STUDIES OF NORMAL AND NEOPLASTIC PROSTATE

雄激素在人类前列腺肿瘤中的可能作用强调了 需要研究靶器官作用中的分子因素， 雄激素，因为它可能产生新的见解适用于生物学的研究 人类前列腺病理学。 为此， 拟议的研究是双重的。 (1)为了研究 核磷蛋白和蛋白激酶（PKs），目的是定义 它们在大鼠腹侧前列腺中雄激素介导的基因作用中的作用。 (2)在正常人和前列腺肿瘤患者中检测这些参数 目的是揭露任何与此相关的潜在变化， 病理 非组蛋白（NHP）磷酸化的增加与 基因组激活暗示了核PKs的关键作用。 等 研究，利用雄激素控制的基因活性，在 前列腺，已经表明在某些活动的快速调制 核cAMP非依赖性PKs可能参与磷酸化 常染色质NHP、核基质NHP和雄激素受体。 因此，在本发明中， 由于这些PK在基因活性方面的可能重要性， 和生长，研究提出了描绘他们的分子调控， 前列腺 将针对cAMP非依赖性PK产生抗体 从细胞核（PK-N2）和细胞质（PK-C2）中纯化。 这些 抗体将用于检查（a）这两种PK是否是 相关，（B）它们的周转响应雄激素介导的基因组 活动，（c）参与其调节的因素。 基因（S） 将克隆前列腺细胞核PK-N2，以研究其分子生物学特性。 由雄激素控制。 由此获得的特异性探针将用于 检查mRNA水平的变化，以及HnRNA的稳定性/加工， 前列腺在雄激素作用方面。 实验也提出了建议 探讨磷酸化的生物学功能， 核基质和雄激素受体。 由于特定的PK反应是 良性增生（BPH）组织的染色质显著升高， 与正常人相比，计划进行研究， 这一观察的机制。 将进行实验， 表征NHP底物及其参与的PK BPH组织的染色质和核基质中的磷酸化。 一个 还建议将这些研究扩展到人前列腺癌。 希望这项研究的结果将有助于我们 了解前列腺肿瘤的生物学改变。

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.