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Analysis on a novel checkpoint mechanism by which centrosomal kinases Lats1/2 regulate the chromosomal stability

Research Project

Project/Area Number 26430112
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionOsaka University

Principal Investigator

YABUTA NORIKAZU  大阪大学, 微生物病研究所, 准教授 (10343245)

Co-Investigator(Renkei-kenkyūsha) NOJIMA Hiroshi  大阪大学, 微生物病研究所, 教授 (30156195)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords染色体不安定性 / キナーゼ / 中心体 / Lats / 細胞質分裂 / Hippo pathway / リン酸化 / チェックポイント / Hippo
Outline of Final Research Achievements

Dysregulation of the centrosome cycle promotes the chromosomal instability (CIN), one of the hallmarks of tumor malignancy, thereby inducing centrosome overduplication, multipolar spindle formation, and chromosome missegregation. This suggests that certain centrosomal kinases stringently regulate the mitotic checkpoint. In this study, we found that the centrosomal kinases, Lats1 and Lats2, regulate centrosome duplication, cytokinesis, accurate chromosome segregation, and a nuclear function after DNA damage by phosphorylating various target proteins, such as Cdc25B, CHO1/MKLP1, and INCENP, thereby avoiding the induction of CIN. Therefore, we proposed a model in which the centrosomes function not only as a mitotic spindle pole for microtubule nucleation but also as an important site for crosstalk of signaling pathways in the mitotic checkpoint.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (31 results)

All 2017 2016 2015 2014 Other

All Journal Article (17 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 16 results,  Open Access: 8 results,  Acknowledgement Compliant: 4 results) Presentation (12 results) (of which Int'l Joint Research: 1 results) Remarks (2 results)

  • [Journal Article] GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase.2017

    • Author(s)
      Fukushima K, Wang M, Naito Y, Uchihashi T, Kato Y, Mukai S, Yabuta N, Nojima H.
    • Journal Title

      Cell Cycle

      Volume: 16 Issue: 5 Pages: 415-427

    • DOI

      10.1080/15384101.2016.1241916

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] LATS2 Positively Regulates Polycomb Repressive Complex 2.2016

    • Author(s)
      Torigata K, Daisuke O, Mukai S, Hatanaka A, Ohka F, Motooka D, Nakamura S,Ohkawa Y, Yabuta N, Kondo Y, Nojima H.
    • Journal Title

      PLoS One

      Volume: 11 Issue: 7 Pages: e0158562-e0158562

    • DOI

      10.1371/journal.pone.0158562

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol.2016

    • Author(s)
      Jagannathan R, Schimizzi GV, Zhang K, Loza AJ, Yabuta N, Nojima H, Longmore GD.
    • Journal Title

      Molecular Cell Biology

      Volume: 36 Issue: 20 Pages: 2526-2542

    • DOI

      10.1128/mcb.00136-16

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Large tumor suppressors 1 and 2 regulate Aurora-B through phosphorylation of INCENP to ensure completion of cytokinesis.2016

    • Author(s)
      Yabuta N, Yoshida K, Mukai S, Kato Y, Torigata K, Nojima H.
    • Journal Title

      Heliyon

      Volume: 2 Issue: 7 Pages: e00131-e00131

    • DOI

      10.1016/j.heliyon.2016.e00131

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Comprehensive phenotypic analysis of knockout mice deficient in cyclin G1 and cyclin G2.2016

    • Author(s)
      Ohno S, Ikeda JI, Naito Y, Okuzaki D, Sasakura T, Fukushima K, Nishikawa Y, Ota K, Kato Y, Wang M, Torigata K, Kasama T, Uchihashi T, Miura D, Yabuta N, Morii E, Nojima H.
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 39091-39091

    • DOI

      10.1038/srep39091

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] AJUBA LIM proteins limit Hippo activity only in proliferating cells by sequestering a cytosolic Hippo core kinase complex.2016

    • Author(s)
      Jagannathan R, Schimizzi GV, Zhang K, Loza AJ, Yabuta N, Nojima H, Longmore GD
    • Journal Title

      Molecular and Cell Biology

      Volume: 印刷中

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] ELAS1-mediated inhibition of the cyclin G1-B'γ interaction promotes cancer cell apoptosis via stabilization and activation of p53.2015

    • Author(s)
      Ohno S, Naito Y, Mukai S, Yabuta N, Nojima H
    • Journal Title

      Oncogene

      Volume: 34 Issue: 49 Pages: 5983-5996

    • DOI

      10.1038/onc.2015.47

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cyclin G2: A novel independent prognostic marker in pancreatic cancer.2015

    • Author(s)
      Hasegawa S, Nagano H, Konno M, Eguchi H, Tomokuni A, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Marubashi S, Nishida N, Koseki J, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H.
    • Journal Title

      Oncology Letters

      Volume: 10 Pages: 2986-2990

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Lats1 suppresses centrosome overduplication by modulating the stability of Cdc25B.2015

    • Author(s)
      Mukai S, Yabuta N, Yoshida K, Okamoto A, Miura D, Furuta Y, Abe T, Nojima H.
    • Journal Title

      Scientific Reports

      Volume: 5 Issue: 1 Pages: 16173-16173

    • DOI

      10.1038/srep16173

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Withaferin A induces cell death selectively in androgen-independent prostate cancer cells but not in normal fibroblast cells.2015

    • Author(s)
      Nishikawa Y, Okuzaki D, Fukushima, K, Mukai S, Ohno S, Ozaki Y, Yabuta N, Nojima H.
    • Journal Title

      PLoS One

      Volume: 10 Issue: 7 Pages: e0134137-e0134137

    • DOI

      10.1371/journal.pone.0134137

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP.2015

    • Author(s)
      Chen Q, Zhang N, Xie R, Wang W, Cai J, Choi KS, David KK, Huang B, Yabuta N, Nojima H, Anders RA, Pan D.
    • Journal Title

      Genes & Development

      Volume: 29 Issue: 12 Pages: 1285-1297

    • DOI

      10.1101/gad.264234.115

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Phosphorylation of CHO1 by Lats1/2 regulates the centrosomal activation of LIMK1 during cytokinesis.2015

    • Author(s)
      Okamoto A, Yabuta N, Mukai S, Torigata K, Nojima H.
    • Journal Title

      Cell Cycle

      Volume: 印刷中

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] ELAS1-mediated inhibition of the Cyclin G1-B'γ interaction promotes cancer cell apoptosis via stabilization and activation of p53.2015

    • Author(s)
      Ohno S, Naito Y, Mukai S, Yabuta N, Nojima H
    • Journal Title

      Oncogene

      Volume: 印刷中

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer.2014

    • Author(s)
      Hasegawa S, Eguchi H, Nagano H, Konno M, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Nishida N, Koseki J, Nishimura T, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H.
    • Journal Title

      Br. J. Cancer

      Volume: 111 Issue: 8 Pages: 1572-80

    • DOI

      10.1038/bjc.2014.454

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Journal Article] Gefitinib and luteolin cause growth arrest of human prostate cancer PC-3 cells via inhibition of Cyclin G-associated kinase and induction of miR-6302014

    • Author(s)
      Sakurai MA, Ozaki Y, Okuzaki D, Naito Y, Sasakura T, Okamoto A, Tabara H, Inoue T, Hagiyama M, Ito A, Yabuta N, and Nojima H.
    • Journal Title

      PLoS One

      Volume: 9 Issue: 6 Pages: e100124-e100124

    • DOI

      10.1371/journal.pone.0100124

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A functional interaction between Hippo-Y AP signalling and FoxO1 mediates the oxidative stress response2014

    • Author(s)
      Shao D, Zhai P, Del Re DP, Sciarretta S, Y abuta N, Nojima H, Lim DS, Pan D, Sadoshima J
    • Journal Title

      Nat. Commun

      Volume: 5 Issue: 1 Pages: 3315-3315

    • DOI

      10.1038/ncomms4315

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Latsキナーゼによる細胞周期と細胞死の制御機構2014

    • Author(s)
      藪田紀一、野島博
    • Journal Title

      医学のあゆみ

      Volume: 251 Pages: 357-364

    • Related Report
      2014 Research-status Report
  • [Presentation] GAKがリン酸化した TAp63はLCE1C 遺伝子を特異的に転写誘導する2016

    • Author(s)
      太田知絵、篠倉悠久、奥崎大介、福島孝士朗、向井智美、藪田紀一、野島博
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] G1/SライセンシングにおけるGAKによるpRbのリン酸化の分子制御機構2016

    • Author(s)
      加藤依香、福島孝士朗、松浦克磨、藪田紀一, 野島博
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] LATS1 suppresses E-cadherin expression through phosphorylation of its transcription regulators in invasive breast cancer.2016

    • Author(s)
      Satomi Mukai, Norikazu Yabuta, Mishie Tanino, Kosuke Torigata, Yoshitaka Sekido, Shinya Tanaka, Hiroshi Nojima
    • Organizer
      第75回日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] ELAS1 peptide caused apoptosis in both adenocarcinoma and squamous cell carcinoma.2016

    • Author(s)
      Kaori Ota, Toshihiro Uchihashi, Yusuke Yabuno, Mikihiko Kogo, Norikazu Yabuta and Hiroshi Nojima
    • Organizer
      第75回日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] Lats1 suppresses centrosome overduplication by modukating the stability of Cdc25B.2016

    • Author(s)
      Kato Y, Mukai S, Yabuta N, Yoshida K, Okamoto A, Miura D, Furuta Y, Abe T, Nojima H.
    • Organizer
      CDB Symposium 2016
    • Place of Presentation
      理研CDB(神戸)
    • Year and Date
      2016-03-28
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] 癌抑制遺伝子Lats1/2キナーゼのダブルノックアウト細胞の表現型解析2015

    • Author(s)
      加藤 依香、向井 智美、鳥形 康輔、藪田 紀一、野島 博
    • Organizer
      第38回日本分子生物学会年会
    • Place of Presentation
      神戸国際会議場(神戸)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Research-status Report
  • [Presentation] Lats1キナーゼはZEB1をリン酸化し、乳癌細胞におけるEMT-METを制御する2015

    • Author(s)
      向井 智美、安藤 有美、加藤 依香、鳥形 康輔、藪田 紀一、野島 博
    • Organizer
      第38回日本分子生物学会年会
    • Place of Presentation
      神戸国際会議場(神戸)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Research-status Report
  • [Presentation] Phosphorylations of ZEB1 by LATS1 and LATS2 regulate EMT-MET plasticity in breast cancer cells.2015

    • Author(s)
      向井 智美、鳥形康輔、藪田 紀一, 野島 博
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(名古屋)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Research-status Report
  • [Presentation] Lats1/2はモータータンパク質であるCHO1のリン酸化を介してLIMK1のM期局在を制御している2014

    • Author(s)
      岡本歩、向井智美、鳥形康輔、藪田紀一、野島博
    • Organizer
      第37回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(横浜市)
    • Year and Date
      2014-11-27
    • Related Report
      2014 Research-status Report
  • [Presentation] Lats1/2キナーゼによる新規EMT制御メカニズムの同定と解析2014

    • Author(s)
      安藤有美、向井智美、鳥形康輔、岡本歩、藪田紀一、野島博
    • Organizer
      第37回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(横浜市)
    • Year and Date
      2014-11-26
    • Related Report
      2014 Research-status Report
  • [Presentation] 癌抑制遺伝子Lats1のCDC25Bを介した新規なシグナル経路の探索2014

    • Author(s)
      向井智美、吉田佳織、安藤有美、岡本歩、鈴木宏和、清成寛、藪田紀一、野島博
    • Organizer
      第37回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(横浜市)
    • Year and Date
      2014-11-25
    • Related Report
      2014 Research-status Report
  • [Presentation] Lats1/2 kinases regulate sphere formation of cancer stem cells.2014

    • Author(s)
      野崎正美、藪田紀一、野島博
    • 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
    • Related Report
      2014 Research-status Report
  • [Remarks] 大阪大学微生物病研究所 分子遺伝研究分野 ホームページ

    • URL

      http://www.biken.osaka-u.ac.jp/lab/molgenet/index.html

    • Related Report
      2015 Research-status Report
  • [Remarks] 大阪大学微生物病研究所・分子遺伝研究分野ホームページ

    • URL

      http://www.biken.osaka-u.ac.jp/lab/molgenet/index.html

    • Related Report
      2014 Research-status Report

URL: 

Published: 2014-04-04   Modified: 2018-03-22  

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