Structure of chromosomal Passenger complex that causes chromosomal instability in cancers
| Project/Area Number |
15H02365
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
Hirota Toru 公益財団法人がん研究会, がん研究所 実験病理部, 部長 (50421368)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥33,410,000 (Direct Cost: ¥25,700,000、Indirect Cost: ¥7,710,000)
Fiscal Year 2017: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
Fiscal Year 2016: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
Fiscal Year 2015: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
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| Keywords | 細胞分裂 / 染色体不安定性 / M期キナーゼ / セントロメア / 動原体 / がん / Aurora B / がん細胞 / 染色体分配 / 異数体 / 染色体動態 / 分裂期キナーゼ |
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| Outline of Final Research Achievements |
Incorrect attachment of kinetochore microtubules is the leading cause of chromosome missegregation in cancers. The highly conserved mitotic kinase Aurora B ensures faithful chromosome segregation through destabilizing incorrect microtubule attachments and promoting bi-orientation of chromosomes on the mitotic spindle. It was unknown whether Aurora B dysfunction affects chromosome segregation fidelity in cancers and, if so, how. Through this study, we show that HP1 is an allosteric activator of Aurora B, required to attain the high activity levels. The contribution of HP1 becomes particularly important when Aurora B phosphorylates kinetochore targets to eliminate erroneous microtubule attachments. Remarkably, a reduced contribution of HP1 is widespread in cancers, which causes an impairment in Aurora B activity. Our work shows that HP1 is an essential modulator for Aurora B's function and identify a molecular basis for chromosome segregation errors in cancer cells.
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| Academic Significance and Societal Importance of the Research Achievements |
増殖性の指標となる細胞の分裂をターゲットとする治療法はこれまで有望視されてきたものの、細胞分裂機構の破壊は、正常細胞にもダメージを与えてしまうというジレンマがあり、そこにどうやって風穴を開けるのかが大きな課題であった。本研究により見出された「HP1のアロステリック効果」を糸口として、がん細胞におけるAurora Bの脆弱性をうまく利用することにより、がんの細胞分裂を選択的に標的とする新規抗がん治療の開発に繋がると期待される。
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Report
(4 results)
Research Products
(41 results)
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[Journal Article] Esco1 Acetylates Cohesin via a Mechanism Different from That of Esco22015
Author(s)
Masashi Minamino, Mai Ishibashi, Ryuichiro Nakato, Kazuhiro Akiyama, Hiroshi Tanaka, Yuki Kato, Lumi Negishi, Toru Hirota, Takashi Sutani, Masashige Bando, Katsuhiko Shirahige
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Journal Title
Current Biology
Volume: 25
Issue: 13
Pages: 1694-1706
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] がんと染色体2015
Author(s)
広田 亨
Organizer
第69回日本臨床細胞学会細胞検査士教育セミナー
Place of Presentation
東京
Year and Date
2015-08-30
Related Report
Invited
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