| 1 | J. Mol。内分泌。2005年6月34日：835-48 |
|---|---|
| PMID | 15956351 |
| Title | TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. |
| Abstract | 这NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease,schizophrenia、躁郁症、动脉粥样化形成阿尔茨海默说ease, rheumatoid arthritis, cancer and apoptosis. This has driven investigations into the mechanism of action, and the identification of small molecule regulators, that may provide the platform for pharmaceutical and therapeutic exploitation. Recently, we found that the purine antimetabolite 6-Mercaptopurine (6-MP), which is widely used as an anti-neoplastic and anti-inflammatory drug, modulated theNR4A1-3 subfamily. Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment. However, the role of the subsequently recruited coactivators, for example CARM-1 and TRAP220, in 6-MP-mediated activation of theNR4A1-3 subfamily remains obscure. In this study we demonstrate that 6-MP modulates the activity of the coactivator TRAP220 in a dose-dependent manner. Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with theNR4A1-3 subgroup in an AF-1-dependent manner in a cellular context. The region of TRAP220 that mediated 6-MP activation and NR4A interaction was delimited to amino acids 1-800, and operates independently of the critical PKC and PKA phosphorylation sites. Interestingly, TRAP220 expression does not increase the relative induction by 6-MP, however the absolute level of NOR-1-mediated trans-activation is increased. This study demonstrates that 6-MP modulates the activity of the NR4A subgroup, and the coactivator TRAP220. |
| SCZ Keywords | schizophrenia |
| 2 | Mol. Psychiatry 2006 Jul 11: 615, 663-79 |
| PMID | 16636682 |
| Title | Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. |
| Abstract | 基因表达中的线粒体缺陷已与躁郁症和schizophrenia。现在，我们已经将对照大脑与pH值低相比，并且表明与线粒体相关途径中有28％的基因符合差异表达的标准。核DNA编码的基因表达的线粒体，伴侣和蛋白酶体途径中的大多数基因随着脑pH的降低而降低，而凋亡和活性氧应激途径中的大多数基因显示出脑pH降低的基因表达增加的基因表达。线粒体DNA拷贝数和线粒体DNA基因表达有显着增加，而激动剂持续时间增加。为了最大程度地减少激动状态对情绪障碍比较的影响，使用了两种经典方法，从分析中删除了所有患有pH值低的受试者，或将低pH和高pH分组为单独的变量。出现了三组潜在的候选基因，可能与情绪障碍有关：（a）对pH没有敏感但在躁郁症或主要抑郁症中差异表达的基因；（b）在一个方向上因激动剂而改变但情绪障碍改变的基因在与激动剂pH相反的方向上改变了，并且（c）具有激动剂敏感性的基因，表现出与情绪障碍变化相同的方向。这些类别的基因，例如NR4A1and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 3 | 精神病。基因。2010年2月20日：39-43 |
| PMID | 20010315 |
| Title | Association of the orphan nuclear receptor NR4A1 with tardive dyskinesia. |
| Abstract | Recent evidence has identified theNR4A1(NUR77, NGFI-B) gene as a strong candidate for involvement in tardive dyskinesia (TD). We have investigated the association of six single nucleotide polymorphisms within the NR4A family of genes with TD in a sample of 171 patients withschizophreniaof Caucasian descent. TheNR4A1single nucleotide polymorphism (SNP) marker rs2603751 showed a nominal association with the risk of TD, as well as with the extent of TD based on the Abnormal Involuntary Movements Scale (AIMS) scores. The haplotype generated by the markers rs2603751 and rs2701124 also showed association with TD and, after adjustment for multiple testing, both theNR4A1marker rs2603751 and the haplotype continued to show a trend toward association with TD. Although the results of this study are limited by a small sample size, it presents important pilot data and warrants further investigation of the involvement ofNR4A1variants in TD. |
| SCZ Keywords | schizophrenia |
| 4 | 基因脑行为。2010年11月9日：910-7 |
| PMID | 20659174 |
| Title | Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder. |
| Abstract | schizophrenia躁郁症和躁郁症与多巴胺神经传递有关，并与烟草依赖性显示高合并症。最近的证据表明，在多巴胺神经元和多巴胺感染性脑区域中表达的NR4A孤儿核受体家族可能在多巴胺介导的作用中起作用。因此，我们已经分析了属于NR4A孤儿核受体家族的三个基因中六个单核苷酸多态性（SNP）的关联NR4A1(rs2603751, rs2701124), NR4A2 (rs12803, rs834835) and NR4A3 (rs1131339, rs1405209), with the degree of smoking in a sample of 204 unrelatedschizophreniapatients, which included 126 smokers and 78 non-smokers. SNPs within the NR4A3 gene (rs1131339 and rs1405209) were significantly associated with heavy smoking in this cohort, using a stepwise analysis of the escalated number of cigarettes smoked per day (P = 0.008 and 0.006, respectively; satisfying the Nyholt significance threshold of 0.009, an adjustment for multiple testing). We then repeated the association analysis of the NR4A3 markers (rs1131339 and rs1405209) in a larger cohort of 319 patients with bipolar disorder, which included 167 smokers and 152 non-smokers. We have replicated the positive association with smoking of the NR4A3 SNP rs1131339 in this group (P = 0.04), providing an important confirmation of the involvement of the NR4A3 gene in nicotine addiction in patients with mental health disease, a population significantly at risk for nicotine addiction. |
| SCZ Keywords | schizophrenia |
| 5 | Front Behav Neurosci 2014 -1 8: 388 |
| PMID | 25414651 |
| Title | Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens. |
| Abstract | 孕产涉及自然奖励的转变，从而使后代变得高度收获。伏隔核（NAC）是自然奖励和成瘾的关键中枢神经系统区域，但迄今为止，尚无大规模评估NAC中的事件，这是自然奖励的产妇变化的基础。在这项研究中，我们利用微阵列和生物信息学方法来评估小鼠产后NAC基因表达变化。模块化的单集富集测试（MSET）表明，在五个独立策划的数据库中的五个（例如，malacards，phenopedia）中的五个中的五个中，与成瘾和奖励有关的基因和奖励相关的基因和奖励相关的基因和奖励都显着富集了产后（相对于Virgin）NAC基因表达谱。Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, andPDYN。TopPluster分析发现，与尼古丁，氯胺酮和dronabinol的药物作用相关的基因，母体NAC表达谱均显着富集。途径分析表明，产后NAC富含RNA处理，CNS开发/分化和转录调控。加权基因共表达网络分析（WGCNA）确定了转录因子的可能网络，包括NR1D1，PER2，FOSB，EGR1和NR4A1。这postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), andschizophrenia。Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. |
| SCZ Keywords | schizophrenia |
| 6 | J Vis Exp 2015 -1 -1: e52963 |
| PMID | 26325389 |
| Title | 生产特定多克隆Antibodie Nurr-1s Free of Cross-reactivity Against Its Close Homologs, Nor1 and Nur77. |
| Abstract | 这nuclear receptor subfamily 4 (NR4A) is composed of 3 related proteins sharing a DNA binding domain (DBD) and a ligand-binding domain (LBD). The nuclear receptor related 1 protein (Nurr1 or NR4A2) plays a key role in the maintenance of the dopaminergic system. Dopamine dysfunctions associated with the Nurr1 gene include Parkinson's disease,schizophreniaand manic depression among others. Furthermore, recent evidence indicates that Nurr1 is also expressed in other brain areas such as the hippocampus and plays critical roles for learning and memory. The other members of the family are nerve growth factor IB (Nur77 orNR4A1）和神经元衍生的孤儿受体1（NOR1或NR4A3）。为了帮助研究Nurr1在多巴胺能和其他大脑区域相关的神经元功能障碍中的精确功能作用，需要对NUR77和NOR1的交叉反应性抗体。由于蛋白质在LBD中的发散性比在其DNA结合结构域中具有纯化的LBD的免疫应产生的DNA结合结构域应产生对Nur77和/或nor1具有最小反应性的NURR1特异性抗体。尽管成功产生了抗Nurr1抗体，这些抗体对家族的其他成员表现出明显的免疫反应性。对固定蛋白A的亲和色谱法对固定化的NUR77和NOR1 LBD进行了预吸附，产生了NURR1特异性抗体，没有交叉反应性。在这里，我们通过对动物最有不同的区域进行免疫动物，然后通过吸附前去除交叉反应性抗体来选择性地靶向针对高度保守的蛋白质家族的特定成员。该方案的目的是通过针对交叉反应性抗原的预吸收来提高多克隆抗体的特异性。 |
| SCZ Keywords | schizophrenia |