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: 3840490
• 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/3840490
• 关键词: corticosteroid receptors; enzyme induction /repression; gel mobility shift assay; genetic regulation; genetic regulatory element; genetic transcription; glucocorticoids; hormone regulation /control mechanism; intracellular; nucleic acid sequence; steroid hormone; 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. 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 binds to those nuclear acceptor sites involved in the regulation of transcription of specific genes. It has long been thought both that half saturation of the whole cell receptors by steroid should afford half of the maximal amount of biological response and that the various induction parameters for each agonist and partial antagonist should be invariant. In contrast, our studies of glucocorticoid induction of tyrosine aminotransferase (TAT) revealed that the concentration of a glucocorticoid agonist required for half maximal induction (EC50) and the amount of agonist activity produced by a partial antiglucocorticoid were not the same for all responsive genes within the same cell. Furthermore, both properties for TAT induction varied over a period of several weeks. This variation has now been reproduced in less than or equal to 40 hr simply by changing the cell density. We are not aware of any previous report of cell growth conditions affecting either the percent agonist activity of a partial antisteroid or the EC50 of a full agonist. These variations were found to require the presence of a 21 bp sequence of the TAT gene. We call this 21 bp sequence, which acts in concert with a trans-acting factor identified by gel shift experiments, a glucocorticoid modulatory element (GME). This GME, which is located at - 3654 to -3634 of the rat TAT gene, is an authentic transcriptional element to the extent that it conveyed its properties to heterologous genes and promoters. A model incorporating this new element is advanced which can explain, for the first time, the observed variations of TAT induction. Future studies of this model should provide useful information for understanding the control of steroid-regulated gene transcription and the control of gene transcription in general.

本项目的目标是定义初始的，细胞内的 糖皮质激素作用和类固醇激素作用的事件 将军 类固醇与细胞内受体结合的第一步 随后是受体-类固醇复合物的活化， 然后结合到那些核受体位点的DNA/核结合物质 参与调节特定基因的转录。 长期 被认为是整个细胞受体的半饱和度， 类固醇应提供最大生物反应量的一半， 每种激动剂和部分激动剂的各种诱导参数 对手应该是不变的。 相反，我们对糖皮质激素的研究 酪氨酸氨基转移酶（达特）的诱导表明， 糖皮质激素激动剂的浓度需要一半的最大 诱导（EC 50）和由部分诱导产生的激动剂活性的量。 抗糖皮质激素对于体内所有反应基因来说并不相同。 相同单元 此外，达特诱导的这两种性质在不同的时间段内变化。 几个星期的时间。 这种变异现在已经在更少的 通过简单地改变细胞密度， 我们不是 了解任何以前的报告，细胞生长条件影响， 部分抗类固醇药物的激动剂活性百分比或完整抗类固醇药物的EC 50 激动剂 发现这些变异需要存在21 bp的 达特基因的序列。 我们称之为21 bp的序列， 与凝胶迁移实验确定的反式作用因子一致， 糖皮质激素调节元件（GME）。 这个GME，位于- 3654至-3634，是一个真实的转录元件 在某种程度上，它将其特性传递给异源基因， 发起人。 提出了一种包含这种新元素的模型， 第一次解释了观察到的达特诱导的变化。 未来对该模型的研究将为以下方面提供有用的信息： 了解类固醇调节基因转录的控制和 基因转录的控制。