This Article Full Text Full Text (PDF) All Versions of this Article: 22/2/344    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Google Scholar Articles by He, B. Articles by O’Malley, B. W. PubMed PubMed Citation Articles by He, B. Articles by O’Malley, B. W.

A Repressive Role for Prohibitin in Estrogen Signaling

Department of Molecular and Cellular Biology (B.H., Q.F., A.M., D.M.L., F.J.D., J.P.L., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; and Department of Molecular and Integrative Physiology (B.S.K.), University of Illinois, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: Bert W. O’Malley, Department of Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: berto{at}bcm.tmc.edu.

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

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR

Coregulators:   REA  |  AIB1

Ligands:   17β-Estradiol  |  R5020

This article has been cited by other articles:

				J. A. Ross, Z. S. Nagy, and R. A. Kirken The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells J. Biol. Chem., February 22, 2008; 283(8): 4699 - 4713. [Abstract] [Full Text] [PDF]