A negative coregulator for the human ER.
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.
Norris
John D
JD
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Fan
Daju
D
Sherk
Andrea
A
McDonnell
Donald P
DP
D000595:Amino Acid Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D016384:Consensus Sequence; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012313:RNA / Q000378:metabolism; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D014018:Tissue Distribution; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D013629:Tamoxifen; D004958:Estradiol; D012313:RNA