INTRACELLULAR TRAFFIC OF STEROID-HORMONE RECEPTORS

The signal responsible for the nuclear localization of the progesteron e receptor has been characterized. It is a complex signal. The study o f the mechanism of this nuclear localization has revealed that the rec eptor continuously shuttles between the nucleus and the cytoplasm. The receptor diffuses into the cytoplasm and is constantly and actively t ransported back into the nucleus. The same phenomenon exists for estra diol and glucocorticoid receptors. The mechanism of entry of proteins into the nucleus is well documented, whereas the mechanism of their ou tward movement into the cytoplasm is not understood. We have grafted d ifferent nuclear localization signals (NLSs) onto beta-galactosidase a nd have studied the traffic of this protein using heterokaryons and mi croinjection experiments. We have demonstrated that the same NLSs are involved in both the inward and the outward movement of proteins throu gh the nuclear membrane. These results suggest that the nucleocytoplas mic shuttling may be a general phenomenon for nuclear proteins that co uld possibly undergo modifications in the cytoplasm and exert some bio logical activities there. These conclusions also imply that at least p art of the cellular machinery involved in the nuclear import of protei ns may function bidirectionally. Using these techniques, we have shown that two major antiprogestins, RU486 and ZK98299, act at the same dis tal level of hormone action.