Function of a membrane-localized nuclear receptor

长期目标是了解核激素受体(NHR)是如何被引导到血浆中的 膜对信号的反应以及它在非核信号转导系统中可能如何发挥作用。 而类固醇信号的经典观点认为，这些激素结合了细胞内的受体，这些受体起着 配体激活的转录因子，广泛的证据表明，类固醇也可以通过非 细胞表面的基因组机制。我们已经鉴定出一种线虫NHR，DPR-1，它可能通过 这种基于膜的信号系统提供了第一个用于解剖膜的遗传系统- 基于NHR的信令系统。在存在亲脂小分子(达尔信息素或 DPR-1从细胞质移动到质膜。多蒙引发了另一种选择， 发育停滞状态，达尔幼虫。DPR-1基因的缺失突变减弱 对Dauer信息素的反应性和加速退出Dauer状态，以及DPR-1的过表达 1会触发不适当的Dauer发育并禁止退出Dauer状态。Dauer监管机构 DPR-1在膜上的重新定位需要途径。拟议的研究将测试 假设DPR-1通过质膜信号转导系统调节DAER的形成。 目的1研究影响DPR-1对Dauer信息素反应重定位的参数， 分析DPR-1的基本功能，测试DPR-1的冗余伙伴，并评估它们之间的关系 在DPR-1和Dauer通路之间。目标2将确定以下所需的结构元素和组件 DPR-1信号转导与膜结合，检测其靶向于膜和膜的信号功能 细胞核，检查达尔幼虫中DPR-1膜坚韧形式的基础，并调查 DPR-1与其他蛋白质的物理相互作用。目标3将检查DPR-1是否对 Dauer信息素在异种细胞中的表达以及DPR-1与调控Dauer的NHR、DAF是否有亲缘关系。 12、在有利于涂抹剂的条件下与膜结合。AIM 4将启动RNAi筛选以 确定负责DPR-1重新定位的组件及其合作的基因。这个 阐明国家人权机构发挥作用的新途径可能会促进我们对许多 发育缺陷及荷尔蒙对正常人体生理和多种人体的影响 病理学。

The long-term goals are to understand how a nuclear hormone receptor (NHR)is directed to the plasma membrane in response to a signal and how it might function in a non-nuclear signal transduction system. While the classical view of steroid signaling holds that these hormones bind intracellular receptors that act as ligand-activated transcription factors, extensive evidence indicates that steroids can also act by a non- genomic mechanism at the cell surface. We have identified a C. elegans NHR, DPR-1, that may act through such a membrane-based signaling system, providing the first genetic system for dissecting a membrane- based NHR signaling system. In the presence of a small lipophilic molecule (dauer pheromone or "daumone") DPR-1 moves from the cytoplasm to the plasma membrane. Daumone triggers an alternative, developmental^ arrested state, the dauer larva. A deletion mutation of the dpr-1 gene attenuates responsiveness to dauer pheromone and accelerates exit from the dauer state, and overexpression of DPR- 1 triggers inappropriate dauer development and inhibits exit from the dauer state. The dauer regulatory pathway is required for relocalization of DPR-1 to the membrane. The proposed studies will test the hypothesis that DPR-1 regulates dauer formation through a plasma membrane signal transduction system. Aim 1 will investigate parameters that influence relocalization of DPR-1 in response to dauer pheromone, analyze the essential function of dpr-1, test for redundant partners of DPR-1, and assess the relationship between DPR-1 and the dauer pathway. Aim 2 will identify structural elements and components required for DPR-1 signaling and membrane association, test its signaling function when targeted to the membrane and nucleus, examine the basis for a membrane-tenacious form of DPR-1in dauer larvae, and investigate physical interactions between DPR-1 and other proteins. Aim 3 will examine whether DPR-1responds to dauer pheromone in heterologous cells and whether DPR-1 relatives and the dauer-regulating NHR, DAF- 12, associate with the membrane under dauer-favoring conditions. Aim 4 will initiate RNAi screens to identify components responsible for relocalization of DPR-1and genes with which it collaborates. The elucidation of novel pathways through which NHRs function may advance our understanding of many developmental defects and the hormonal influences on normal human physiology and a variety of human pathologies.