Molecular mechanism of separase deregulation in cancer cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07677
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: SHINDO Norihisa 公益財団法人がん研究会, がん研究所 実験病理部, 研究員 (00512253)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: セパレース / 活性制御 / バイオセンサー / 染色体不安定性

Outline of Final Research Achievements

Separase biosensor revealed that separase was sharply activated at the onset of anaphase in normal diploid cell lines. In multiple types of cancer cell lines, however, separase was precociously activated long before the onset of anaphase and only weak activity was detected during chromosome segregation. This separase deregulation was more pronounced in cancer cell lines with longer mitosis and was exacerbated when anaphase delay was induced by low dose of microtubule polymerization inhibitors. There are two well-known separase inhibitors, securin and cyclin B1-cdk1. Regulation by securin is widely conserved among eukaryotes whereas regulation by cyclin B1-cdk1 complex is rather vertebrate specific. Our results indicated that the separase deregulation caused by delayed anaphase was due to attenuation of the latter mechanism.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

がん細胞を特異的に死滅させるにはがん特有の弱点を標的とすることが重要である。そのため、がん特有の染色体不安定性を増大させる方法が注目され、紡錘体チェックポイントなどを標的とする基礎研究は行われてきたが、いずれの研究もまだ萌芽段階にある。本研究で、がん特有のセパレース制御異常の原因がcyclin B1-cdk1による抑制の減衰であることが見いだせたことで、染色体不安定性を増大させる新たな治療法の開発の端緒とすることができる。セパレースとcyclin B1-cdk1の結合様式に関する理解も進んできており、治療標的として今後飛躍的に開発が進む可能性がある。