PROSTATIC ANDROGEN RECEPTORS--FORM AND FUNCTION

这些研究旨在检验前列腺癌的意义。 雄激素受体物种的组织，由于在 它们对雄激素配体的亲和力，可能起到调节 雄激素敏感细胞的反应性。为了追求我们的观察 这种受体的两种细胞质形式确实共存，我们建议 定义这些形式的各种物理化学性质，以及任何 其他可能发生的情况，特别是核和热转化 细胞质部分。重点将放在以下几个方面： 与雄激素的相互作用，以及对A 已发现并将被提纯的细胞质因子 进一步表征的。不同受体形式的相对水平 将在各种实验诱导的变化下进行评估 内源性激素环境，包括阉割-替代，衰老，和 服用各种类固醇激素和催乳素。我们 将利用分离细胞质受体形式的能力，通过 硫酸铵分级实验中的动力学 核摄取和受体核滞留的机制将是 探索过了。对特定蛋白质合成的模式诱导 雄激素将作为亲属的函数进行调查 由受体决定的细胞反应性；这些分析是一种 初步观察的结果表明一个潜在的重要 相关性。虽然不在此初始阶段的范围内， 项目中，这些研究对于定义一个 功能性雄激素受体浓度与雄激素水平的关系 前列腺癌对内分泌治疗反应性的预测 肯定将构成这项工作的下一个主要阶段。

These studies are designed to examine the significance within prostatic tissue of androgen receptor species which, by virtue of differences in their avidity for androgenic ligands, may function as regulators of the responsiveness of androgen-sensitive cells. In pursuit of our observation that two such cytoplasmic forms of this receptor do co-exist, we propose to define various physicochemical properties of these forms, as well as any others which may occur, including especially nuclear and heat-transformed cytoplasmic moieties. The emphasis will be on comparative aspects of interaction with androgens, and susceptibility to interconversion by a cytoplasmic factor which has been discovered and which will be purified and characterized further. The relative levels of the different receptor forms will be assessed under a variety of experimentally-induced changes in endogenous hormonal milieu, including castration-replacement, aging, and administration of assorted types of steroid hormones and prolactin. We will exploit the ability to separate the cytoplasmic receptor forms by ammonium sulfate fractionation in experiments wherein the dynamics of nuclear uptake and mechanisms of nuclear retention of receptor will be explored. Patterned induction of specific protein synthesis in response to androgen will be investigated as a function of the relative receptor-dictated responsiveness of the cells; these analyses are an outgrowth of preliminary observations which suggest a potentially important correlation. While not within the scope of this initial stage of the project, the implications of these studies with respect to defining a relationship between functional androgen receptor concentration and prediction of responsiveness of human prostatic cancer to endocrine therapy will certainly constitute the next major phase of this work.