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.
Schulz
Martin
M
Institute for Genetics, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 58-62, D-35392 Giessen, Germany.
Eggert
Martin
M
Baniahmad
Aria
A
Dostert
Anja
A
Heinzel
Thorsten
T
Renkawitz
Rainer
R
D002478:Cells, Cultured; D003907:Dexamethasone / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D011485:Protein Binding; D011487:Protein Conformation; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D012097:Repressor Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D006727:Hormone Antagonists; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D015735:Mifepristone; D003907:Dexamethasone; D005982:Glutathione Transferase