Intracellular inactivation, reactivation and dynamic status of prostate androgen receptors

The dynamic status of the androgen receptor in prostate cells was studied by incubation of rat ventral prostate with radioactive 17beta-hydroxy-5alpha-androstan-3-one (5alpha-dihydrotestosterone) in the presence and absence of respiratory poisons and inhibitors of protein and RNA synthesis and also by isotope chasing of the radioactive androgen-receptor complexes. The androgen receptor in the prostate appears to go through a dynamic process of recycling between the cytoplasm and the nucleus as well as an inactivation process. The radioactive androgen-receptor complex, however, is maintained at a constant level for at least 2h during incubation at 37 degrees C, even in the absence of new protein synthesis, suggesting that early androgen actions may not require a depletion of a major portion of cellular receptor. In the presence of 2,4-dinitrophenol, the androgen receptor is rapidly deactivated (half life, 2min). The inactive receptor can be reactivated efficiently by an energy-dependent process, even in the absence of protein synthesis. Receptor binding of androgen and nuclear chromatin binding of the androgen-receptor complex are fast processes; half-maximum binding can be achieved within 1 and 10min respectively. On the contrary, the overall process of the release of the receptor complex from nuclear chromatin and its reappearance in the cytosol fraction has a long half life of about 70min. This slow process may reflect the involvement of the steroid-receptor complex in a time-consuming mechanism that is essential for hormone responses. Actinomycin D can increase the nuclear receptor level by 50% or more. This increase is not due to a decrease in the rate of receptor release from nuclei or to inhibition of DNA degradation by the antibiotic.