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The steroid antagonist RU486 exerts different effects on the glucocorticoid and progesterone receptors.
Beck, C A; Estes, P A; Bona, B J; Muro-Cacho, C A; Nordeen, S K; Edwards, D P.
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  • Beck CA; Department of Pathology, University of Colorado Health Sciences Center, Denver 80262.
Endocrinology ; 133(2): 728-40, 1993 Aug.
Article em En | MEDLINE | ID: mdl-8344212
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.
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Base de dados: MEDLINE Assunto principal: Receptores de Glucocorticoides / Receptores de Progesterona / Mifepristona Limite: Animals / Humans Idioma: En Revista: Endocrinology Ano de publicação: 1993 Tipo de documento: Article
Buscar no Google
Base de dados: MEDLINE Assunto principal: Receptores de Glucocorticoides / Receptores de Progesterona / Mifepristona Limite: Animals / Humans Idioma: En Revista: Endocrinology Ano de publicação: 1993 Tipo de documento: Article