| Project/Area Number |
16K08512
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | Microbial Chemistry Research Foundation |
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Principal Investigator |
TATSUDA Daisuke 公益財団法人微生物化学研究会, 微生物化学研究所, 研究員 (20442569)
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| Research Collaborator |
MOMOSE Isao
KAWADA Manabu
OHBA Shunichi
YOSHIDA Junjiro
OHISHI Tomokazu
SAWA Ryuichi
TAKAHASHI Yuko
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 抗腫瘍効果 / p53依存的細胞死 / in vivo 抗腫瘍効果 / アフィニティービーズ / キノフラシン結合タンパク質 / リン酸化 / キノフラシン感受性 / 大量培養 / 癌 / 遺伝子 / 細胞 / 微生物 / シグナル伝達 |
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| Outline of Final Research Achievements |
Mdm2 binds to and ubiquitinates p53, a tumor suppressor, and induces degradation of p53 by 26S proteasome in tumor cells. Suppression of p53 degradation, however, can activate p53, and induce cell cycle arrest and apoptosis. To search for a new activator of the p53-dependent signaling pathway, we screened microbial metabolites using human glioblastoma LNZTA3 cells in which p53 expression can be regulated by tetracycline. As a result of screening, we identified quinofuracins A-E from Staphylotrichumboninense PF1444 and coccoquinones A and B from Staphylotrichum coccosporum PF1460, novel anthraquinone derivatives. Quinofuracins and coccoquionones induced p53-dependent cell death upregulated the expression of p53 and stimulated PARP degradation in p53-expressing LNZTA3 cells. Quinofraciine D specifically bound to several proteins in p53-expressing LNZTA3 cells. In a xenograft model, quinofuracins and coccoquinones suppressed prostate cancer tumor growth.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では我々の見出した新規化合物であるキノフラシンやコッコキノンが特異的な作用によってp53依存的細胞死を誘導することを示唆しており新しい作用機序を持つユニークな化合物として学術的に興味深い成果を得た。またキノフラシンやコッコキノンはin vitroだけでなくin vivoでも抗腫瘍効果を示すことが明らかとなった。このことはこれらの化合物が新しいがん治療薬の開発へとつながる可能性を有しており本研究成果は社会的意義が高いと考えられる。
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