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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.

类风湿关节炎(RA)是一种与关节疼痛相关的疾病，威胁着人们的生活质量。RA影响全球约1%的人口，但其具体治疗方法尚不清楚。我们最近成功地克隆了一种E3泛素连接酶SynoViin，并证明了该分子是关节病的致病因素之一。此外，我们还提出了新的疾病概念：类风湿关节炎是一种高内质网相关性降解性疾病。通过进一步的分析，我们发现，使用基因打靶系统进行胚胎发育时，聚乙醇胺是必不可少的。突触素基因缺陷小鼠(Syno^&lt；-L-&gt；)表现为胎肝细胞凋亡增强所致的贫血。也就是说，胎肝对红细胞的护理活性存在缺陷。这一现象具有类风湿性关节炎的对称性，即类风湿性关节炎骨髓基质细胞具有滋养细胞样的活性，而类风湿性关节炎是一种加速这种护理活动的疾病。因此，从syno^-lt；-1-&gt；的结果可以清楚地看出胚胎发生与RA有密切的关系，并提示通过对syno^-lt；-1-&gt；相反的方面的分析，可能开发出治疗RA的新方法。为了阐明这些问题，我们分析了突触素缺失细胞中的蛋白质表达谱。在这里，我们报告了赛诺维林针对肿瘤抑制基因P53的泛素化。赛诺维林在细胞质中隔离和代谢P53，负调控P53的细胞水平和生物学功能，包括转录、细胞周期调节和细胞凋亡。此外，Synoviin的这些P53调节功能与P53的其他E3泛素连接酶如MDM2、Pirh2和Cop1无关，它们形成自我调节反馈环。我们的结果为研究由赛诺维林介导的P53信号通路提供了新的见解。

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

DOI：
发表时间：
2007
期刊：
EMBO J 26
影响因子：
0
作者：
Suzuki;Y. et al.;Satoshi Yamasaki et al.
通讯作者：
Satoshi Yamasaki et al.

Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'

DOI：
10.1038/sj.emboj.7601490
发表时间：
2007-01-10
期刊：
EMBO JOURNAL
影响因子：
11.4
作者：
Yamasaki, Satoshi;Yagishita, Naoko;Nakajima, Toshihiro
通讯作者：
Nakajima, Toshihiro

Role of Synoviolin in rheumatoid arthritis : possible clinical relevance

滑膜素在类风湿性关节炎中的作用：可能的临床相关性

DOI：
发表时间：
2006
期刊：
Future Rheumatol 1・1
影响因子：
0
作者：
Naoko Yagishita et al.
通讯作者：
Naoko Yagishita et al.

Identification of a Crucial Site for Synoviolin Expression

滑膜蛋白表达关键位点的鉴定

DOI：
10.1128/mcb.25.16.7344-7356.2005
发表时间：
2005
期刊：
Molecular and Cellular Biology
影响因子：
5.3
作者：
K. Tsuchimochi;N. Yagishita;S. Yamasaki;T. Amano;Y. Kato;K. Kawahara;S. Aratani;Hidetoshi Fujita;Fengyun Ji;A. Sugiura;Toshihiko Izumi;Asako Sugamiya;I. Maruyama;A. Fukamizu;S. Komiya;K. Nishioka;T. Nakajima
通讯作者：
T. Nakajima