REGULATION OF STEROID HORMONE RECEPTOR ACTIVITY

类固醇激素受体活性的调节

• 批准号: 3230525
• 负责人: THOMAS G. MULDOON
• 金额: $ 13.58万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3230525
• 关键词: androgens; antineoplastics; bromocriptine; chemical binding; estradiol; estrogen receptors; hormone binding protein; hormone receptor; hormone regulation /control mechanism; laboratory mouse; laboratory rat; mammary gland; monoclonal antibody; mouse mammary tumor virus; ovariectomy; peptides; pituitary gland; progesterone; prolactin; protein biosynthesis; radiotracer; steroid hormone; testosterone; tritium; ultracentrifugation

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.

类固醇激素受体水平和 控制的功能性代表了这些研究的重点。 模型系统将被使用，我们可以检查受体 通过类固醇激素本身，通过肽激素， 可能直接干扰核反应的化合物 类固醇-受体复合物的相互作用。 第一系统 利用大鼠的雌激素和雄激素反应组织 （主要是子宫、腹侧前列腺和垂体前叶） 探索雌激素和雄激素受体转换的动力学， 受各自喜欢的类固醇激素类的影响， 自己 这些研究在现阶段的一个主要特点是 发展的关键是对以下问题进行细致而系统的分析： 所有细胞内受体群体的波动。 一个关闭- 这件作品的拍摄是对一组离散的 高亲和力微粒体结合位点，其特异于 类固醇激素，似乎掩盖了微粒体受体位点， 经典的类固醇-受体复合物，因此能够 调节这些复合物的核内水平。 未来 在这些研究的第一阶段，我们将定义受体特异性， 探索微粒体结合剂作为受体的功能， 引发类固醇的基因组外作用，以及，使用 雌激素受体的单克隆抗体， 和这些蛋白质的周转。 在特定的本地化 细胞器和纯化的初步尝试也将是 进行。 第二个主要系统，受体控制肽 激素，将继续由催乳素乳腺癌 腺雌激素受体相互作用 我们将使用病毒感染 研究MMTV水平与 乳腺组织对催乳素的表达和敏感性 雌激素受体活性的调节剂。 我们会继续研究 催乳素调节这些受体的机制， 不同核结合亲和力的浓度 催乳素诱导受体与直接雌激素诱导受体， 可以产生分级反应的条件。 我们将开始 寻找参与受体调节的其他因素， 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， 直接与DNA相互作用，改变受体与其 效应位点。 我们手头有一种天然产品， 乳腺肿瘤雌激素反应群体的形成 调节受体活性，而不直接与 受体的 这可能代表了一种新的受体活性形式 调控