title: New antiprogestins with partial agonist activity: potential selective progesterone receptor modulators (SPRMs) and probes for receptor- and coregulator-induced changes in progesterone receptor induction properties.
abstract: A pharmacologically relevant property of steroid hormone-regulated gene induction is the partial agonist activity of antisteroid complexes. We now report that dexamethasone-mesylate (Dex-Mes) and dexamethasone-oxetanone (Dex-Ox), each a derivative of the glucocorticoid-selective steroid dexamethasone (Dex), are two new antiprogestins with significant amounts of agonist activity with both the A and B isoforms of progesterone receptor (PR), for different progesterone-responsive elements, and in several cell lines. These compounds continue to display activity under conditions where another partial antiprogestin (RTI-020) is inactive. These new antiprogestins were used to determine whether the partial agonist activity of PR complexes can be modified by changing concentrations of receptor or coregulator, as we have recently demonstrated for glucocorticoid receptors (GRs). Because GR and coregulator concentrations simultaneously altered the position of the physiologically relevant dose-response curve, and associated EC(50), of GR-agonist complexes, we also examined this phenomenon with PR. We find that elevated PR or transcriptional intermediary factor 2 (TIF2) concentrations increase the partial agonist activity of Dex-Mes and Dex-Ox, and the EC(50) of agonists, independently of changes in total gene transactivation. Furthermore, the corepressors SMRT (silencing mediator for retinoid and thyroid receptors) and NCoR (nuclear receptor corepressor) each suppresses gene induction but NCoR acts opposite to SMRT and, like the coactivator TIF2, reduces the EC(50) and increases the partial agonist activity of antiprogestins. These comparable responses of GR and PR suggest that variations in receptor and coregulator concentrations may be a general mechanism for altering the induction properties of other steroid receptors. Finally, the magnitude of coregulator effects on PR induction properties are often not identical for agonists and the new antagonists, suggesting subtle mechanistic differences. These properties of Dex-Mes and Dex-Ox, plus the sensitivity of their activity to cellular differences in PR and coregulator concentrations, make these steroids potential new SPRMs (selective progesterone receptor modulators) that should prove useful as probes of PR induction properties.
authors.affiliation: Steroid Hormones Section, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0805, USA.
authors.forename: G
authors.initials: G
authors.lastname: Giannoukos
authors.forename: D
authors.initials: D
authors.lastname: Szapary
authors.forename: C L
authors.initials: CL
authors.lastname: Smith
authors.forename: J E
authors.initials: JE
authors.lastname: Meeker
authors.forename: S S
authors.initials: SS
authors.lastname: Simons
mesh_terms: D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000494:pharmacology; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids; D006727:Hormone Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000494:pharmacology; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D051958:Nuclear Receptor Coactivator 2; D010957:Plasmids / Q000235:genetics; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors*; D011397:Promegestone / Q000378:metabolism; D011980:Receptors, Progesterone / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000494:pharmacology; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006727:Hormone Antagonists; C498001:NCOA2 protein, human; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D051958:Nuclear Receptor Coactivator 2; D011372:Progestins; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D014157:Transcription Factors; C041706:dexamethasone oxetanone; D011374:Progesterone; D003907:Dexamethasone; D011397:Promegestone; C031710:dexamethasone 21-methanesulfonate