Significance of the casein kinase system in cell growth and proliferation with emphasis on studies of the androgenic regulation of the prostate.

Protein phosphorylation is a significant mechanism in many cellular functions, including genomic regulation and control of cell proliferation. Thus, investigations of protein kinases (PKs) in appropriate experimental models are of intense current interest. Employing androgenic regulation of the rat ventral prostate (RVP) as an experimental model, we have investigated certain nuclear PK reactions with the aim of defining their role in androgen-mediated genomic regulation in the prostate and their implications for human prostate pathobiology. The author's laboratory identified androgen-sensitive PKs in the prostatic cell nucleus that might be involved in regulation of the gland. These PKs are analogous to casein kinase 1 (CK-1) and casein kinase 2 (CK-2), which are important multipotential enzymes in growth regulation and cell proliferation. Because CK-2 demonstrated a greater androgen sensitivity, we investigated the mechanism of its regulation at the level of transcription in the RVP, finding that androgens exert a substantial tissue-specific effect on its expression. However, regulation of CK-2 gene transcription does not appear to be an early event in androgen action, an observation that did not accord with our previous documentation of an early androgenic modulation of nuclear CKs in the prostate. Studies to uncover alternative mechanisms of regulation of CK-2 yielded a potentially important observation that androgenic regulation involves changes in the association of the enzyme with subnuclear compartments as an early event in its growth control function. Additionally, chromatin preparations from human benign prostatic hyperplasia (BPH) demonstrate a large enhancement in intrinsic CK-2 activity compared with normal tissue. An increase also is observed in specimens of prostatic carcinoma, although the change is less substantial than that in BPH. There appears to be a correlation between the localization of CK-2 in sections of prostatic carcinoma and the Gleason grade, a measure of the degree of differentiation. Further investigations of the cellular as well as the molecular mechanisms of CK-2 regulation in the prostate as an experimental model of the response to influences on growth may yield new insight into the function of this PK.