Androgen-driven prostate epithelial cell proliferation and differentiationin vivo involve the regulation of p27

Androgens control both growth and differentiation of the normal prostate gl and. However, the mechanisms by which androgens act upon the cell cycle mac hinery to regulate these two fundamental processes are largely unknown. The cyclin-dependent kinase (cdk) inhibitor p27 Is a negative cell cycle regul ator involved in differentiation-associated growth arrest. Here, we investi gate the role and regulation of p27 in the testosterone proprionate (TP)-st imulated regeneration of the ventral prostate (VP) of castrated rats. Conti nuous TP administration to castrated rats triggered epithelial cell prolife ration, which peaked at 72 h, and then declined despite further treatment. Castration-induced atrophy of the VP was associated with a significant incr ease in p27 expression as compared with the VP of intact animals. Twelve ho urs after the initiation of androgen treatment, total p27 levels as well as its fraction bound to cdk2, its main target, significantly dropped in the VP of castrated rats. Thereafter, concomitantly to the induction of epithel ial cell proliferation, the glandular morphology of VP was progressively re stored at 48-96 h of TP treatment. During this period of the regenerative p rocess, whereas both proliferating basal and secretory epithelial cells did not express p27, the protein was selectively up-regulated in the nonprolif erating secretory epithelial compartment This up-regulation of p27 expressi on was coincident with an increase in its association with, and presumably inhibition of, cdk2. At each time point of TP treatment, p27 abundance in the VP was inversely c orrelated with the level of its proteasome-dependent degradation activity m easured in vitro in VP lysates, whereas only slight changes in the amount o f p27 transcripts were detected. In addition, the antiandrogen flutamide bl ocked maximal TP-induced p27 degradation completely. Finally, the expressio n of skp2, the ubiquitin ligase that targets p27 for degradation, was seen to increase with androgen administration, preceding maximal proliferation a nd concomitantly to augmented p27 degradation activity. Taken together, our data indicate that androgens mediate both proliferation and differentiation signals in normal prostate epithelial cells in vivo, t hrough regulation of p27.