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A negative coregulator for the human ER.

John D Norris·Daju Fan·Andrea Sherk·Donald P McDonnell
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Abstract

ERalpha is a ligand-activated transcription factor and a key regulator of the processes involved in cellular proliferation and differentiation. In addition, aberrant ERalpha activity is linked to several pathological conditions including breast cancer. A complex network of coregulatory proteins is largely believed to determine the transcriptional activity of ERalpha. We report here the isolation of a protein, denoted RTA for repressor of tamoxifen transcriptional activity, which contains an RNA recognition motif and interacts with the receptor N-terminal activation domain. RTA interacts with RNA in vitro, and its overexpression inhibits the partial agonist activity manifest by the antiestrogen tamoxifen while minimally affecting E2-activated transcription. Mutation of the RNA recognition motif alters RNA binding specificity and results in a dominant negative form of RTA that leads to derepression of ERalpha transcriptional activity, allowing all classes of antiestrogens to manifest partial agonist activity and enhancing agonist efficacy. These findings suggest a role for RNA binding proteins as coregulatory factors of the nuclear receptor family and reveal a novel mechanism by which antiestrogens can manifest agonist activities in some tissues.

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Amino Acid SequenceBinding SitesBlotting, NorthernConsensus SequenceEstradiolEstrogen AntagonistsEstrogen Receptor alphaGene ExpressionHeLa CellsHumansMolecular Sequence DataMutagenesisRNARNA Splicing FactorsRNA-Binding ProteinsReceptors, EstrogenRepressor ProteinsTamoxifenTissue DistributionTranscription, GeneticTransfectionTumor Cells, CulturedJournal ArticleResearch Support, U.S. Gov't, P.H.S.

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John D Norris, Daju Fan, Andrea Sherk, Donald P McDonnell. 2002. A negative coregulator for the human ER.. https://doi.org/10.1210/mend.16.3.0787

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