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Mol Endocrinol. 2008 Feb;22(2):344-60. Epub 2007 Oct 11.

A repressive role for prohibitin in estrogen signaling.

Author information

1
Department of Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Abstract

Nuclear receptor-mediated gene expression is regulated by corepressors and coactivators. In this study we demonstrate that prohibitin (PHB), a potential tumor suppressor, functions as a potent transcriptional corepressor for estrogen receptor alpha (ERalpha). Overexpression of PHB inhibits ERalpha transcriptional activity, whereas depletion of endogenous PHB increases the expression of ERalpha target genes in MCF-7 breast cancer cells. Chromatin immunoprecipitation experiments demonstrate that PHB is associated with the estrogen-regulated pS2 promoter in the absence of hormone and dissociates after estradiol treatment. We demonstrate that PHB interacts with the repressor of estrogen receptor activity (REA), a protein related to PHB, to form heteromers and enhance the protein stability of both corepressors. Interestingly, the corepressor activity of PHB is cross-squelched by the coexpression of REA (and vice versa), suggesting that PHB and REA repress transcription only when they are not paired. We further demonstrate that coiled-coil domains located in the middle of PHB and REA are responsible for their heteromerization, stabilization, and cross-squelching actions. Finally, ablation of PHB function in the mouse results in early embryonic lethality, whereas mice heterozygous for the PHB null allele exhibit a hyperproliferative mammary gland phenotype. Our results indicate that PHB functions as a transcriptional corepressor for ERalpha in vitro and in vivo, and that its heteromerization with REA acts as a novel mechanism to limit its corepressor activity.

PMID:
17932104
PMCID:
PMC2234581
DOI:
10.1210/me.2007-0400
[Indexed for MEDLINE]
Free PMC Article

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