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Structure of chromosomal Passenger complex that causes chromosomal instability in cancers

Research Project

Project/Area Number 15H02365
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionJapanese 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
Project Status Completed (Fiscal Year 2018)
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)
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
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.

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。

Report

(4 results)
  • 2018 Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (41 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (5 results) Journal Article (12 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 7 results,  Acknowledgement Compliant: 7 results) Presentation (16 results) (of which Int'l Joint Research: 6 results,  Invited: 16 results) Book (2 results) Remarks (2 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 2 results)

  • [Int'l Joint Research] European Molecular Biology Laboratory(Germany)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Colorado State University(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Colorado State University(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] European Molecular Biology Laboratory(Germany)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Colorado State University(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] <b>Quantitative analyses of the metaphase-to-anaphase transition reveal differential kinetic regulation for securin and cyclin </b><b>B1 </b>2018

    • Author(s)
      Makoto Konishi, Norihisa Shindo, Masataka Komiya, Kozo Tanaka, Takehiko Itoh, and Toru Hirota
    • Journal Title

      Biomedical Research

      Volume: 39 Issue: 2 Pages: 75-85

    • DOI

      10.2220/biomedres.39.75

    • NAID

      130006708566

    • ISSN
      0388-6107, 1880-313X
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] M期における染色体構築のメカニズム2017

    • Author(s)
      高橋元子、広田 亨
    • Journal Title

      生化学

      Volume: 89

    • NAID

      40021312467

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] HP1-assisted Aurora B kinase activity prevents chromosome segregation errors2016

    • Author(s)
      Yusuke Abe, Kosuke Sako, Kentaro Takagaki, Youko Hirayama, Kazuhiko S.K. Uchida, Jacob A. Herman, Jennifer G. DeLuca and Toru Hirota
    • Journal Title

      Developmental Cell

      Volume: 36 Issue: 5 Pages: 487-497

    • DOI

      10.1016/j.devcel.2016.02.008

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] System-level deficiencies in Aurora B control in cancers.2016

    • Author(s)
      Abe, Y., Hirota, T.
    • Journal Title

      Cell Cycle

      Volume: 15 Issue: 16 Pages: 2091-2092

    • DOI

      10.1080/15384101.2016.1185850

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Sister chromatid resolution is an intrinsic part of chromosome organization in prophase.2016

    • Author(s)
      Nagasaka, K., Hossain, JM., Roberti, JM., Ellenberg, J., Hirota, T.
    • Journal Title

      Nature Cell Biology

      Volume: 18 Issue: 6 Pages: 1-10

    • DOI

      10.1038/ncb3353

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Condensin I-mediated mitotic chromosome assembly requires association with chromokinesin KIF4A.2016

    • Author(s)
      Takahashi, M., Wakai, T., and Hirota, T.
    • Journal Title

      Genes and Development

      Volume: 30 Issue: 17 Pages: 1931-1936

    • DOI

      10.1101/gad.282855.116

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] <b>Phosphoproteomic analysis of human mitotic chromosomes identified a chromokinesin </b><b>KIF4A </b>2016

    • Author(s)
      Takahashi, M., Tanaka, K., Wakai, T., Hirota, T.
    • Journal Title

      Biomedical Research

      Volume: 37 Issue: 2 Pages: 161-165

    • DOI

      10.2220/biomedres.37.161

    • NAID

      130005147428

    • ISSN
      0388-6107, 1880-313X
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Chromosomal instability: a common feature and a therapeutic target of cancer.2016

    • Author(s)
      Tanaka, K., and Hirota, T.
    • Journal Title

      Biochim Biophys Acta

      Volume: 1866 Issue: 1 Pages: 64-75

    • DOI

      10.1016/j.bbcan.2016.06.002

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Phosphoproteomic analysis of human mitotic chromosomes identified a chromokinesin KIF4A.2016

    • Author(s)
      Takahashi, M., Tanaka, K., Wakai, T., Hirota, T.
    • Journal Title

      Biomedical Research

      Volume: 37 Pages: 161-165

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Clarifying the role of condensins in shaping chromosomes2015

    • Author(s)
      Nagasaka, K. and Hirota, T.
    • Journal Title

      Nature Cell Biology

      Volume: 17 Issue: 6 Pages: 711-713

    • DOI

      10.1038/ncb3183

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      Current Biology

      Volume: 25 Issue: 13 Pages: 1694-1706

    • DOI

      10.1016/j.cub.2015.05.017

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 染色体不安定性の成因2015

    • Author(s)
      小西 惇、松高 愛、広田 亨
    • Journal Title

      細胞

      Volume: 47 Pages: 5-8

    • Related Report
      2015 Annual Research Report
  • [Presentation] Molecular grounds underlying chromosomal instability in cancers2018

    • Author(s)
      Toru Hirota
    • Organizer
      沖縄科学技術大学院大学・セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Cooperative acts of condensins and topoisomerases in shaping mitotic chromsomes2017

    • Author(s)
      Toru Hirota
    • Organizer
      The 2nd meeting on SMC proteins: Chromosomal organizers from bacteria to human
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Kinetic control of the M/A transition in failsafe mitosis2017

    • Author(s)
      Toru Hirota
    • Organizer
      The 76th Annual Meeting of the Japanese Cancer Association
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular grounds for chromosomal instability in cancers2017

    • Author(s)
      Toru Hirota
    • Organizer
      平成29年度名古屋大学大学院基盤医学特論・特徴あるプログラム・Cancer Science Course
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Molecular grounds underlying chromosomal instability in cancers2017

    • Author(s)
      Toru Hirota
    • Organizer
      理化学研究所 統合生命医科学研究センター・疾患生物学セミナーシリーズ
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] がん細胞における染色体制御システムの破綻2017

    • Author(s)
      広田 亨
    • Organizer
      福井大学学術研究院工学系部門・セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] がんにおける染色体不安定性の分子背景の解明2016

    • Author(s)
      広田 亨
    • Organizer
      第4回Joint Nature Conference of Respirology
    • Place of Presentation
      東京
    • Year and Date
      2016-11-10
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Kinetic control of the M/A transition in failsafe mitosis.2016

    • Author(s)
      Hirota, T.
    • Organizer
      SKKU International symposium on biomedical science.
    • Place of Presentation
      Suwon
    • Year and Date
      2016-10-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] クロマチン分子HP1によるAurora Bキナーゼの活性化:明かされつつあるがん染色体動態の分子背景2016

    • Author(s)
      広田 亨
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台市
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 分子イメージング顕微鏡解析法が見出した動原体のストレッチング2016

    • Author(s)
      広田 亨
    • Organizer
      第57回日本組織細胞化学会総会・学術集会
    • Place of Presentation
      三鷹市
    • Year and Date
      2016-09-04
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 分子イメージングによって見出されたキネトコアの動的構造2016

    • Author(s)
      広田 亨
    • Organizer
      第68回日本細胞生物学会大会・第11回日本ケミカルバイオロジー学会年会・合同大会
    • Place of Presentation
      京都市
    • Year and Date
      2016-06-17
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] A system level deficiency of the chromosomal passenger complex in cancer cells2015

    • Author(s)
      Toru Hirota
    • Organizer
      The 74th Annual Meeting of the Japanese Cancer Association (JCA)
    • Place of Presentation
      Nagoya
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] An origin of chromosome missegregation in mitosis2015

    • Author(s)
      Toru Hirota
    • Organizer
      The 27th International Conference of the Korean Society for Molecular and Cellular Biology
    • Place of Presentation
      Seoul
    • Year and Date
      2015-09-21
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] がん細胞における染色体制御システムの破綻:明かされつつある染色体不安定性の分子背景2015

    • Author(s)
      広田 亨
    • Organizer
      新学術領域「がん研究分野の特性等を踏まえた支援活動」公開シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2015-09-09
    • Related Report
      2015 Annual Research Report
    • Invited
  • [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
      2015 Annual Research Report
    • Invited
  • [Presentation] Dynamic deformation of kinetochores controls mitotic progression2015

    • Author(s)
      Toru Hirota
    • Organizer
      EMBO Workshop Dynamic Kinetochore
    • Place of Presentation
      Copenhagen
    • Year and Date
      2015-05-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] Spindle assembly checkpoint: its control and aberration. F. Hanaoka and K. Sugasawa (eds.), DNA Replication, Recombination, and Repair: Molecular Mechanisms and Pathology2016

    • Author(s)
      Uchida, KSK and Hirota, T.
    • Total Pages
      555
    • Publisher
      Springer
    • Related Report
      2016 Annual Research Report
  • [Book] DNA Replication, Recombination, and Repair2016

    • Author(s)
      Uchida, KSK., and Hirota, T.
    • Total Pages
      555
    • Publisher
      Springer
    • Related Report
      2015 Annual Research Report
  • [Remarks] がん研究所実験病理部

    • URL

      http://www.jfcr.or.jp/tci/exppathol/

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report 2015 Annual Research Report
  • [Remarks] がん研究会がん研究所

    • URL

      http://www.jfcr.or.jp/laboratory/index.html

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report 2015 Annual Research Report
  • [Patent(Industrial Property Rights)] HP1の機能に着目した抗がん剤のスクリーニング方法及び評価系2017

    • Inventor(s)
      広田 亨、阿部 優介
    • Industrial Property Rights Holder
      広田 亨、阿部 優介
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-035505
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] 細胞観察用蛍光プローブ及びこれを使用する方法2017

    • Inventor(s)
      広田 亨、進藤軌久、熊田和貴
    • Industrial Property Rights Holder
      広田 亨、進藤軌久、熊田和貴
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2014-010635
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] HP1の機能に着目した抗がん剤のスクリーニング方法及び評価系2017

    • Inventor(s)
      広田 亨、阿部 優介
    • Industrial Property Rights Holder
      広田 亨、阿部 優介
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017-02-27
    • Related Report
      2016 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] HP1の昨日に着目した抗がん剤のスクリーニング方法及び評価系2016

    • Inventor(s)
      広田 亨、阿部 優介
    • Industrial Property Rights Holder
      広田 亨、阿部 優介
    • Industrial Property Rights Type
      特許
    • Filing Date
      2016-02-26
    • Related Report
      2015 Annual Research Report

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Published: 2015-04-16   Modified: 2022-08-22  

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