A repressive role for prohibitin in estrogen signaling

Bin He, Qin Feng, Atish Mukherjee, David M. Lonard, Francesco J. DeMayo, Benita S. Katzenellenbogen, John P. Lydon, Bert W. O'Malley

Research output: Contribution to journalArticle

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 α (ERα). Overexpression of PHB inhibits ERα transcriptional activity, whereas depletion of endogenous PHB increases the expression of ERα 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 ERα in vitro and in vivo, and that its heteromerization with REA acts as a novel mechanism to limit its corepressor activity.

Original languageEnglish (US)
Pages (from-to)344-360
Number of pages17
JournalMolecular Endocrinology
Volume22
Issue number2
DOIs
StatePublished - Feb 1 2008

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

He, B., Feng, Q., Mukherjee, A., Lonard, D. M., DeMayo, F. J., Katzenellenbogen, B. S., Lydon, J. P., & O'Malley, B. W. (2008). A repressive role for prohibitin in estrogen signaling. Molecular Endocrinology, 22(2), 344-360. https://doi.org/10.1210/me.2007-0400