Autoregulation of the androgen receptor in the rat ventral prostate

The rat prostate is a hormonally regulated gland, which responds to the depravation of testosterone by regression. Similarly, brief exposure of male rats to estrogens during the neonatal period interrupts normal prostate development and alters cell differentiation with aging. Previous work with both castrated and neonatal estrogenized rats has demonstrated that the reduced growth and androgen sensitivity that are observed in the adult rat prostate are a function of reduced androgen receptor (AR) levels. In earlier studies, it was noted that this decrease in AR expression persisted through adulthood, despite normal mRNA levels in the prostate. To determine the mechanism of AR down regulation by castration and estrogen treatment, the present study examined the effect of these treatments on AR gene transcription, mRNA levels, protein translation and protein degradation in the rat prostate gland. Northern blot analysis revealed that AR mRNA levels are down-regulated by androgens in all prostate lobes, since their levels increase following castration. Quantitative RT-PCR revealed no difference in mRNA levels in response to estrogen exposure or castration in the rat ventral prostate, which indicates that estrogen down regulation of AR is mediated at the post-transcriptional level. Nuclear run-on experiments showed no alteration in AR gene transcription following estrogen treatment or two days after castration, when compared to the intact rats, indicating that post-transcriptional mechanisms are involved in AR mRNA auto-regulation. AR translation was assessed with an in vitro transcription-translation assay in the presence of prostatic lysates from oil and estrogen-exposed animals and no treatment affect was noted. AR degradation was also examined in an in vitro assay. Prostatic lysates from intact rats initiated AR degradation with a t1/2 of 2.31hr whereas proteins from castrate rats accelerated AR degradation to a t1/2 of 1.34hr (P < 0.001). Prostatic lysates from control day 10 prostates induced AR degradation with a t1/2 of 1.49hr while estrogenized prostates increased AR degradation to a t 1/2 of 1.11hr (P < 0.001). Proteosome inhibitors were able to reverse this AR degradation in all treatment groups demonstrating that hormonal regulation of AR degradation was mediated, at least in part, through the proteosome pathway.