title: Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486.
abstract: Selective receptor modulators, such as the antiprogestin RU486, are known to exhibit partial agonist activities in a cell-type-dependent manner. Employing an in vitro chromatin transcription system that recapitulates progesterone receptor (PR)-mediated transcription in vivo, we have investigated the molecular basis by which the antiprogestin RU486 regulates transcription in a cell-type-specific manner. We have compared the effects of RU486 on PR-dependent transcription in vitro using T47D and HeLa cell nuclear extracts. RU486 exhibits a differential ability to activate transcription within these two cell types. The differential effect on transcription correlates with different ratios of endogenous coactivators/corepressors in these cells. Unlike agonist-bound PR that interacts only with coactivators such as steroid receptor coactivator-1 (SRC-1), RU486-bound PR binds to both coactivator SRC-1 and corepressor silencing mediator for retinoid and thyroid hormone receptor (SMRT) in vitro. Both SRC-1 and SMRT have the capacity to modulate RU486-dependent activity. Moreover, a change in the relative levels of SRC-1 and SMRT contained in our chromatin transcription system modulates agonist/antagonist effects of RU486 on transcription by PR. Our data indicate that the ability of RU486 to activate transcription is modulated by the ratio of coactivators to corepressors and substantiate the important roles of coregulators in the regulation of steroid receptor mediated transactivation in response to selective receptor modulators.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
authors.forename: J Don
authors.initials: JD
authors.lastname: Chen
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D006067:Gonanes / Q000494:pharmacology; D006367:HeLa Cells; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D015735:Mifepristone / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D011980:Receptors, Progesterone / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
chemical_list: D006067:Gonanes; D006727:Hormone Antagonists; D008024:Ligands; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D015735:Mifepristone; C053238:onapristone