RU486-induced glucocorticoid receptor agonism is controlled by the receptor N terminus and by corepressor binding.
Glucocorticoid-induced gene transcription has been shown to be mediated by coactivators bound to the glucocorticoid receptor (GR). The glucocorticoid antagonist RU486 interferes with the steroid-mediated activation and can also exhibit partial agonist activity, a response in which corepressors have been implicated. Here we have shown that deletion of the N ... terminus of GR totally abolishes the agonist activity of RU486. Furthermore, we have demonstrated that corepressors bind directly to the RU486-bound GR as determined by glutathione S-transferase pull-down, mammalian two-hybrid assay, and coimmunoprecipitation. Fine mapping of the interaction regions within GR and the corepressor NCoR reveals a complex interaction profile that involves a number of domains in each protein. Notably, the N and the C termini of GR are both involved in corepressor binding. Thus, the N terminus of GR is a major determinant for RU486-dependent NCoR interaction as well as for RU486-mediated agonist activity.
Mesh Terms:
Cells, Cultured, Dexamethasone, Glutathione Transferase, Hormone Antagonists, Humans, Mifepristone, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Protein Binding, Protein Conformation, Receptors, Glucocorticoid, Repressor Proteins, Structure-Activity Relationship, Transfection
Cells, Cultured, Dexamethasone, Glutathione Transferase, Hormone Antagonists, Humans, Mifepristone, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Protein Binding, Protein Conformation, Receptors, Glucocorticoid, Repressor Proteins, Structure-Activity Relationship, Transfection
J. Biol. Chem.
Date: Jul. 19, 2002
PubMed ID: 12011091
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