The research of rheumatoid arthritis from aspect of developmental biology.

风湿性关节炎（rheumatoid arthritis，RA）是一种以关节疼痛为主要表现的疾病，严重威胁着人们的生活质量. RA影响全球约1%的人口，但其具体的治疗方法尚未获得。我们最近成功克隆了一种E3泛素连接酶Synoviolin，并证明该分子是关节病的致病因子之一。并提出了新的疾病概念：类风湿性关节炎是一种高内质网相关的降解性疾病。通过基因打靶系统进一步分析，我们发现滑膜素是胚胎发生所必需的。滑膜素缺陷小鼠（Syno）显示贫血是由胎肝中细胞凋亡的增强引起的。<-l->即合胎肝表现出对红细胞护理活性的缺陷。<-1->这一现象具有类风湿关节炎的对称性特征，即类风湿关节炎骨髓基质细胞具有护理细胞样活性，而类风湿关节炎是一种加速这种护理活动的疾病。因此，从Syno ^的结果可以看出，胚胎发生与RA有着密切的关系，并建议通过分析一个完全相反的方面-Syno ^来开发新的RA治疗方法。<-1-><-1->为了澄清这些问题，我们分析了滑膜素无效细胞中蛋白质表达的概况。在这里，我们报告，滑膜蛋白靶向肿瘤抑制基因p53的泛素化。滑膜素在细胞质中螯合和代谢p53，并负调节其细胞水平和生物学功能，包括转录、细胞周期调节和凋亡。此外，这些p53的调节功能的滑膜蛋白是无关的其他E3泛素连接酶的p53，如MDM 2，Pirh 2和Cop1，形成自动调节反馈回路。我们的研究结果提供了新的见解p53信号介导的Synoviolin。

Rheumatoid arthritis (RA) is a disease associated with painful joint, and threatens the quality of life. RA affects approximately 1% of the population worldwide, however its specific cure is not available yet. We recently succeeded cloning of Synoviolin, an E3 ubiquitin ligase, and proved this molecule is one of the causative factors for arthropathy. Furthermore, we proposed the new disease concept ; RA is a hyper endoplasmic reticulum associated degradation disease. From further analysis, we found that Synoviolin is essential for embryogenesis using gene targeting system. synoviolin deficient mice (syno^<-l->) showed that anemia caused by enhancement of apoptosis in fetal liver. Namely, syno^<-1-> fetal liver demonstrated the defect of nursing activity to erythrocyte. This phenomenon has a symmetrical feature of RA, that is, RA bone marrow stromal cells have nurse cell like activity, and RA is a disease which accelerated this nursing activity. Therefore, from the results of syno^<-1->, it becomes clear that embryogenesis and RA have close relation, and suggested that new cure of RA might be developed by analysis of quite an opposite aspect ; syno^<-1->.However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolin null cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin.