NRIP1 in vitamin A signaling pathways

维生素A（类维生素A）对生物过程产生多种影响，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，视黄酸受体（RAR）和类视黄酸受体（RXR），其通过在视黄酸（RA）存在下招募辅激活子和在其不存在下招募辅抑制子来调节基因表达。 核受体相互作用蛋白1（Nuclear Receptor Interacting Protein 1，NRIP 1），以前称为RIP 140，是一种新的辅阻遏物，在激素存在下抑制基因表达。 据推测，NRIP 1作为一个配体依赖性，负辅调节因子的沉默特定的基因表达激素的存在下，引起的基因调控电路。 提出了三个目标来测试这一假设，通过使用RAR/RXR系统。 第一个目的是大力研究NRIP 1与holo-RAR/RXR相互作用的分子基础，其中涉及一种新的NRIP 1（PRLTKTNPILYYMLQK）的C-末端基序，该基序从典型的辅激活基序LXXLL或辅阻遏基序CoRNR盒转移。 第二个目的是比较NRIP 1复合物与典型的配体依赖性辅激活因子复合物SRC-1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NRIP 1对Oct-3/4基因的作用来解决NRIP 1的RA依赖性辅阻遏物活性的生理学相关性，所述Oct-3/4基因通过RAR/RXR结合RA应答元件（RARE）RAREoct而被RA直接抑制，和B）比较辅激活物SRC-1对RAR β 2基因的作用，所述RAR β 2基因通过典型的DR 5型RARE而被RA直接诱导. 在这三个目标中提出的研究将促进我们对介导维生素A激素作用的分子机制多样性的理解。 此外，我们将测试目前的工作模式的激素核受体-辅调节器是否可以修改，以适应复杂的行动，激素在不同的生物系统。 最后，我们的最终目标是确定NRIP 1的独特性质是否与维生素A作用于特定基因启动子的特异性有关。

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.