DNA binding properties of glucocorticosteroid receptors bound to the steroid antagonist RU-486.
RU-486 is an anti-fertility steroid which also has anti-glucocorticosteroid effects. RU-486 is shown to be a strong antagonist of the glucocorticosteroid-induced cytolytic response of the murine thymoma lines W7TB and T1M1b , and of the induction of mouse mammary tumor virus (MMTV) mRNA in T1M1b cells. The glucocorticosteroid receptor of W7 cells has high affinity for RU-486 (Kd = 3 X 10(-9) M) but the complex formed has low nuclear transfer capacity. Binding of RU-486, as compared with the glucocorticosteroid agonist triamcinolone acetonide, to mouse receptor results in a decreased affinity for DNA in general and a reduced specific recognition of a site in the promoter region of MMTV proviral DNA. The RU-486 complex formed with rat liver receptor exhibits the same behavior; in addition, it is shown that only a fraction of these complexes are activated by temperature and these form highly salt-sensitive interactions with DNA. These results indicate that the binding of RU-486 to glucocorticosteroid receptors mimics pharmacologically the properties of a class of receptor variants (nt-) which are non-functional and have reduced nuclear transfer and altered DNA binding capacity. These results substantiate the importance of DNA binding in receptor function.
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism; D004963:Estrenes / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D015735:Mifepristone; D012333:RNA, Messenger / Q000096:biosynthesis; D012367:RNA, Viral / Q000096:biosynthesis; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D013945:Thymoma / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D004279:DNA, Viral; D004963:Estrenes; D005938:Glucocorticoids; D012333:RNA, Messenger; D012367:RNA, Viral; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D015735:Mifepristone; D003907:Dexamethasone; D004247:DNA