REGULATION OF STEROID HORMONE RECEPTOR ACTIVITY

类固醇激素受体水平和 功能受控是这些研究的重点。 将使用模型系统，在其中我们可以检查受体 类固醇激素本身的调节，多肽激素的调节，以及 由一类可能直接干扰核的化合物 类固醇受体复合体的相互作用。第一个系统 利用大鼠雌激素和雄激素反应组织 (主要是子宫、前列腺腹侧和垂体前叶)至 探讨雌激素和雄激素受体周转的动态变化 受各自偏爱的类固醇激素的影响 他们自己。这些研究在现阶段的一个主要特点是 发展的关键是艰苦而系统地分析 所有细胞内受体种群的波动。一个Off- 这部作品的拍摄描述了一组离散的 特异结合的高亲和力微粒结合位点 类固醇激素和似乎掩盖微粒体的受体部位 经典的类固醇受体复合体，因此能够 调节这些复合体的核内水平。在下一个 在这些研究的阶段，我们将定义受体特异性， 探讨微生物体结合蛋白作为受体的功能 激起类固醇的基因组外作用，并使用 抗雌激素受体的单抗，探索其来源 和这些蛋白质的周转。特定区域内的本地化 细胞器和纯化的初步尝试也将是 承担了。第二个主要系统，多肽控制的受体 荷尔蒙，将继续由催乳素-乳房处理 腺体雌激素受体相互作用。我们将使用病毒感染 调查MMTV水平之间相关性的研究 乳腺组织中催乳素的表达及对催乳素的敏感性 雌激素受体活性的调节剂。我们将继续研究 催乳素调节这些受体的机制， 不同核结合亲和力的浓度 催乳素诱导的受体与直接雌激素诱导的受体在 可以产生分级反应的条件。我们将开始 寻找与受体调节有关的其他因素 组织。第三个系统涉及类固醇受体的调节。 在核水平上的复杂相互作用的代理人可能 直接与DNA相互作用改变受体与其结合 效应器位置。我们手头有一种天然产品，可以防止 乳腺肿瘤雌激素敏感群体的形成 调节受体活性，而不与受体直接相互作用 受体。这可能代表了一种新的受体活性形式。 监管。

Mechanisms by which steroid hormone receptor levels and functionality are controlled represent the focus of these studies. Model systems will be used in which we can examine receptor regulation by steroid hormones themselves, by peptide hormones, and by a class of compounds that may directly interfere with nuclear interactions of steroid-receptor complexes. The first system utilizes estrogen- and androgen-responsive tissues of the rat (primarily uterus, ventral prostate and anterior pituitary) to probe the dynamics of estrogen and androgen receptor turnover as influenced by the respective favored classes of steroid hormones themselves. A key feature of these studies at their present stage of development is the painstaking and systematic analysis of fluctuations in all populations of intracellular receptor. An off- shoot of this work has been the description of a discrete set of high affinity microsomal binding sites that are specific for steroid hormones and appear to mask microsomal acceptor sites for classical steroid-receptor complexes, thus being capable of regulating intranuclear levels of these complexes. In the next phase of these investigations, we will define acceptor specificity, explore the function of the microsomal binders as receptors for elicitation of extra-genomic actions of steroids, and, using monoclonal antibodies to the estrogen receptor, probe the origin and turnover of these proteins. Localization within specific organelles and initial attempts at purification will also be undertaken. The second major system, receptor control by peptide hormones, will continue to be addressed by the prolactin-mammary gland estrogen receptor interplay. We will use viral infection studies to investigate a correlation between levels of MMTV expression and sensitivity of mammary tissue to prolactin as a regulator of estrogen receptor activity. We will continue to study the mechanism by which prolactin regulates these receptors, concentration on differential nuclear binding affinities of prolactin-induced vs direct-estrogen-induced receptors, under conditions where graded responses can be engendered. We will begin to look for other factors involved in receptor regulation in this tissue. The third system involves modulation of steroid-receptor complex interactions at the nuclear level by agents which may interact directly with DNA to alter receptor binding to its effector sites. We have at hand a natural product that prevents formation of estrogen-responsive populations of mammary tumors by regulating receptor activity without direct interaction with the receptor. This may represent a novel form of receptor activity regulation.