NRIP1 in vitamin A signaling pathways

维生素 A 信号通路中的 NRIP1

• 批准号: 6620340
• 负责人: Li-Na Wei
• 金额: $ 25.29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620340
• 关键词: DNA footprinting; animal genetic material tag; biological signal transduction; gel mobility shift assay; gene expression; gene induction /repression; genetic promoter element; immunoprecipitation; molecular biology; molecular cloning; nuclear receptors; nutrition related tag; protein protein interaction; protein sequence; protein structure; receptor binding; receptor expression; retinoids; surface plasmon resonance; yeast two hybrid system

Vitamin A (the retinoids) exerts a wide variety of effects on biological processes, and are commonly used for preventive and therapeutic purposes. Their action is mediated primarily by two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid receptors (RXRs), which regulate gene expression by recruiting coactivators in the presence of retinoic acid (RA) and corepressors in its absence. Nuclear Receptor Interacting Protein 1 (NRIP1), previously named RIP140, is a novel corepressor that represses gene expression in the presence of hormones. It is hypothesized that NRIP1 serves as a ligand-dependent, negative coregulator for hormone-elicited gene regulatory circuits to silence specific gene expression in the presence of hormones. Three aims are proposed to test this hypothesis by using the RAR/RXR system. The first aim is to vigorously examine the molecular basis of NRIP1 interaction with holo-RAR/RXR, which involves a novel C-terminal motif of NRIP1 (PRLTKTNPILYYMLQK) that diverts from a typical coactivator motif, LXXLL, or a corepressor motif, CoRNR box. The second aim is to compare NRIP 1 complex to a typical ligand-dependent coactivator complex, SRC-1, with regards to the efficiency of their interaction with receptors and their specific associate proteins. The third aim is to address the physiological relevance of RA- dependent corepressor activity of NRIP1 by a) testing the effects of NRIP1 on Oct-3/4 gene that is directly suppressed by RA through RAR/RXR binding to an RA response element (RARE) RAREoct, and b) comparing the effects of coactivator SRC-1 on RARbeta2 gene that is directly induced by RA through a typical DR5 type RARE. Studies proposed in the three aims will advance our understanding of the diversity of molecular mechanisms mediating the effects of vitamin A hormones. Additionally, we will test whether the current working model of hormone nuclear receptor- coregulator can be modified to accomodate complicated actions of hormones in different biological systems. Finally, it is our ultimate goal to determine if the unique property of NRIP1 bears a physiological relevance in terms of the specificity of vitamin A action on a particular gene promoter.

维生素A（类视网膜类似）对生物过程产生了多种影响，通常用于预防和治疗目的。 它们的作用主要是由两个核受体家族，视黄酸受体（RARS）和类视黄素受体（RXR）介导的，它们在缺乏视黄酸（RA）的情况下通过募集共激活剂和核糖核心在没有的情况下调节基因表达。 核受体相互作用蛋白1（NRIP1）先前称为RIP140，是一种新型的核压剂，在存在激素的情况下抑制基因表达。 假设NRIP1用作依赖的配体依赖性的，负激素的基因调节回路，可在存在激素的情况下沉默特异性基因表达。 提出了三个目的，以使用RAR/RXR系统检验该假设。 第一个目的是大力研究NRIP1与Holo-Rar/RXR相互作用的分子基础，该相互作用涉及NRIP1（PRLTKTNPilyyMlQK）的新型C末端基序，该基序从典型的共振因子序列，LXXLL，LXXLL或Corepressorpressor Motif，Cornr Box中转移。 第二个目的是将NRIP 1复合物与典型的配体依赖性共激活器复合物SRC-1与它们与受体及其特定相关蛋白相互作用的效率进行比较。第三个目的是通过a）通过a）测试NRIP1对OCT-3/4基因的影响来解决NRIP1的生理相关性。 在这三个目标中提出的研究将提高我们对介导维生素A激素作用的分子机制多样性的理解。 此外，我们将测试是否可以修改激素核受体基团结剂的当前工作模型，以适应不同生物系统中激素的复杂作用。 最后，我们的最终目标是确定NRIP1的独特特性在维生素A对特定基因启动子的作用方面是否具有生理意义。