Identification of the functional domain of glucocorticoid receptor involved in RU486 antagonism |
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Authors: | Mi-Sook Lee Hoon-Sung Choi Seung-Hae Kwon Kyoji Morita Song Her |
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Affiliation: | aDivision of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon 200-701, Republic of Korea;bLaboratory of Neuropharmacology, Department of Nursing, Shikoku University School of Health Sciences, Ohjin, Tokushima 771-1192, Japan |
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Abstract: | Mifepristone, also known as RU486, is a potent glucocorticoid receptor (GR) antagonist that inhibits GR-mediated transactivation. As an alternative to existing antidepressants, RU486 has been shown to rapidly reverse psychotic depression, most likely by blocking GR. Although a number of studies have demonstrated RU486-induced GR antagonism, the precise mechanism of action still remains unclear. To identify the GR domain involved in RU486-induced suppression, GR transactivation and nuclear translocation were examined using cells transfected with human GR (hGR), Guyanese squirrel monkey GR (gsmGR), and GR chimeras into COS-1 cells. RU486 showed a much more potent suppressive effect in gsmGR-expressing cells versus hGR-expressing cells, without significant cortisol- or RU486-induced changes in nuclear translocation. A GR chimera containing the gsmGR AF1 domain (amino acids 132–428) showed a marked decrease in luciferase activity, suggesting that this domain plays an important role in RU486-induced GR antagonism. Furthermore, fluorescence recovery after photobleaching (FRAP) analysis indicated that, in the presence of RU486, gsmGR AF1 domain contributes to GR mobility in living COS-1 cells. Taken together, these results demonstrate, for the first time, that the antagonistic effects of RU486 on GR transactivation involve a specific GR domain. |
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Keywords: | Mifepristone (RU486) Glucocorticoid receptor Antagonism Transactivation Guyanese squirrel monkey |
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