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Norris, JD, Fan, D, Sherk, A and McDonnell, DP (2002) A negative coregulator for the human ER. Mol. Endocrinol. 16:459-68


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.




Amino Acid Sequence; Binding Sites; Blotting, Northern; Consensus Sequence; Estradiol/pharmacology; Estrogen Antagonists/pharmacology; Estrogen Receptor alpha; Gene Expression; HeLa Cells; Humans; Molecular Sequence Data; Mutagenesis; RNA/metabolism; RNA-Binding Proteins/chemistry; RNA-Binding Proteins/genetics; RNA-Binding Proteins/physiology; Receptors, Estrogen/drug effects; Receptors, Estrogen/physiology; Repressor Proteins/chemistry; Repressor Proteins/genetics; Repressor Proteins/physiology; Tamoxifen/pharmacology; Tissue Distribution; Transcription, Genetic/drug effects; Transfection; Tumor Cells, Cultured