NORMAL AND NEOPLASTIC PROSTATE

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A possible role of androgens in human prostate neoplasia underscores the need for investigating the molecular factors in target organ action of androgens as it may yield new insights applicable to studies of the biology of human prostatic pathology. To this end, long term objectives of the proposed studies are two-fold. (1) To investigate the biochemistry of nuclear phosphoproteins and protein kinases (PKs) with the aim of defining their role in the androgen-mediated gene action in rat ventral prostate. (2) To examine these parameters in human normal and neoplastic prostate with the aim of uncovering any underlying alterations associated with such pathology. Increased non-histone protein (NHP) phosphorylation is associated with genomic activation implicating a crucial role of nuclear PKs. Such studies, making use of the androgenic control of gene activity in the prostate, have indicated rapid modulations in the activity of certain nuclear cAMP-independent PKs which may be involved in the phosphorylation of euchromatin NHP, nuclear matrix NHP, and androgen receptor. Thus, because of the possible importance of these PKs in regard to gene activity and growth, studies are proposed to delineate their molecular regulation in the prostate. Antibodies will be raised against a cAMP-independent PK purified from the nucleus (PK-N2) and from the cytosol (PK-C2). These antibodies will be utilized to examine (a) whether or not these two PKs are related, (b) their turnover in reponse to androgen-mediated genomic activity, and (c) factors involved in their regulation. Gene(s) for the nuclear PK-N2 from the prostate will be cloned to study its molecular control by androgen. Specific probes thus obtained will be utilized to examine changes in the level of mRNA, and stability/processing of HnRNA in the prostate in regard to androgen action. Experiments are also proposed to inquire into the biological function(s) of the phosphorylation of nuclear matrix and androgen receptor. Since a specific PK reaction was markedly elevated in chromatin from benign hyperplastic (BPH) tissue as compared with the normal, studies are planned to delineate the underlying mechanism of this observation. Experiments will be undertaken to characterize the NHP substrates and the PK involved in their phosphorylation in the chromatin and nuclear matrix of BPH tissue. An expansion of these studies to human prostatic carcinoma is also proposed. It is hoped that the results from this research will contribute to our understanding of the altered biology of prostatic neoplasia.