Protein phosphorylation is a significant mechanism in the control of cellular functions, including genomic regulation and cell proliferation. Thus, investigations of protein kinases (PKs) in appropriate experimental models are of intense current interest. To this end, the overall goals of our studies, employing androgenic regulation of the prostate as an experimental model, have been two-fold: (1) to investigate certain nuclear PK reactions with the aim of defining their role in the rat ventral prostate; and (2) to apply the information gained from these studies to human normal and neoplastic prostate to uncover alterations that may be associated with prostate pathology. A possible role of androgens in human prostatic neoplasia underscores the need for investigating the molecular factors in target organ action of androgens. Casein kinase 2 (CK-2), a messenger-independent serine/threonine kinase, is a major multipotential PK involved in growth regulation and cell proliferation. In the prostate, its activity in the cell nucleus, where many of its substrates are localized, is profoundly influenced by androgens in a tissue specific manner. This appears to relate to androgenic modulation of association of the enzyme with subnuclear compartments, as an early event pertinent to its growth control function. We propose to test the hypothesis that CK-2 in prostatic cells, in response to stimulation by androgens and certain growth factors, becomes associated with the subnuclear compartments, such as euchromatin and nuclear matrix, involved in gene activity and cell proliferation. A second major goal of these studies is to identify the mechanisms involved in such stimulus-mediated translocation of CK-2 to the nucleus in prostatic cells. Multiple strategies are proposed to address these aims. Androgenic regulation of the transcription of CK-2 gene appears to be of a secondary nature. For further understanding of the nature of the transcriptional regulation of CK-2, we propose a sequence analysis of the 5'-flanking region of the CK-2 alpha subunit gene, which we have cloned. The sequence data will eventually allow us to identify the promoter and regulatory elements in this gene. With respect to studies on human prostate, we have documented that CK-2 activity is elevated in human prostatic carcinoma chromatin, possibly related to Gleason's grade. To explore this further, we propose to use pathologically well defined human prostate tissues to delineate the nature of nuclear association of CK-2 with chromatin and nuclear matrix, as well as its molecular expression in the prostatic carcinoma samples. The proposed studies on the nature of CK-2 regulation in the prostate in response to growth control and of the mechanisms underlying this regulation should yield important new information, not only on the role of this PK in growth control, but also on the mechanism of androgenic and growth factor regulation of the prostate, and thus may have implications in the pathobiology of the human prostatic neoplasia.
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