MOLECULAR MECHANISMS OF GLUCOCORTICOID HORMONE ACTION

糖皮质激素和孕激素调节许多过程在正常 生理和疾病，包括怀孕、肺和乳房发育， 应激反应炎症和癌症这些受体 类固醇激素通过调节转录来控制这些过程， 目标基因。 我们的长期目标是了解这些监管 机制等 这些知识可以推动现有的 治疗方案和发展新的途径， 干预，特别是内分泌依赖性肿瘤， 炎症性疾病。 第一个目标的重点是耦合 类固醇反应机制与其他信号转导途径。 特异性细胞信号转导抑制的激活 途径可以显著影响类固醇受体介导的 转录调控 激素反应可能会增强， 抑制高达10倍。 我们建议确定TATA的区域 结合蛋白，其是蛋白质之间偶联的靶标 激酶A途径和糖皮质激素依赖性转录， 识别这种耦合的中介。 在某些情况下，类固醇 受体甚至可以在没有激素的情况下被激活。 额外 实验将调查的基础上的差异能力， 糖皮质激素和孕激素受体进行非依赖性 activation. 我们将检验这是一个函数的假设， 糖皮质激素的差异定位的结果， 孕酮受体 在第二个目标中，我们将重点关注 基因表达的差异控制机制， 糖皮质激素和孕酮受体。因为几种类固醇 受体具有相似的，如果不是相同的，DNA序列识别 性质，靶基因的差异调节如何的问题 是理解激素生物学的核心 行动上 提出了一个全面的方法来确定新的例子 并研究其机制， 靶启动子的差异反应性。 中心这些 研究是使用逆转录病毒为基础的陷阱系统，以确定 差异调节的启动子和染色体位置。

Glucocorticoids and progestins regulate numerous processes in normal physiology and disease including pregnancy, lung and breast development, stress response, inflammation, and cancer. The receptors for these steroid hormones control these processes by regulating transcription of target genes. Our long term goal is to understand these regulatory mechanisms. Such knowledge could drive the improvement of existing therapeutic regimens and the development of novel avenues for intervention, particularly in endocrine-dependent neoplasia and inflammatory disease. The focus of the first aim is the coupling of steroid response mechanisms with other signal transduction pathways. The activation of inhibition of specific cellular signal transduction pathways can dramatically influence steroid receptor-mediated transcriptional regulation. The hormone response may be potentiated or inhibited up to 10-fold. We propose to identify the region of the TATA biding protein that is the target for the coupling between the protein kinase A pathway and glucocorticoid-dependent transcription and to identify the mediators of this coupling. In some circumstances, steroid receptors may even be activated in the absence of hormone. Additional experiments will investigate the basis of the differential capacity of glucocorticoid and progesterone receptors to undergo hormone-independent activation. We will test the hypothesis that this is a functional consequence of differential localization of the glucocorticoid and progesterone receptors. In the second aim we will focus on the mechanisms that govern differential control of gene expression by glucocorticoid and progesterone receptors. Since several steroid receptors have similar, if not identical, DNA sequence recognition properties, the question of how differential regulation of target genes is accomplished is central to understanding the biology of hormone action. A comprehensive approach is proposed to identify new examples of differential induction and to investigate the mechanisms that govern differential responsiveness of target promoters. Central to these studies is the use of a retrovirus-based trap system to identify differentially regulated promoters and chromosomal locations.