DNA binding properties of glucocorticosteroid receptors bound to the steroid antagonist RU-486.

Abstract

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.