Expression of G1 cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors in androgen-induced prostate proliferation in castrated rats.

Abstract

Androgen induces prostate cell proliferation in the castrated rat. We hypothesized that G1 cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors mediate this cellular response to mitogenic signals. In this study, induction of cyclins D1, D2, D3, E, and cdks 2, 4, and 6 expression was observed at various time points during testosterone replacement in the ventral prostate of castrated rats. The induction followed prostate epithelium proliferation, which peaked at 48 h and decreased at 120 h during the treatment. The study of cyclin/cdk complex formation revealed that more cyclin D1/cdk4 and cyclin D1/cdk6 complexes were formed at 48 h than at 120 h of treatment, but cyclin D1/cdk2 complexes remained the same. Furthermore, both hyperphosphorylated and hypophosphorylated forms of Rb were detected at 48 h, but only the hypophosphorylated form was detected at 120 h of treatment. p21Cip1, which was very abundant in the ventral prostate of castrated and intact rats, was not detected when the prostate started proliferation and increased gradually as proliferation decreased during the androgen treatment. Meanwhile, p27Kip1 dramatically increased after androgen treatment, and the induction levels were less at the peak of prostate proliferation and higher when proliferation was low. The results presented here suggest that expression of G1 cyclins and their related kinases and kinase inhibitors are well regulated after androgen replacement in the ventral prostate of castrated rats. The cooperation between these cell cycle regulators leads to a well-controlled prostate regeneration.