NRIP1 in vitamin A signaling pathways

维生素A(类维甲酸)对生物过程有多种影响，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)和维甲酸受体(RXRs)，它们在有维甲酸(RA)存在的情况下通过招募辅助激活因子来调节基因的表达，在没有维甲酸的情况下通过招募辅助抑制因子来调节基因的表达。核受体相互作用蛋白1(NRIP1)，以前被称为RIP140，是一种在激素存在下抑制基因表达的新的辅阻遏子。假设NRIP1作为激素诱导的基因调控回路的配基依赖的负共调节因子，在激素存在的情况下沉默特定基因的表达。通过使用RAR/RXR系统，提出了三个目的来检验这一假设。第一个目标是大力研究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-末端基序(PRLTKTNPILYMLQK)，该基序偏离了典型的共激活基序LxxLL或辅阻遏子基序CoRNR box。第二个目的是比较NRIP 1复合体和典型的配体依赖的辅活化子复合体SRC-1与受体及其特定结合蛋白相互作用的效率。第三个目的是通过a)检测NRIP1对通过RAR/RXR与RA反应元件(RARE)RAREoct结合而直接被RA抑制的Oct-3/4基因的影响，以及b)比较辅助激活剂SRC-1对RA通过典型的DR5型Rare直接诱导的RARbeta2基因的影响，以解决NRIP1对RA依赖的辅阻遏子活性的生理学相关性。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的多样性的理解。此外，我们还将测试目前激素核受体-辅助调节的工作模式是否可以修改，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的独特性质是否与特定基因启动子上维生素A作用的特异性具有生理相关性。

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.