Elucidation of the molecular mechanism of a novel response to microtubule-targeting agents and evaluation of their molecular as a potential therapeutic target.

• Project/Area Number: 25870501
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics; Tumor biology
• Research Institution: Kyushu University
• Principal Investigator: IIMORI Makoto 九州大学, 医学(系)研究科(研究院), 助教 (20546460)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 微小管結合性抗癌剤 / 有糸分裂 / 微小管 / Aurora B / EB2 / ゲノム不安定性 / 有糸分裂期 / ゲノム安定性

Outline of Final Research Achievements

Temporal regulation of microtubule dynamics is essential for proper progression of mitosis, and control of microtubule plus-end tracking proteins by phosphorylation is an essential component of this regulation. Here we show that Aurora B and CDK1 phosphorylate microtubule end-binding protein 2 (EB2) at multiple sites within the N-terminus and a cluster of serine/threonine residues in the linker connecting the calponin homology and end-binding homology domains. EB2 phosphorylation, which is strictly associated with mitotic entry and progression, reduces the binding affinity of EB2 for microtubules. Expression of non-phosphorylatable EB2 delayed formation of bipolar metaphase plates in a microtubule binding-dependent manner, and led to aneuploidy even in unperturbed mitosis. We propose that Aurora B and CDK1 temporally regulate EB2, as a downstream target of the spindle assembly checkpoint, thereby ensuring proper mitotic progression and genome stability.

Research Products

• [Journal Article] Rad9, Rad17, TopBP1 and claspin play essential roles in heat-induced activation of ATR kinase and heat tolerance. (2013)
  • Author(s): Tuul M, Kitao H, Iimori M, Matsuoka K, Kiyonari S, Saeki H, Oki E, Morita M, Maehara Y.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Presentation] 微小管結合性抗がん剤に対する新規細胞応答の分子機構 (2015)
  • Author(s): 飯森 真人
  • Organizer: 藤井節郎先生記念シンポジウム
  • Place of Presentation: 九州大学コラボステーションⅠ・福岡市
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] Aurora B and CDK1 cooperate to phosphorylate EB2 to ensure the mitotic progression and genomic stability (2014)
  • Author(s): M. Iimori, S. Watanabe, H. Saeki, E. Oki, E. Tokunaga, Y. Tou, H. Kitao, Y. Maehara
  • Organizer: 第73回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜・横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Aurora BおよびCDK1による微小管結合因子EB2の制御機構 (2013)
  • Author(s): 飯森真人、北尾洋之、前原喜彦
  • Organizer: 第25回 高遠シンポジウム
  • Place of Presentation: 延暦寺会館 ・大津市
• [Presentation] Aurora BおよびCDK1による微小管結合因子EB2の制御機構 (2013)
  • Author(s): 飯森真人、北尾洋之、渡邊すぎ子、前原喜彦
  • Organizer: 第36回 日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド・神戸市
• [Presentation] Physiological role of Aurora B and CDK1 in regulating microtubule-associated protein EB2 (2013)
  • Author(s): M. Iimori, H. Kitao, S. Watanabe, Y. Maehara
  • Organizer: The 2013 ASCB Annual Meeting
  • Place of Presentation: ニューオリンズ・アメリカ
• [Remarks] 九州大学 消化器・総合外科（第二外科）
  • URL: http://www.kyudai2geka.com
• [Remarks] 九州大学消化器・総合外科(第二外科)
  • URL: http://www.kyudai2geka.com/index.html