NRIP1 in vitamin A signaling pathways

维生素A（类维生素A）对生物过程有多种作用，通常用于预防和治疗目的。它们的作用主要由两个核受体家族介导，即视黄酸受体（RARs）和类视黄酸受体（RXRs），它们通过在视黄酸（RA）存在时募集共激活因子和在视黄酸缺失时募集共抑制因子来调节基因表达。核受体相互作用蛋白1 (NRIP1)，以前被命名为RIP140，是一种在激素存在下抑制基因表达的新型辅抑制因子。据推测，NRIP1在激素诱导的基因调控回路中作为一种配体依赖的负调节因子，在激素存在时沉默特定基因的表达。通过RAR/RXR系统，提出了三个目标来验证这一假设。第一个目标是积极研究NRIP1与holo-RAR/RXR相互作用的分子基础，其中涉及NRIP1的一个新的c端基序（PRLTKTNPILYYMLQK），该基序与典型的辅激活基序LXXLL或辅抑制基序CoRNR盒不同。第二个目的是比较NRIP 1复合物与典型的配体依赖性共激活物复合物SRC-1，关于它们与受体及其特异性相关蛋白相互作用的效率。第三个目的是通过a)测试NRIP1通过RAR/RXR结合RA反应元件（RARE） RAREoct对RA直接抑制的Oct-3/4基因的影响，b)比较共激活因子SRC-1通过典型DR5型RARE对RA直接诱导的rarbet2基因的影响，来解决RA依赖的NRIP1共抑制因子活性的生理相关性。在这三个目标中提出的研究将促进我们对调节维生素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目前的激素核受体-共调节剂的工作模型，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的独特特性是否与维生素a对特定基因启动子的特异性作用具有生理相关性。

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.