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Abstract

A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor (PDF) (HTML) 
Zhang,Xun; Jeyakumar,M.; Petukhov,Sergei; Bagchi,Milan K.
Molecular Endocrinology 12(4): 513-524
Publication date: 1998

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Synthetic steroid hormone antagonists are clinically importantcompounds that regulate physiological responses to steroid hormones.The antagonists bind to the hormone receptors, which are ligand-inducibletranscription factors, and modulate their gene-regulatory activities.In most instances, a steroid receptor, such as progesteronereceptor (PR) or estrogen receptor (ER), is transcriptionallyinactive when complexed with an antagonist and competitivelyinhibits transactivation of a target steroid-responsive geneby the cognate hormone-occupied receptor. In certain cellularand promoter contexts, however, antagonist-occupied PR or ERacquires paradoxical agonist-like activity. The cellular mechanismsthat determine the switch from the negative to the positivemode of transcriptional regulation by an antagonist-bound steroidreceptor are unknown. We now provide strong evidence supportingthe existence of a cellular inhibitory cofactor that interactswith the B form of human PR (PR-B) complexed with the antiprogestinRU486 to maintain it in a transcriptionally inactive state.In the presence of unliganded thyroid hormone receptor (TR)or ER complexed with the antiestrogen 4-hydroxytamoxifen, whichpresumably sequesters a limiting pool of the inhibitory cofactor,RU486-PR-B functions as a transcriptional activator of a progesterone-responsivegene even in the absence of hormone agonist. In contrast, hormone-occupiedTR or ER fails to induce transactivation by RU486-PR-B. Recentstudies revealed that a transcriptional corepressor, NCoR (nuclearreceptor corepressor), interacts with unliganded TR but notwith liganded TR. Interestingly, coexpression of NCoR efficientlysuppresses the partial agonistic activity of antagonist-occupiedPR-B but fails to affect transactivation by agonist-bound PR-B.We further demonstrate that RU486-PR-B interacts physicallywith NCoR in vitro. These novel observations suggest that theinhibitory cofactor that associates with RU486-PR-B and repressesits transcriptional activity is either identical or structurallyrelated to the corepressor NCoR. We propose that cellular mechanismsthat determine the switch from the antagonistic to the agonisticactivity of RU486-PR-B involve removal of the corepressor fromthe antagonist-bound receptor so that it can effect partialbut significant gene activation.

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