The fate of aneuploid cells

• Project/Area Number: 15H02398
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Mie University
• Principal Investigator: Inagaki Masaki 三重大学, 医学系研究科, 教授 (30183007)
• Co-Investigator(Kenkyū-buntansha): 後藤 英仁 三重大学, 医学系研究科, 特任准教授(研究担当) (20393126) ; 笠原 広介 三重大学, 医学系研究科, 准教授 (90455535) ; 猪子 誠人 愛知県がんセンター(研究所), 腫瘍医化学部, 主任研究員 (30393127) ; 井澤 一郎 愛知県がんセンター(研究所), 腫瘍医化学部, 室長 (20311441) ; 田中 宏樹 愛知県がんセンター(研究所), 腫瘍医化学部, リサーチレジデント (20725452)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥39,910,000 (Direct Cost: ¥30,700,000、Indirect Cost: ¥9,210,000); Fiscal Year 2018: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2017: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2016: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2015: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: 染色体異数性 / 中間径フィラメント / 細胞質分裂 / 老化 / がん化 / 染色体不安定性 / aneuploidy / 分化 / 中心体 / 染色体 / 中間系フィラメント

Outline of Final Research Achievements

Intermediate filaments (IFs) are dramatically reorganized during mitosis. Some protein kinases activated in mitosis control spatial and temporal IF reorganization through IF phosphorylation. Here, we analyzed the dorsal skin wound healing in phospho-vimentin-deficient mice. In response to skin injury, vimentin expression was elevated at wound areas of subcutaneous fibroblast in a genotype-independent manner. During the acute phase of wound healing when vimentin expression was relatively high, IF-bridge formation, binuclation, and extra-centrosome formation was observed specifically in fibroblast of phospho-vimentin-deficient mice. These cellular structures disappeared with decreased expression, leading to increased numbers of aneuploid fibroblasts. Subsequently the fibroblasts exhibited a significant elevation of major senescence-relative markers. These abnormalities resulted in implicated wound healing, one of the premature aging phenotypes.

Academic Significance and Societal Importance of the Research Achievements

aneuploidy（染色体異数性）はがん発生において直接的な引き金になるのかという生物学的に非常に重要な問いに対して、、本研究成果は、間葉系組織で高効率にanuploid細胞が生じる遺伝子改変マウスにおいては、むしろ白内障や皮下脂肪減少、創傷治癒遅延といった老化症状を引きおこうすことを示した。さらに、aneuploidyから老化に至る分子メカニズムの糸口となりうるモデルマウスの開発に成功した。

Research Products

• [Journal Article] Primary Cilia as Signaling Hubs in Health and Disease (2018)
  • Author(s): Nishimura Yuhei、Kasahara Kousuke、Shiromizu Takashi、Watanabe Masatoshi、Inagaki Masaki
  • Journal Title: Advanced Science Volume: 6 Issue: 1 Pages: 1801138-1801138
  • DOI: 10.1002/advs.201801138
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase (2018)
  • Author(s): Kasahara K, Aoki H, Kiyono T, Wang S, Kagiwada H, Yuge M, Tanaka T, Nishimura Y, Mizoguchi A, Goshima N, Inagaki M
  • Journal Title: Nat Commun Volume: 9 Issue: 1 Pages: 758-758
  • DOI: 10.1038/s41467-018-03117-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tetraploidy in cancer and its possible link to aging. (2018)
  • Author(s): Tanaka K, Goto H, Nishimura Y, Kasahara K, Mizoguchi A, Inagaki M.
  • Journal Title: Cancer Science Volume: 109 Issue: 9 Pages: 2632-2640
  • DOI: 10.1111/cas.13717
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of keratin 5/14 intermediate filaments by CDK1, Aurora-B, and Rho-kinase (2018)
  • Author(s): Inaba H, Yamakawa D, Tomono Y, Enomoto A, Mii S, Kasahara K, Goto H, Inagaki M
  • Journal Title: Biochem Biophys Res Commun Volume: 498 Issue: 3 Pages: 544-550
  • DOI: 10.1016/j.bbrc.2018.03.016
  • Peer Reviewed / Open Access
• [Journal Article] Increased Neuronal Differentiation of Neural Progenitor Cells Derived from Phosphovimentin-Deficient Mice (2018)
  • Author(s): Chen M, Puschmann TB, Marasek P, Inagaki M, Pekna M, Wilhelmsson U, Pekny M.
  • Journal Title: Mol Neurobiol Volume: 印刷中 Issue: 7 Pages: 5478-5489
  • DOI: 10.1007/s12035-017-0759-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression (2017)
  • Author(s): Andrieu G, Ledoux A, Branka S, Bocquet M, Gilhodes J, Walzer T, Kasahara K, Inagaki M, Sabbadini RA, Cuvillier O, Hatzoglou A
  • Journal Title: Sci Signal Volume: - Issue: 472
  • DOI: 10.1126/scisignal.aah4007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mechanisms of ciliogenesis suppression in dividing cells. (2017)
  • Author(s): Goto H., Inaba H., and Inagaki M.
  • Journal Title: Cell. Mol. life Sci. Volume: 74 Issue: 5 Pages: 881-890
  • DOI: 10.1007/s00018-016-2369-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Desmin phosphorylation by Cdk1 is required for efficient separation of desmin intermediate filaments in mitosis and detected in murine embryonic/newborn muscle and human rhabdomyosarcoma tissues. (2016)
  • Author(s): Makihara H., Inaba H., Enomoto A., Tanaka H., Tomono Y., Ushida K., Goto M., Kurita K., Nishida Y., Kasahara K., Goto H., and Inagaki M.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 478 Issue: 3 Pages: 1323-1329
  • DOI: 10.1016/j.bbrc.2016.08.122
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ndel1 suppresses ciliogenesis in proliferating cells by regulating the trichoplein-Aurora A pathway. (2016)
  • Author(s): Inaba H, Goto H, Kasahara K, Kumamoto K, Yonemura S, Inoko A, Yamano S, Wanibuchi H, He D, Goshima N, Kiyono T, Hirotsune S, Inagaki M.
  • Journal Title: J Cell Biol. Volume: 212 Issue: 4 Pages: 409-423
  • DOI: 10.1083/jcb.201507046
  • Peer Reviewed / Open Access
• [Journal Article] Phospho-Specific Antibody Probes of Intermediate Filament Proteins (2016)
  • Author(s): Goto H, Tanaka H, Kasahara K, Inagaki M.
  • Journal Title: Methods in Enzymology Volume: 568 Pages: 85-111
  • DOI: 10.1016/bs.mie.2015.07.010
  • ISBN: 9780128034705
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 一次線毛の形成動態によるがん細胞増殖制御機構の解明 (2018)
  • Author(s): 笠原広介, 稲垣昌樹
  • Organizer: 第77回日本癌学会学術総会
  • Invited
• [Presentation] Primary cilia and cell cycle (2016)
  • Author(s): Inagaki M, Kasahara K.
  • Organizer: The 28th CDB meeting “Cilia and Centrosomes”
  • Place of Presentation: RIKEN CDB (Kobe, Japan)
  • Year and Date: 2016-11-27
  • Int'l Joint Research / Invited
• [Presentation] Primary cilia and cell cycle (2016)
  • Author(s): Inagaki M. and Kasahara K.
  • Organizer: The 28th CDB meeting "Cilia and Centrosomes"
  • Place of Presentation: RIKEN CDB (Kobe, Japan)
  • Year and Date: 2016-11-27
  • Int'l Joint Research / Invited
• [Book] メディカル・サイエンス・ダイジェスト4月号 (2019)
  • Author(s): 笠原広介、稲垣昌樹
  • Total Pages: 4
  • Publisher: ニューサイエンス社