| Co-Investigator(Kenkyū-buntansha) |
NISHIOKA Kusuki St. Marianna University School of Medicine, Institute of Medical Science, Professor, 難病治療研究センター, 教授 (60049070)
NAKAJIMA Toshihiro St. Marianna University School of Medicine, Institute of Medical Science, Professor, 難病治療研究センター, 教授 (90260752)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
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.
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