERalpha binding sites of repressed genes, and its knockdown prevented estrogen-mediated gene repression. Because p300 is involved in transcription initiation, we tested whether ERalpha might be trying to stimulate transcription at repressed genes, with ultimately failure and a shift to a repressive program. We found that estrogen increases transcription in a rapid but transient manner at early estrogen-repressed genes but that this is followed by recruitment of the corepressor CtBP1, a p300-interacting partner that plays an essential role in the repressive process. Thus, at early estrogen-repressed genes, ERalpha initiates transient stimulation of transcription but fails to maintain the transcriptional process observed at estrogen-stimulated genes; rather, it uses p300 to recruit CtBP1-containing complexes, eliciting chromatin modifications that lead to transcriptional repression.

PubMed ID: 19188451 Exiting the NIEHS site

MeSH Terms: Acetylation/drug effects; Alcohol Oxidoreductases/metabolism*; Binding Sites; Cell Line, Tumor; DNA-Binding Proteins/metabolism*; E1A-Associated p300 Protein/metabolism*; Estradiol/pharmacology; Estrogen Receptor alpha/metabolism*; Gene Expression Regulation, Neoplastic/drug effects; Histones/metabolism; Humans; Lysine/metabolism; Models, Genetic; Protein Binding/drug effects; Protein Transport/drug effects; RNA, Small Interfering/metabolism; Repressor Proteins/metabolism*; Time Factors; Transcription, Genetic*/drug effects

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