title: The steroid antagonist RU486 exerts different effects on the glucocorticoid and progesterone receptors.
abstract: To determine whether the steroid antagonist RU486 mediates its antiglucocorticoid and antiprogestin activities by the same or different receptor mechanisms, a direct comparison of RU486 interaction with glucocorticoid (GR) and progesterone (PR) receptors was made. The effects of RU486 on transformation of GR and PR 8-10S complexes in the intact cell and in vitro were analyzed by sucrose density gradient centrifugation, and the in vitro stability of receptor-heat shock protein-90 interactions was analyzed by coimmunoprecipitation. Compared to agonist, RU486 binding produced a reduction in the amount of GR converted from 8S to 4S and stabilized the GR-heat shock protein-90 complex. By contrast, PR-RU486 complexes were transformed both in vitro and in the intact cell to the same extent as receptor-agonist complexes. PR-RU486 complexes sedimented at 5-6S, whereas PR-R5020, GR-RU486, and GR-agonist complexes sedimented at 4S. The portion of GR that undergoes nuclear transformation when bound to RU486 was examined for binding to the glucocorticoid-progesterone response element of the mouse mammary tumor virus by an immunoprecipitation assay. The nuclear-transformed GR-RU486 complex bound the glucocorticoid-progesterone response element with the same affinity as the nuclear-transformed GR-triamcinolone acetonide complex. The electrophoretic mobilities of GR-RU486 complexes and GR-agonist complexes were the same, as determined by gel retardation assay. These results suggest that RU486 exerts its antiglucocorticoid activity at two levels of receptor action: prevention of complete GR transformation and alteration of a step subsequent to GR-DNA binding. As an antiprogestin, RU486 action is exerted predominantly at a post-DNA-binding step.
authors.affiliation: Department of Pathology, University of Colorado Health Sciences Center, Denver 80262.
authors.forename: C A
authors.initials: CA
authors.lastname: Beck
authors.forename: P A
authors.initials: PA
authors.lastname: Estes
authors.forename: B J
authors.initials: BJ
authors.lastname: Bona
authors.forename: C A
authors.initials: CA
authors.lastname: Muro-Cacho
authors.forename: S K
authors.initials: SK
authors.lastname: Nordeen
authors.forename: D P
authors.initials: DP
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002499:Centrifugation, Density Gradient; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015735:Mifepristone / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009994:Osmolar Concentration; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000378:metabolism; D014222:Triamcinolone Acetonide / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D006360:Heat-Shock Proteins; D006728:Hormones; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D015735:Mifepristone; D004247:DNA; D014222:Triamcinolone Acetonide