DNA-BINDING PROPERTIES OF GLUCOCORTICOSTEROID RECEPTORS BOUND TO THE STEROID ANTAGONIST RU-486

KU-486 [17.beta.-hydroxy-11.beta.-(4-methylaminophenyl)-17.alpha.-(1-propynyl)estra-4,9-dien-3 one] is an anti-fertility steroid which also has anti-glucocorticosteroid effects. RU-486 is 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 .times. 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. Only a fraction of these complexes are activated by temperature and these form highly salt-sensitive interactions with DNA. 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. The importance of DNA binding in receptor function is substantiated.