A repressive role for prohibitin in estrogen signaling

Mol Endocrinol. 2008 Feb;22(2):344-60. doi: 10.1210/me.2007-0400. Epub 2007 Oct 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Dimerization
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / pharmacology*
  • Female
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transcription, Genetic / drug effects
  • Trefoil Factor-1
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Estrogen Receptor alpha
  • Estrogens
  • Repressor Proteins
  • TFF1 protein, human
  • Trefoil Factor-1
  • Tumor Suppressor Proteins
  • prohibitin