| Project/Area Number |
12557045
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
内科学一般
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| Research Institution | St. Marianna University School of Medicine |
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Principal Investigator |
NAKAJIMA Toshihiro St. Marianna University School of Medicine, Associate Professor, 難病治療研究センター, 助教授 (90260752)
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| Co-Investigator(Kenkyū-buntansha) |
AONO Hiroyuki Santen Pharmaceutical CO., LTD,Team Reader, 研究開発部リウマチグループ, チームリーダー
FUKAMIZU Akiyoshi Tsukuba University, Professor, 応用生物化学系, 教授 (60199172)
NISHIOKA Kusuki St. Marianna University School of Medicine, Professor, 難病治療研究センター, 教授 (60049070)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥10,300,000 (Direct Cost: ¥10,300,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥4,000,000 (Direct Cost: ¥4,000,000)
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| Keywords | transcriptional coactivator / rheumatoid arthritis / CREB binding protein (CBP) / synovial cell / Notch 1 / yeast 2 hybrid screening / acetylation / tumor necrosis factor (TNF)-α / 細胞周期 / CREB結合蛋白質 / CREB結合タンパク質(CBP) / Notch-1 / 腫瘍壊死因子(TNF-α) / presenilin / 抑制剤 / 慢性関節リウマチ / 転写コアチクベーター / yeast 2-hybrid法 / NF-κB |
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| Research Abstract |
To assess the implication of transcriptional coactivator in rheumatoid synoviocytes activation, we attempted the following two approaches. One is evaluation of nuclear acetylation, one of the critical roles as coactivator function of CREB binding protein (CBP). The other is molecular cloning of CBP-interaction proteins in rheumatoid synoviocytes by yeast two-hybrid systems.
1) Using a specific antibody against acetylated lysine, we detected potent nuclear acetylation in rheumatoid synoviocytes and revealed that p53 is one of characteristically acetylated proteins. We further found that TNFα induced acetylation of p53 but attenuated its transcriptional activation in synoviocytes. As overexpression of CBP resulted in p53 promoter activation by TNFα, CBP recruitment is required for p53 activation.
2) We cloned Notch-1 as one of CBP-binding proteins from cDNA library prepared from rheumatoid synoviocytes. Notch-1 signal was characteristically activated in rheumatoid synoviocytes though TNFα signaling and implicated in synoviocytes proliferation by TNFα.
These results clearly suggested that coactivator takes crucial roles for rheumatoid synoviocytes activation and might contribute to clarifying the pathogenesis of RA.
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