INITIAL INTRACELLULAR EVENTS OF STEROID HORMONE ACTION

类固醇激素作用的初始细胞内事件

• 批准号: 5202048
• 负责人: S S SIMONS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5202048
• 关键词: DNA binding protein; biological signal transduction; corticosteroid receptors; gene induction /repression; genetic regulation; genetic regulatory element; genetic transcription; glucocorticoids; hormone regulation /control mechanism; intracellular transport; microtubules; reporter genes; steroid hormone; steroid hormone receptor; transcription factor; tyrosine transaminase

The objective of this project is to define the initial, intracellular events of glucocorticoid hormone action and steroid hormone action in general. Such studies are of particular current relevance since steroid hormone receptors are arguably the best understood regulators of eukaryotic gene transcription. The first step of steroid binding to the intracellular receptor is followed by activation of the receptor-steroid complex to a DNA/nuclear-binding species that then associates with those nuclear acceptor sites involved in the regulation of transcription of selected genes in specific cells. We have concentrated on the nuclear localization of glucocorticoid receptors and how these nuclear receptors influence gene transcription. Glucocorticoid receptors are predominantly cytoplasmic in the absence of steroid and several lines of evidence suggest that microtubules may be intimately involved in the relocalization of steroid-bound glucocorticoid receptors from the cytoplasm to the nucleus. However, this hypothesis is now discredited by our finding that microtubule disruption with micromolar concentrations of colchicine had no effect on nuclear translocation as assayed by the induction of a transiently transfected reporter gene by endogenous receptors. The mechanism of how the nuclear receptor-steroid complexes regulate gene transcription is becoming increasingly complicated with the discovery of new DNA elements and trans-acting factors. We had previously reported that glucocorticoid induction of the tyrosine aminotransferase (TAT) gene involves a novel cis-acting element, called a glucocorticoid modulatory element (GME). We now find that two apparently novel proteins of 88 and 67 kDa bind to this GME in a manner that correlates with the expression of GME activity. Another new, cis-acting element of the TAT gene has now been defined that can block the effects of the GME. These new elements and binding proteins offer additional mechanisms for modifying glucocorticoid regulated gene expression. Collectively, our findings contribute to our long term goal of defining the action of steroid hormones at a molecular level and of understanding their role in human physiology.

该项目的目标是定义初始的细胞内 糖皮质激素作用和类固醇激素作用事件 一般的。 此类研究具有特别的当前相关性，因为类固醇 激素受体可以说是最了解的调节因子 真核基因转录。 类固醇结合的第一步 细胞内受体随后是受体类固醇的激活 与 DNA/核结合物质形成复合物，然后与这些物质结合 参与转录调控的核受体位点 特定细胞中的选定基因。 我们把注意力集中在核问题上 糖皮质激素受体的定位以及这些核受体如何 影响基因转录。 糖皮质激素受体主要是 在没有类固醇和几条证据的情况下是细胞质的 表明微管可能密切参与 类固醇结合的糖皮质激素受体从 细胞质到细胞核。 然而，这一假设现在已不再可信 通过我们的发现，微摩尔浓度的微管破坏 经测定，秋水仙碱对核转位没有影响 内源性瞬时转染报告基因的诱导 受体。 核受体-类固醇复合物的机制 基因转录调控变得越来越复杂 新的 DNA 元件和反式作用因子的发现。 我们有 先前报道糖皮质激素诱导酪氨酸 转氨酶（TAT）基因涉及一种新的顺式作用元件，称为 糖皮质激素调节元件（GME）。 我们现在发现两个 88 和 67 kDa 的显然新颖的蛋白质以某种方式与该 GME 结合 与 GME 活性的表达相关。 另一个新的， TAT 基因的顺式作用元件现已被定义为可以阻断 GME 的影响。 这些新元素和结合蛋白提供 修饰糖皮质激素调节基因的其他机制 表达。 总的来说，我们的发现有助于我们的长期目标 在分子水平上定义类固醇激素的作用 了解它们在人体生理学中的作用。