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Regulation of the Chromosomal Passenger Complex identifies pathology of chromosomal instability in cancers

Research Project

Project/Area Number 18H04034
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

広田 亨  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) 2018-04-01 – 2022-03-31
Project Status Granted (Fiscal Year 2021)
Budget Amount *help
¥43,810,000 (Direct Cost: ¥33,700,000、Indirect Cost: ¥10,110,000)
Fiscal Year 2021: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
Fiscal Year 2020: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000)
Fiscal Year 2019: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Fiscal Year 2018: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Keywordsがん / 染色体不安定性 / Aurora B / セントロメア / M期キナーゼ / 染色体分配 / 天然編成領域 / 原子間力顕微鏡 / 分裂期キナーゼ / 動原体 / HP1 / タンパク質構造解析 / M期キナーゼ / 構造解析
Outline of Annual Research Achievements

染色体パセンジャー複合体(Chromosomal Passenger Complex; CPC)はセントロメアに局在し染色体の正確な分配を制御している。この機能においてはAurora Bキナーゼ活性が動原体分子をリン酸化することが必要だが、いかにセントロメアから動原体までの距離を超えて活性を及ぼせるのかが不明であった。本研究ではこれまでにin vitroの再構成系で、CPCは動的な構造をとりそのコンフォマーが伸長することを見出し、セントロメアに局在しながらも活性を動原体まで直接届けることができることが示唆されている。これを踏まえて2020年度は、動的構造を作り出す構造学的解析を進め、細胞内で動的構造を見いだし、その意義を検討するための実験系を作成した。

1) Aurora Bの機能において重要な構造変化であるCPCの伸長の制御を明らかにするために、伸長に主に寄与するINCENPのドメイン解析を行った。つまり伸縮を担うと思われるINCENPの分子内で、形の変化に寄与するドメイン、複合体全体のコンフォマーに寄与するドメイン、その部分がHP1の結合によって制御を受ける可能性を明らかにした。

2)CPCの伸長が実際に細胞内で起こるのかを検討するために、FRET反応を利用したプローブを作成し、これと動原体分子のリン酸化状態、及び動原体と微小管との結合状態を同時に解析し、分裂期進行に伴うCPCの構造変換制御を検討した。さらに、in vitro見出されたCPCの構造変換特性の細胞内での意義を検討するために、CPCの伸張をラパマイシンにより条件的に制御する実験系を構築した。

Current Status of Research Progress
Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

コロナ禍で生化学的な実験が制限されたことが影響し、リコンビナントタンパク質を用いる実験計画の遅延は避けられなかった。しかし再現性のある結果が得られ始めているので、研究の速度を上げつつ試験管内でCPC複合体の構造特性を明らかにしいく。

Strategy for Future Research Activity

試験管内でCPC複合体の構造特性の解析から、CPCが自己集合に関与するドメインの存在が見えてきた。複合体全体の動的構造とともに、自己集合活性がCPCのセントロメアへの濃縮するどのように関わっているのかも合わせて検討していきたい。

Report

(3 results)
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(43 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (5 results) Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 9 results) Presentation (16 results) (of which Int'l Joint Research: 16 results,  Invited: 8 results) Book (1 results) Remarks (6 results) Patent(Industrial Property Rights) (2 results) Funded Workshop (2 results)

  • [Int'l Joint Research] Colorado State University(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Newcastle University(英国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Colorado State University(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Colorado State University(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] European Molecular Biology Organization(ドイツ)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Pathogenicity assessment of variants for breast cancer susceptibility genes based on BRCAness of tumor sample2021

    • Author(s)
      Yoshida Reiko、Hagio Taichi、Kaneyasu Tomoko、Gotoh Osamu、Osako Tomo、Tanaka Norio、Amino Sayuri、Yaguchi Noriko、Nakashima Eri、Kitagawa Dai、Ueno Takayuki、Ohno Shinji、Nakajima Takeshi、Nakamura Seigo、Miki Yoshio、Hirota Toru、Takahashi Shunji、Matsuura Masaaki、Noda Tetsuo、Mori Seiichi
    • Journal Title

      Cancer Sci.

      Volume: 112 Pages: 1310-1319

    • DOI

      10.1111/cas.14803

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolonged mitosis causes separase deregulation and chromosome nondisjunction2021

    • Author(s)
      Shindo Norihisa、Otsuki Makoto、Uchida Kazuhiko S.K.、Hirota Toru
    • Journal Title

      Cell Reports

      Volume: 34 Pages: 108652-108652

    • DOI

      10.1016/j.celrep.2020.108652

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kinase inhibition profiles as a tool to identify kinases for specific phosphorylation sites2020

    • Author(s)
      Watson Nikolaus A.、Cartwright Tyrell N.、Lawless Conor、Camara-Donoso Marcos、Sen Onur、Sako Kosuke、Hirota Toru、Kimura Hiroshi、Higgins Jonathan M. G.
    • Journal Title

      Nature Communications

      Volume: 11 Pages: 1684-1684

    • DOI

      10.1038/s41467-020-15428-0

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of a novel nucleolar protein complex required for mitotic chromosome segregation through centromeric accumulation of Aurora B2020

    • Author(s)
      Fujimura, A., Hayashi, Y., Kato, K., Kogure, Y., Kameyama, M., Shimamoto, H., Daitoku, H., Fukamizu, A., Hirota, T., and Kimura, K.
    • Journal Title

      Nucleic Acids Research

      Volume: 48 Pages: 6583-6596

    • DOI

      10.1093/nar/gkaa449

    • NAID

      120007147865

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation.2020

    • Author(s)
      Nakayama Izuma, Hirota Toru, Shinozaki Eiji
    • Journal Title

      Cancers

      Volume: 12 Pages: 3236-3236

    • DOI

      10.3390/cancers12113236

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Folding the genome into mitotic chromosomes2019

    • Author(s)
      Motoko Takahashi, Toru Hirota
    • Journal Title

      Current Opinion in Cell Biology

      Volume: 60 Pages: 19-26

    • DOI

      10.1016/j.ceb.2019.03.005

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cdkl-mediated DIAPHI phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase.2019

    • Author(s)
      Nishimura K, Johmura Y, Deguchi K, Jiang Z, Uchida KSK, Suzuki N, Shimada M, Chiba Y, Hirota T, Yoshimura SH, Kono K, Nakanishi M.
    • Journal Title

      Nat commun.

      Volume: 10 Issue: 1 Pages: 1-10

    • DOI

      10.1038/s41467-019-08957-w

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enrichment of CLDN18‐ARHGAP fusion gene in gastric cancers in young adults2019

    • Author(s)
      Nakayama Izuma、Shinozaki Eiji、Sakata Seiji、Yamamoto Noriko、Fujisaki Junko、Muramatsu Yusuke、Hirota Toru、Takeuchi Kengo、Takahashi Shunji、Yamaguchi Kensei、Noda Tetsuo
    • Journal Title

      Cancer Science

      Volume: 110 Pages: 1352-1363

    • DOI

      10.1111/cas.13967

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dynamics of sister chromatids through the cell cycle: Together and apart2018

    • Author(s)
      Takahashi Motoko、Hirota Toru
    • Journal Title

      The Journal of Cell Biology

      Volume: 217 Pages: 1887-1889

    • DOI

      10.1083/jcb.201804091

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nucleolar integrity during interphase supports faithful Cdk1 activation and mitotic entry2018

    • Author(s)
      Hayashi Yuki、Fujimura Akiko、Kato Kazashi、Udagawa Rina、Hirota Toru、Kimura Keiji
    • Journal Title

      Science Advances

      Volume: 4

    • DOI

      10.1126/sciadv.aap7777

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

      Biomed. Res.

      Volume: 39 Issue: 2 Pages: 75-85

    • DOI

      10.2220/biomedres.39.75

    • NAID

      130006708566

    • ISSN
      0388-6107, 1880-313X
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] がん細胞における染色体不安定性の病理機構2020

    • Author(s)
      広田 亨
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 分裂期染色体制御の破綻によるがん幹細胞のプロイディ変化2020

    • Author(s)
      趙 民知、サンペトラ・オルテア、佐谷秀行、広田 亨
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] セパレース制御異常が誘導するがん細胞の染色体分配異常2020

    • Author(s)
      進藤軌久、広田 亨
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 液液相分離を介したAurora Bキナーゼの活性化の時空間的な制御機構2020

    • Author(s)
      野澤竜介、広田 亨
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A robust mitotic regulation facilitates karyotypic evolution in cancer stem cells2020

    • Author(s)
      Toru Hirota
    • Organizer
      The 43rdnd Annual meeting of the Molecular Biology Society of Japan
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Chromosomal passenger complex creates a nuclear compartment regulating Aurora B kinase activity through liquid-liquid phase separation2020

    • Author(s)
      Ryu-Suke Nozawa, Toru Hirota
    • Organizer
      The 43rdnd Annual meeting of the Molecular Biology Society of Japan
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The homeostatic control of chromosomes. Symposium (Organizer)2019

    • Author(s)
      Toru Hirota and Katsuhiko Shirahige
    • Organizer
      The 71st Annual meeting of the Japan Society for Cell Biology (JSCB)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A robust control of mitotic transitions prevents chromosome missegregation.2019

    • Author(s)
      Toru Hirota
    • Organizer
      International Symposium Cancer Etiology. Tohoku Forum for Creativity
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Chromosome dynamics in cancers. Symposium (Organizer)2019

    • Author(s)
      Toru Hirota and Satoshi Tashiro
    • Organizer
      The 78th Annual meeting of the Japanese Cancer Association (JCA)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Possible contribution of chromosomal instability in cancer progression.2019

    • Author(s)
      Jo Minji, Oltea Sampetrean, Hideyuki Saya, Toru Hirota
    • Organizer
      The 78th Annual meeting of the Japanese Cancer Association (JCA)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Spatial control of Aurora B activity at centromeres in mitosis.2019

    • Author(s)
      Toru Hirota
    • Organizer
      The 42nd Annual meeting of the Molecular Biology Society of Japan (MBSJ)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Characterization of DNA binding mode of human condensin I and II.2018

    • Author(s)
      Motoko Takahashi and Toru Hirota
    • Organizer
      The 7th Meeting on Grant-in-Aid for scientific research on innovative areas “Chromosome Orchestration System”
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A robust transition from metaphase to anaphase prevents chromosome missegregation2018

    • Author(s)
      Toru Hirota
    • Organizer
      The 77th Annual meeting of the Japanese Cancer Association (JCA)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Single stranded DNA in interphase is a key chromatin structure for mitotic chromosome organization2018

    • Author(s)
      Motoko Takahashi and Toru Hirota
    • Organizer
      The 11th 3R+3C Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Troubles of the brake and engine driving chromosome segregation in cancer2018

    • Author(s)
      Toru Hirota
    • Organizer
      Symposium. Genoproteomic signature of human diseases
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A robust control of metaphase-to-anaphase transition ensures stable chromosome segregation2018

    • Author(s)
      Toru Hirota
    • Organizer
      The 41st Annual meeting of the Molecular Biology Society of Japan (MBSJ)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] 染色体分配:マルチステップに進む姉妹染色分体の分離. 実験医学2018

    • Author(s)
      内田和彦、広田 亨
    • Total Pages
      6
    • Publisher
      羊土社
    • Related Report
      2018 Annual Research Report
  • [Remarks] がん研 広田亨研究室

    • URL

      https://www.jfcr.or.jp/tci/exppathol/index.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] がん研究所 実験病理部

    • URL

      https://www.jfcr.or.jp/laboratory/department/experiment/index.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] がん研究所実験病理部・広田亨研究室

    • URL

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

    • Related Report
      2019 Annual Research Report
  • [Remarks] Researchmap(広田 亨)

    • URL

      https://researchmap.jp/toru_hirota/

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
  • [Remarks] がん研究所実験病理部

    • URL

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

    • Related Report
      2018 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
      2018 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2019

    • 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
      2019-168849
    • Filing Date
      2019
    • Related Report
      2019 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2019

    • 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
      2019
    • Acquisition Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Funded Workshop] The 37th Chromosome Workshop2019

    • Related Report
      2019 Annual Research Report
  • [Funded Workshop] The 11th 3R+3C Symposium2018

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2021-12-27  

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