Androgen-Driven Prostate Epithelial Cell Proliferation and Differentiation in Vivo Involve the Regulation of p27

Abstract

Androgens control both growth and differentiation of the normal prostate gland. However, the mechanisms by which androgens act upon the cell cycle machinery to regulate these two fundamental processes are largely unknown. The cyclin-dependent kinase (cdk) inhibitor p27 is a negative cell cycle regulator involved in differentiation-associated growth arrest. Here, we investigate the role and regulation of p27 in the testosterone proprionate (TP)-stimulated regeneration of the ventral prostate (VP) of castrated rats. Continuous TP administration to castrated rats triggered epithelial cell proliferation, which peaked at 72 h, and then declined despite further treatment. Castration-induced atrophy of the VP was associated with a significant increase in p27 expression as compared with the VP of intact animals. Twelve hours 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 epithelial cell proliferation, the glandular morphology of VP was progressively restored at 48-96 h of TP treatment. During this period of the regenerative process, whereas both proliferating basal and secretory epithelial cells did not express p27, the protein was selectively up-regulated in the nonproliferating secretory epithelial compartment. This up-regulation of p27 expression 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 correlated with the level of its proteasome-dependent degradation activity measured in vitro in VP lysates, whereas only slight changes in the amount of p27 transcripts were detected. In addition, the antiandrogen flutamide blocked maximal TP-induced p27 degradation completely. Finally, the expression of skp2, the ubiquitin ligase that targets p27 for degradation, was seen to increase with androgen administration, preceding maximal proliferation and 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, through regulation of p27.

Androgen Receptor Controls EGFR and ERBB2 Gene Expression at Different Levels in Prostate Cancer Cell Lines

“…Posttranscriptional control of EGFR and ERBB2 receptors might result from indirect androgenic regulation of the protein stability. This mechanism has been previously observed for the androgen-induced up-regulation of p27 protein levels, which results from the transcriptional repression of the E3 ubiquitin ligase Skp2 involved in p27 degradation (39,40). Another possibility lies in an androgenic regulation of translation.…”

Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer

“…It has previously been shown to be androgen regulated (Waltregny et al, 2001) and the expression being associated with a short biochemical recurrence following prostatectomy (Nguyen et al, 2011). However, to our knowledge, this is the first report showing elevated levels of SKP2 transcripts in CRPCs.…”

Age-induced apoptosis in the male genital tract of the mouse

“…This suggests that testosterone treatment could be effective in restoring some of the reproductive organs. In fact, supplementation with low doses of testosterone has some beneficial effects on the male rat, such as preventing the loss of body and bone mass (Waltregny et al 2001). Moreover, androgen supplementation in the old rat is partially able to restore sperm numbers in the epididymis (Vanderschueren et al 2000), suggesting that the male tract in the old animal is able to respond to exogenous stimulation.…”