Role of kinetochore stretching in controlling the spindle-assembly checkpoint

• Project/Area Number: 21370082
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Molecular biology
• Research Institution: 公益財団法人がん研究会 (2011); Japanese Foundation For Cancer Research (2009-2010)
• 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)
• Co-Investigator(Renkei-kenkyūsha): 高垣 謙太郎 公益財団法人がん研究会, がん研究所・実験病理部, 博士研究員 (70419951) ; 内田 和彦 公益財団法人がん研究会, がん研究所・実験病理部, 博士研究員 (40380555) ; 進藤 軌久 公益財団法人がん研究会, がん研究所・実験病理部, 博士研究員 (00512253) ; 熊田 和貴 公益財団法人がん研究会, がん研究所・実験病理部, 博士研究員 (10370149)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2011: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2010: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2009: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 細胞分裂 / 染色体 / 動原体 / 微小管 / M期チェックポイント / 中期後期移行 / 染色体分配 / 紡錘体形成チェックポイント / 後期促進因子

Research Abstract

Faithful segregation of chromosomes relies on the spindle-assembly checkpoint(SAC), which delays anaphase onset until all kinetochores are attached to microtubules(MT). The SAC monitors MT attachment at kinetochores, but whether it also senses the presence of 'tension' has long been a matter of debate. We found that 'tension' applied across sister kinetochores, which stretches centromeres, is dispensable, but stretching of kinetochores is required for silencing the SAC(Uchida et al., 2009). It is therefore crucial to investigate if 'tension' underlies kinetochore stretching. We addressed this question experimentally by engineering the conditions that microtubules are attached to kinetochors but free from the pulling force. Under these conditions, we found that kinetochores underwent stretching upon MT attachment. These results suggest that intact kinetochore-pulling force is not required for kinetochore stretching, thus challenging the notion that SAC directly monitors the presence of tension.

Research Products

• [Journal Article] The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II (2011)
  • Author(s): Abe, S., Nagasaka, K., Hirayama, Y., Kozuka-Hata, H., Oyama, M., Aoyagi, Y., Obuse, C., and Hirota, T
  • Journal Title: Genes Dev Volume: 25 Pages: 863-874
  • Peer Reviewed
• [Journal Article] CAMP(C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment (2011)
  • Author(s): Ito, G., Kanno, S., Uchida, K. S. K, Chiba, S., Sugino, S., Watanabe, K., Mizuno, K., Yasui, A., Hirota, T., and Tanaka, K
  • Journal Title: EMBO J Volume: 30 Pages: 130-134
  • Peer Reviewed
• [Journal Article] Differential control of Eg5 dependent centrosome separation by Plk1 and Cdk1 (2011)
  • Author(s): Smith, E., Hegarat, N., Vesely, C., Roseboom, I., Streicher, H., Straatman, K., Flynn, H., Skehel, M., Hirota, T., Kuriyama, R., Hochegger, H
  • Journal Title: EMBO J Volume: 30 Pages: 2233-2245
  • Peer Reviewed
• [Journal Article] The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II (2011)
  • Author(s): Abe, S., Nagasaka, K., Hirayama, Y., Kozuka-Hata, H., Oyama, M., Aoyagi, Y., Obuse, C., Hirota, T.
  • Journal Title: Genes & Dev Volume: 25 Pages: 863-874
  • Peer Reviewed
• [Journal Article] CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment (2011)
  • Author(s): Ito, G., Kanno, S., Uchida, K S, Chiba, S., Sugino, S., Watanabe, K., Mizuno, K., Yasui, A., Hirota, T., Tanaka, K.
  • Journal Title: EMBO J Volume: 30 Pages: 130-144
  • Peer Reviewed
• [Journal Article] A single starfish Aurora performs dual functions of Auroras A and B in human cells (2010)
  • Author(s): Abe, Y., Okumura, E., Hosoya, T., Hirota, T., and Kishimoto, T.
  • Journal Title: J. Cell Sci Volume: 123 Pages: 3978-3988
  • Peer Reviewed
• [Journal Article] Human POGZ modulates HP1 dissociation from mitotic chromosome arms through Aurora B activation (2010)
  • Author(s): Nozawa, R., Nagao, K., Masuda, H., Iwasaki, O., Hirota, T., Nozaki, N., Kimura, H., and Obuse, C.
  • Journal Title: Nat. Cell Biol Volume: 12 Pages: 719-727
  • Peer Reviewed
• [Journal Article] TRF1 mediates mitotic abnormalities induced by Aurora-A overexpression (2010)
  • Author(s): Ohishi, T., Hirota, T., Tsuruo, T., Seimiya, H.
  • Journal Title: Cancer Res Volume: 70 Pages: 2041-2052
  • Peer Reviewed
• [Journal Article] Requirement of ATM for Rapid p53 Phosphorylation at Ser46 without Ser/Thr-Gln Sequences (2010)
  • Author(s): Kodama, M., Otsubo, C., Hirota, T., Yokota, J., Enari, M., Taya, Y
  • Journal Title: Mol. Cell. Biol Volume: 30 Pages: 1620-1633
  • Peer Reviewed
• [Journal Article] Differential control of Eg5 dependent centrosome separation by Plk1 and Cdk1. (2010)
  • Author(s): Smith, E., Hegarat, N., Vesely, C., Roseboom, I., Streicher, H., Straatman, K., Flynn, H., Skehel, M., Hirota, T., Kuriyama, R., Hochegger, H.
  • Journal Title: EMBO Journal Volume: 30 Pages: 130-144
  • Peer Reviewed
• [Journal Article] The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II. (2010)
  • Author(s): Abe, S., Nagasaka, K., Hirayama, Y., Kozuka-Hata, H., Oyama, M., Aoyagi, Y., Obuse, C., Hirota, T.
  • Journal Title: Genes and Development Volume: 12 Pages: 719-727
  • Peer Reviewed
• [Journal Article] CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule at tachment. (2010)
  • Author(s): Ito, G., Kanno, S., Uchida, K.S.K, Chiba, S., Sugino, S., Watanabe, K., Mizuno, K., Yasui, A., Hirota, T., Tanaka, K.
  • Journal Title: EMBO Journal Volume: 30 Pages: 130-144
  • Peer Reviewed
• [Journal Article] A single starfish Aurora performs dual functions of Auroras A and B in human cells. (2010)
  • Author(s): Abe, Y., Okumura, E., Hosoya, T., Hirota, T., Kishimoto, T.
  • Journal Title: Journal of Cell Science Volume: 123 Pages: 3978-3988
  • Peer Reviewed
• [Journal Article] Human POGZ modulates HP1 dissociation from mitotic chromosome arms through Aurora B activation. (2010)
  • Author(s): Nozawa, R., Nagao, K., Masuda, H., Iwasaki, O., Hirota, T., Nozaki N., Kimura, H., Obuse, C.
  • Journal Title: Nature Cell Biology Volume: 12 Pages: 719-727
  • Peer Reviewed
• [Journal Article] Requirement of ATM for Rapid p53 Phosphorylation at Ser46 without Ser/Thr-GIn Sequences. (2010)
  • Author(s): Kodama M, Otsubo C, Hirota T, Yokota J, Enari M, Taya Y.
  • Journal Title: Molecular and Cellular Biology Volume: 30 Pages: 1620-1633
  • Peer Reviewed
• [Journal Article] TRF1 mediates mitotic abnormalities induced by Aurora A overexpression. (2010)
  • Author(s): Ohishi, T., Hirota, T., Tsuruo, T., Seimiya, H.
  • Journal Title: Cancer Research Volume: 70 Pages: 2041-2052
  • Peer Reviewed
• [Journal Article] 染色体動態を制御する動原体微小管のダイナミクス (2010)
  • Author(s): 広田亨
  • Journal Title: 細胞工学 Volume: 29 Pages: 862-867
• [Journal Article] Requirement of ATM for Rapid p53 Phosphorylation at Ser46 without Ser/Thr-Gln Sequences (2010)
  • Author(s): Kodama M, Otsubo C, Hirota T, Yokota J, Enari M, Taya Y.
  • Journal Title: Molecular and Cellular Biology 30 Pages: 1620-1633
  • Peer Reviewed
• [Journal Article] TRF1 mediates mitotic abnormalities induced by Aurora A overexpression (2010)
  • Author(s): Ohishi, T., Hirota, T., Tsuruo, T., Seimiya, H.
  • Journal Title: Cancer Research 70 Pages: 2041-2052
  • Peer Reviewed
• [Journal Article] Kinetochore stretching inactivates the spindle assembly checkpoint (2009)
  • Author(s): Uchida, K. S. K., Takagaki, K., Kumada, K, Noda, T., and Hirota, T
  • Journal Title: J. Cell Biol Volume: 184 Pages: 384-390
  • Peer Reviewed
• [Journal Article] Chromosome segregation machinery and cancer (2009)
  • Author(s): Tanaka, K., and Hirota, T
  • Journal Title: Cancer Sci Volume: 100 Pages: 1158-1165
  • Peer Reviewed
• [Journal Article] Chromosome segregation machinery and cancer (2009)
  • Author(s): Tanaka K, Hirota T.
  • Journal Title: Cancer Science 100 Pages: 383-390
  • Peer Reviewed
• [Journal Article] ヒストンの化学修飾:新たな標的エピジェネティクスを目指して (2009)
  • Author(s): 進藤軌久、広田亨
  • Journal Title: 臨床血液 50 Pages: 282-288
• [Presentation] がん細胞における異数性の発生要因を考える (2012)
  • Author(s): 広田亨
  • Organizer: 第28回新潟県立中央病院集談会・特別講演
  • Place of Presentation: 上越
  • Year and Date: 2012-03-02
• [Presentation] Separaseは染色体分離において一人二役を果たす (2012)
  • Author(s): 進藤軌久、広田亨
  • Organizer: 第29回染色体ワークショップ
  • Place of Presentation: 秋保温泉
• [Presentation] Separaseの自己切断による染色体分配制御 (2012)
  • Author(s): 熊田和貴、広田亨
  • Organizer: 第29回染色体ワークショップ
  • Place of Presentation: 秋保温泉
• [Presentation] アナログ感受性変異体によるGreatwallキナーゼの機能解析 (2012)
  • Author(s): 阿部優介、広田亨
  • Organizer: 第29回染色体ワークショップ
  • Place of Presentation: 秋保温泉
• [Presentation] Does the spindle-assembly checkpoint monitor the presence of tension? (2011)
  • Author(s): Kazuhiko Uchida, Toru Hirota
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: Yokohama
  • Year and Date: 2011-12-16
• [Presentation] Probing separase activity reveals its switch-like activation at the metaphase-to-anaphase transition (2011)
  • Author(s): Toru Hirota
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: Yokohama
  • Year and Date: 2011-12-15
• [Presentation] How mitotic kinases control chromosome segregation (2011)
  • Author(s): Hirota, T.
  • Organizer: 熊本大学GCOE・リエゾンラボ研究会
  • Place of Presentation: 熊本
  • Year and Date: 2011-11-02
• [Presentation] 染色体分離の正確性を保証するメカニズム (2011)
  • Author(s): 広田亨
  • Organizer: ケミカルバイオロジー勉強会・理化学研究所
  • Place of Presentation: 和光
  • Year and Date: 2011-10-26
• [Presentation] Heterochromatin protein 1 is an essential component of the chromosomal passenger complex to prevent missegregation of chromosomes (2011)
  • Author(s): Hirota, T
  • Organizer: 平成23年度遺伝研研究会クロマチンダイナミクスの分子機構
  • Place of Presentation: 三島
  • Year and Date: 2011-10-20
• [Presentation] The switch-like activation of separase ensures chromosome segregation (2011)
  • Author(s): Hirota, T
  • Organizer: The GCOE International Workshop Mitosis
  • Place of Presentation: Yokohama
  • Year and Date: 2011-07-04
• [Presentation] The switch-like activation of separase ensures chromosome segregation (2011)
  • Author(s): Toru Hirota
  • Organizer: 6th GCOE International Symposium : Mitosis
  • Place of Presentation: Yokohama
  • Year and Date: 2011-07-04
• [Presentation] Probing separase activity reveals its switch-like activation at the metaphase-to-anaphase transition (2011)
  • Author(s): Toru Hirota
  • Organizer: MEXT International Symposium : Cell Division
  • Place of Presentation: Hakone
  • Year and Date: 2011-06-30
• [Presentation] 染色体分離の同期性を保証するメカニズム (2011)
  • Author(s): 広田亨
  • Organizer: 北海道大学大学院・先端生命科学研究院・分子生物学特別セミナー
  • Place of Presentation: 札幌
  • Year and Date: 2011-06-24
• [Presentation] がん細胞における異数性の発生要因を考える (2011)
  • Author(s): 広田亨
  • Organizer: 第52回日本臨床細胞学術総会(春期大会)
  • Place of Presentation: 福岡
  • Year and Date: 2011-05-21
• [Presentation] How chromosome assembly is triggered in cells entering mitosis (2011)
  • Author(s): Hirota, T
  • Organizer: Impromptu Seminar at the IMP
  • Place of Presentation: Vienna
  • Year and Date: 2011-04-14
• [Presentation] How chromosome assembly is triggered in cells entering mitosis (2011)
  • Author(s): Hirota, T
  • Organizer: 6th UK-Japan Cell Cycle Meeting
  • Place of Presentation: Windermere
• [Presentation] がん細胞における異数性の発生要因を考える (2011)
  • Author(s): 広田亨
  • Organizer: 第52回日本臨床細胞学会総会
  • Place of Presentation: 福岡
• [Presentation] Probing separase activity reveals its switch-like activation at the metaphase-to-anaphase transition (2011)
  • Author(s): Hirota, T
  • Organizer: The 2^<nd> Dynamic Kinetochore Workshop
  • Place of Presentation: Vienna
• [Presentation] Probing separase activity reveals its switch-like activation at the metaphase-to-anaphase transition (2011)
  • Author(s): Hirota, T
  • Organizer: The MEXT Priority Research International Symposium Cell Division
  • Place of Presentation: Hakone
• [Presentation] Dual role of separase during the metaphase-to-anaphase transition ensures chromosome segregation in mammalian cells (2011)
  • Author(s): Shindo, N., Hirota, T.
  • Organizer: Annual meeting of American Society of Cell Biology
  • Place of Presentation: Denver
• [Presentation] Probing separase activity reveals its switch-like activation at the metaphase-to-anaphase transition (2011)
  • Author(s): Hirota, T
  • Organizer: 第30回日本分子生物学会.シンポジウム
  • Place of Presentation: 横浜
• [Presentation] Does the spindle-assembly checkpoint monitor the presence of tension (2011)
  • Author(s): Uchida, K. S. K., Hirota, T.
  • Organizer: 第30回日本分子生物学会・ワークショップ
  • Place of Presentation: 横浜
• [Presentation] Cdk1によるCondensin IIのリン酸化が染色体凝縮を誘導する (2011)
  • Author(s): 長坂浩太、阿部聡司、広田亨
  • Organizer: 第28回染色体ワークショップ
  • Place of Presentation: 山代温泉
• [Presentation] セパレースの可視化でわかってきたこと (2011)
  • Author(s): 進藤軌久、広田亨
  • Organizer: 第28回染色体ワークショップ
  • Place of Presentation: 山代温泉
• [Presentation] 新規Mad2L2結合分子CAMPによるキネトコア-微小管結合の制御 (2011)
  • Author(s): 田中耕三、伊藤剛、安井明、広田亨
  • Organizer: 第28回染色体ワークショップ
  • Place of Presentation: 山代温泉
• [Presentation] Visualization of separase activity defines the activation timing at the metaphase-to-anaphase transition (2010)
  • Author(s): Shindo, N., Hirota, T.
  • Organizer: Annual meeting of American Society of Cell Biology
  • Place of Presentation: Philadelphia
  • Year and Date: 2010-12-11
• [Presentation] How chromosomes are assembled in cells entering mitosis (2010)
  • Author(s): Hirota, T.
  • Organizer: The MEXT Priority Research International Symposium Mitosis
  • Place of Presentation: Tokyo
  • Year and Date: 2010-11-08
• [Presentation] How chromosomes are assembled in mitosis (2010)
  • Author(s): Hirota T.
  • Organizer: MEXT Priority Research Project "Cell Proliferation Control" International Workshop.
  • Place of Presentation: JFCR Cancer Institute (Tokyo)
  • Year and Date: 2010-11-08
• [Presentation] 染色体分離の瞬間を規定するメカニズム (2010)
  • Author(s): 広田亨
  • Organizer: かずさDNA研究所・セミナー
  • Place of Presentation: 木更津
  • Year and Date: 2010-09-17
• [Presentation] ヒト細胞における染色体の分配機構 (2010)
  • Author(s): 広田亨
  • Organizer: 国立がん研究センター研究所・セミナー
  • Place of Presentation: 東京
  • Year and Date: 2010-05-28
• [Presentation] Toward targeting chromosome segregation machinery for cancer therapeutics (2010)
  • Author(s): Hirota, T
  • Organizer: 8th Annual meeting of Japanese Society of Medical Oncology
  • Place of Presentation: Tokyo
  • Year and Date: 2010-03-29
• [Presentation] Toward targeting chromosome segregation machinery for cancer therapeutics (2010)
  • Author(s): Hirota T.
  • Organizer: The 8th Annual Meeting of Japanese Society of Medical Oncology
  • Place of Presentation: Big Sight, Tokyo
  • Year and Date: 2010-03-19
• [Presentation] Aurora BはHP1αの動態制御を介し安定した染色体分配を保証する (2010)
  • Author(s): 高垣謙太郎、内田和彦、広田亨
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 新規Mad2L2結合分子CAMPによるキネトコア-微小管結合の制御 (2010)
  • Author(s): 田中耕三、伊藤剛、安井明、広田亨
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II (2010)
  • Author(s): 長坂浩太、阿部聡司、広田亨
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] Charactrization of the Smc5/6 complex in human cells (2010)
  • Author(s): リナ・マルセロ・ガジェゴ・パエツ、坂東優篤、広田亨、白髭克彦
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] Aurora BはHP1αの動態制御を介し安定した染色体分配を保証する (2010)
  • Author(s): 高垣謙太郎、広田亨
  • Organizer: 第27回染色体ワークショップ
  • Place of Presentation: 御殿場
• [Presentation] ヒト細胞における染色体分離開始とセパレース活性化のタイミング (2010)
  • Author(s): 進藤軌久、広田亨
  • Organizer: 第27回染色体ワークショップ
  • Place of Presentation: 御殿場
• [Presentation] How mammalian cells trigger chromosome segregation at the correct time (2009)
  • Author(s): Hirota, T
  • Organizer: Seminar at European Molecular Biology Laboratories
  • Place of Presentation: Heidelberg
  • Year and Date: 2009-11-23
• [Presentation] ヒト細胞における染色体分離の制御 (2009)
  • Author(s): 広田亨
  • Organizer: 東京大学医科学研究所. GCOE特別セミナー
  • Place of Presentation: 東京
  • Year and Date: 2009-11-08
• [Presentation] How chromosomes segregation is triggered in human cells (2009)
  • Author(s): Hirota, T
  • Organizer: Seminar at Eidgenossische Technische Hochschule Zurich
  • Place of Presentation: Zurich
  • Year and Date: 2009-08-28
• [Presentation] Chromosome segregation machinery (2009)
  • Author(s): Hirota, T., Kishimoto, T. Organizer
  • Organizer: The MEXT Priority Research International Workshop
  • Place of Presentation: Tokyo
  • Year and Date: 2009-06-05
• [Presentation] Kinetochore stretching promotes the metaphase-to-anaphase transition (2009)
  • Author(s): Hirota T.
  • Organizer: The 61st Annual Meeting of the Japan Society for Cell Biology(JSCB), Symposium "Mitotic Checkpoint and Chromosome Segregation"
  • Place of Presentation: Nagoya Congress Center, Nagoya
  • Year and Date: 2009-06-04
• [Presentation] Kinetochore stretching promotes the metaphase-to-anaphase transition (2009)
  • Author(s): Hirota, T
  • Organizer: 61st Annual Meeting of the Japanese Society for Cell Biology
  • Place of Presentation: Nagoya
• [Presentation] Kinetochore stretching promotes the metaphase-to-anaphase transition (2009)
  • Author(s): Hirota, T. Uchida K. S. K
  • Organizer: FASEB Meeting Mitosis : Spindle assembly and function
  • Place of Presentation: Lucca
• [Presentation] Kinetochore stretching : Is it sensed by the SAC? (2009)
  • Author(s): Hirota T.
  • Organizer: FASEB conference "Mitosis : Spindle assembly and Function"
  • Place of Presentation: II Ciocco Resort, Lucca, Italy
• [Book] Mitosis and Meiosis : Molecular Control of Chromosome Separation. Review Encyclopedia of Life Sciences (2011)
  • Author(s): Nagasaka, K., Gallego-Paez, L. M., Hirota, T
• [Book] Separase. Review. Handbook of Proteolytic Enzymes 3rd Edition (2011)
  • Author(s): Kumada, K., Hirota, T
• [Book] Review, in Encyclopedia of Life Sciences (Mitosis and meiosis : Molecular control of chrmosome separation) (2011)
  • Author(s): K.Nagasaka, L.M.Gallego-Paez, T.Hirota
  • Total Pages: 10
  • Publisher: John Wiley & Sons, Ltd.
• [Book] 紡錘体形成チェックポイント (2010)
  • Author(s): 広田亨
  • Publisher: 細胞工学
• [Book] 紡錘体形成チェックポイント (2010)
  • Author(s): 広田亨
  • Publisher: 東京、共立出版
• [Book] 細胞周期フロンティア(紡錘体形成チェックポイント)(広田亨) (2010)
  • Author(s): 佐方功幸, ほか編(執筆分担)
  • Total Pages: 8
  • Publisher: 共立出版(東京)
• [Book] ヒストンのリン酸化によるクロマチンの制御 (2009)
  • Author(s): 広田亨、進藤軌久
  • Publisher: 実験医学
• [Remarks]
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• [Remarks]
  • URL: http://www.jfcr.or.jp/tci/exppathol/index.html
• [Remarks]
  • URL: http://www.jfcr.or.jp/tci/exppathol/index.html
• [Remarks]
  • URL: http://www.jfcr.or.jp/tci/exppathol/index.html