Structure of chromosomal Passenger complex that causes chromosomal instability in cancers

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H02365
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Japanese Foundation for Cancer Research
• 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)
• Project Period (FY): 2015-04-01 – 2019-03-31
• 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

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.

Free Research Field

細胞生物学、腫瘍生物学

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。