A repressive role for prohibitin in estrogen signaling.
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.
Mesh Terms:
Animals, Blotting, Western, Cell Line, Cell Line, Tumor, Chromatin Immunoprecipitation, Dimerization, Estrogen Receptor alpha, Estrogens, Female, Humans, Immunoprecipitation, Mice, Mice, Knockout, Models, Genetic, Promoter Regions, Genetic, Protein Binding, RNA Interference, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription, Genetic, Tumor Suppressor Proteins
Animals, Blotting, Western, Cell Line, Cell Line, Tumor, Chromatin Immunoprecipitation, Dimerization, Estrogen Receptor alpha, Estrogens, Female, Humans, Immunoprecipitation, Mice, Mice, Knockout, Models, Genetic, Promoter Regions, Genetic, Protein Binding, RNA Interference, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription, Genetic, Tumor Suppressor Proteins
Mol. Endocrinol.
Date: Feb. 01, 2008
PubMed ID: 17932104
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