Henry II Kenneth W, Spencer Michael L, Theodosiou Maria, Lou Dingyuan, Noonan Daniel J
Department of Molecular and Cellular Biochemistry, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA.
Nucl Recept. 2003 Sep 10;1(1):7. doi: 10.1186/1478-1336-1-7.
The specificity of a nuclear receptor's ability to modulate gene expression resides in its ability to bind a specific lipophilic ligand, associate with specific dimerization partners and bind specific DNA sequences in the promoter regions of genes. This sequence of events appears to be the basis for targeting an additional regulatory complex composed of a variety of protein and RNA components that deliver signals for facilitation or inhibition of the RNA polymerase complex. Characterization of the tissue and cell-specific components of these coregulatory complexes appear to be integral to our understanding of nuclear receptor regulation of transcription. RESULTS: A novel yeast screen sensitive to retinoid-X receptor (RXR) transcriptional activation resulted in the isolation of the rat homologue of the mouse NPDC-1 gene. NPDC-1 has been shown to be involved in the control of neural cell proliferation and differentiation, possibly through interactions with the cell cycle promoting transcription factor E2F-1. Although the amino acid sequence of NPDC-1 is highly conserved between mouse, rat and human homologues, their tissue specific expression was seen to vary. A potential for direct protein:protein interaction between NPDC-1, RXR and retinoic acid receptor beta (RARbeta) was observed in vitro and NPDC-1 facilitated RXR homodimer and RAR-RXR heterodimer DNA binding in vitro. Expression of NPDC-1 was also observed to repress transcription mediated by retinoid receptors as well as by several other nuclear receptor family members, although not in a universal manner. CONCLUSIONS: These results suggest that NPDC-1, through direct interaction with retinoid receptors, functions to enhance the transcription complex formation and DNA binding function of retinoid receptors, but ultimately repress retinoid receptor-mediated gene expression. As with NPDC-1, retinoids and their receptors have been implicated in brain development and these data provide a point of convergence for NPDC-1 and retinoid mediation of neuronal differentiation.
核受体调节基因表达的特异性在于其结合特定亲脂性配体、与特定二聚化伙伴结合以及结合基因启动子区域特定DNA序列的能力。这一系列事件似乎是靶向由多种蛋白质和RNA成分组成的额外调节复合物的基础，该复合物传递促进或抑制RNA聚合酶复合物的信号。这些共调节复合物的组织和细胞特异性成分的表征似乎是我们理解核受体转录调节不可或缺的。结果：一种对维甲酸X受体（RXR）转录激活敏感的新型酵母筛选方法，分离出了小鼠NPDC - 1基因的大鼠同源物。NPDC - 1已被证明参与神经细胞增殖和分化的控制，可能是通过与促进细胞周期的转录因子E2F - 1相互作用。尽管NPDC - 1在小鼠、大鼠和人类同源物之间的氨基酸序列高度保守，但其组织特异性表达有所不同。在体外观察到NPDC - 1、RXR和维甲酸受体β（RARβ）之间存在直接蛋白质 - 蛋白质相互作用，并且NPDC - 1在体外促进了RXR同源二聚体和RAR - RXR异源二聚体与DNA的结合。还观察到NPDC - 1的表达抑制了维甲酸受体以及其他几个核受体家族成员介导的转录，尽管并非以普遍方式。结论：这些结果表明，NPDC - 1通过与维甲酸受体的直接相互作用，增强维甲酸受体的转录复合物形成和DNA结合功能，但最终抑制维甲酸受体介导的基因表达。与NPDC - 1一样，维甲酸及其受体与脑发育有关，这些数据为NPDC - 1和维甲酸介导的神经元分化提供了一个交汇点。
