The research of rheumatoid arthritis from aspect of developmental biology.

从发育生物学角度研究类风湿性关节炎。

基本信息

批准号：
17591058
负责人：
YAGISHITA Naoko
金额：
$ 2.24万
依托单位：
St. Marianna University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591058/
关键词：
rheumatoid arthritis synovial cells Synoviolin E3 ubiquitin ligase degradation endoplasmic reticulum associated degradation KO mice p53 apoptosis 肝細胞

项目摘要

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.

类风湿性关节炎（RA）是一种与关节疼痛相关的疾病，威胁生活质量。 RA 影响着全世界大约 1% 的人口，但目前尚无具体的治疗方法。我们最近成功克隆了E3泛素连接酶Synoviolin，并证明该分子是关节病的致病因素之一。此外，我们提出了新的疾病概念； RA是一种与内质网过度降解相关的疾病。通过进一步分析，我们发现Synoviolin对于使用基因靶向系统的胚胎发生至关重要。滑膜素缺陷小鼠(syno^<-l->)显示胎儿肝脏细胞凋亡增强导致贫血。即，syno^<-1->胎儿肝脏表现出对红细胞的护理活动的缺陷。这种现象具有RA的对称特征，即RA骨髓基质细胞具有类似护理细胞的活性，而RA正是加速这种护理活动的疾病。因此，从syno^<-1->的结果来看，胚胎发生与RA有着密切的关系，并提示通过相反方面的分析可能会开发出治疗RA的新方法； syno^<-1->。然而，人们对 Synoviolin 在这些作用中的分子机制知之甚少。为了澄清这些问题，我们分析了滑膜缺失细胞中的蛋白质表达谱。在这里，我们报告 Synoviolin 靶向肿瘤抑制基因 p53 进行泛素化。 Synoviolin 在细胞质中隔离和代谢 p53，并负向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，Synoviolin 的这些 p53 调节功能与 p53 的其他 E3 泛素连接酶（例如 MDM2、Pirh2 和 Cop1）无关，它们形成自动调节反馈环。我们的结果为滑膜蛋白介导的 p53 信号传导提供了新的见解。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Resistance to endoplasmic reticulum stress is an acquired cellular characteristic of rheumatoid synovial cells.

DOI：
10.3892/ijmm.18.1.113
发表时间：
2006-07
期刊：
International journal of molecular medicine
影响因子：
5.4
作者：
S. Yamasaki;N. Yagishita;K. Tsuchimochi;Y. Kato;Takeshi Sasaki;T. Amano;M. Beppu;H. Aoki;Hiroshi Nakamura;K. Nishioka;T. Nakajima
通讯作者：
S. Yamasaki;N. Yagishita;K. Tsuchimochi;Y. Kato;Takeshi Sasaki;T. Amano;M. Beppu;H. Aoki;Hiroshi Nakamura;K. Nishioka;T. Nakajima

Cytoplasmic destruction of p53 by the endoplasmic reticulum-residentubiauitin liease "Synoviolin"

内质网驻留泛素释放酶“Synoviolin”对 p53 的细胞质破坏