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Systematic analysis of Ras/ERK pathway with FRET imaging

Research Project

Project/Area Number 23701052
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Tumor biology
Research InstitutionKyoto University

Principal Investigator

AOKI Kazuhiro  京都大学, 医学(系)研究科(研究院), 准教授 (80511427)

Project Period (FY) 2011-04-28 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2012: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
KeywordsFRETイメージング / 分子標的薬 / Ras / ERK / PI3K / mTOR / シミュレーション / FRET / Akt / フィードバック / イメージング
Outline of Final Research Achievements

Raf/ERK signaling pathway is involved in cell proliferation, differentiation,and tumorigenesis. In this study, we attempted to visualize activities of signaling molecules in the Ras/ERK pathway by live-cell imaging with or without chemical inhibitors, and build mathematical models based on the imaging data. We identified several feedback and feedforward reactions in the Ras/ERK pathway, and found that these feedback/feedforward reactions attenuated the effect of a molecular targeting drugs by reactivating other pathways. Based on mathematical model, we propose combination treatment of molecular targeting drugs to achieve better antitumor effect in cancer cells harboring gene mutation in the Ras/ERK pathway.

Report

(5 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (19 results)

All 2015 2014 2013 2012 2011 Other

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 1 results,  Acknowledgement Compliant: 1 results) Presentation (8 results) (of which Invited: 1 results) Remarks (2 results)

  • [Journal Article] mTORC1 upregulation via ERK-dependent gene expression change confers intrinsic resistance to MEK inhibitors in oncogenic KRas-mutant cancer cells.2015

    • Author(s)
      Komatsu N, Fujita Y, Matsuda M, Aoki K
    • Journal Title

      Oncogene

      Volume: in press Issue: 45 Pages: 5607-5616

    • DOI

      10.1038/onc.2015.16

    • NAID

      120005712924

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Fluorescence resonance energy transfer based quantitative analysis of feedforward and feedback loops in epidermal growth factor receptor signaling and the sensitivity to molecular targeting drugs.2014

    • Author(s)
      Fujita, Y., Komatsu, N., Matsuda, M., and Aoki, K
    • Journal Title

      The FEBS journal

      Volume: 281 Issue: 14 Pages: 3177-3192

    • DOI

      10.1111/febs.12852

    • NAID

      120005647503

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a FRET Biosensor with High Specificity for Akt2014

    • Author(s)
      Miura H, Matsuda M, Aoki K.
    • Journal Title

      Cell Structure and Function

      Volume: 39 Issue: 1 Pages: 9-20

    • DOI

      10.1247/csf.13018

    • NAID

      130004137600

    • ISSN
      0386-7196, 1347-3700
    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Stochastic ERK Activation Induced by Noise and Cell-to-Cell Propagation Regulates Cell Density-Dependent Proliferation2013

    • Author(s)
      Kazuhiro Aoki, Yuka Kumagai, Atsuro Sakurai, Naoki Komatsu, Yoshihisa Fujita, Clara Shionyu and Michiyuki Matsuda
    • Journal Title

      Molecular Cell

      Volume: 52 Issue: 4 Pages: 529-540

    • DOI

      10.1016/j.molcel.2013.09.015

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Quantitative Model of ERK MAP Kinase Phosphorylation in Crowded Media2013

    • Author(s)
      Aoki, K.
    • Journal Title

      Scientific Reports

      Volume: 3 Issue: 1 Pages: 1541-1541

    • DOI

      10.1038/srep01541

    • Related Report
      2013 Research-status Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fluorescence resonance energy transfer imaging of cell signaling from in vitro to in vivo: Basis of biosensor construction, live imaging, and image processing2013

    • Author(s)
      Aoki, K.
    • Journal Title

      Development Growth and Differentiation

      Volume: in press Issue: 4 Pages: 515-522

    • DOI

      10.1111/dgd.12039

    • NAID

      40019735187

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Stable expression of FRET biosensors: a new light in cancer research.2012

    • Author(s)
      Aoki, K.
    • Journal Title

      Cancer Science

      Volume: 103 Issue: 4 Pages: 614-619

    • DOI

      10.1111/j.1349-7006.2011.02196.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Processive phosphorylation of ERK MAP kinase in mamalian cells2011

    • Author(s)
      K.Aoki, M.Yamada, K.Kunida, S.Yasuda, M.Matsuda
    • Journal Title

      Proc.Natl.Acad.Sci.USA

      Volume: 108 Issue: 31 Pages: 12675-12680

    • DOI

      10.1073/pnas.1104030108

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of an optimized backbone of FRET biosensors for kinases and GTPases2011

    • Author(s)
      Komatsu N, Aoki K, Yamada M, Yukinaga H, Fujita Y, Kamioka Y, Matsuda M
    • Journal Title

      Molecular Biology of the Cell

      Volume: 22 Issue: 23 Pages: 4647-4656

    • DOI

      10.1091/mbc.e11-01-0072

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] KRas遺伝子、またはBRaf遺伝子変異陽性がん細胞株の生細胞イメージングによるMEK阻害剤感受性のシステム解析2013

    • Author(s)
      青木 一洋、松田 道行
    • Organizer
      第72回 日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜
    • Related Report
      2013 Research-status Report
  • [Presentation] Stochastic oscillation of ERK MAPK activity induced cell proliferation.2012

    • Author(s)
      Kazuhiro Aoki
    • Organizer
      International Scientific Coordination Network (ISCN) FRANCE-JAPAN
    • Place of Presentation
      Shikoku (Tokushima), Japan
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] Analysis of ERK-induced cell proliferation by FRET imaging.2012

    • Author(s)
      Kazuhiro Aoki
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌市、北海道、日本
    • Related Report
      2012 Research-status Report
  • [Presentation] FRET imaging reveals a functional link between cell growth and oscillation frequency of ERK activity.2012

    • Author(s)
      Kazuhiro Aoki
    • Organizer
      Molecular Imaging and Systems Biology(招待講演)
    • Place of Presentation
      Tokyo, Japan
    • Related Report
      2011 Research-status Report
  • [Presentation] FRET imaging revealed a functional link between frequency of ERK oscillation and growth control by cell density.2011

    • Author(s)
      Aoki K, and Matsuda M
    • Organizer
      The 12th International Conference on Systems Biology,
    • Place of Presentation
      Heidelberg/Mannheim, Germany
    • Related Report
      2011 Research-status Report
  • [Presentation] FRETイメージングを用いたERKによる細胞増殖制御機構の解析2011

    • Author(s)
      青木一洋、松田道行
    • Organizer
      第84回日本生化学会大会(招待講演)
    • Place of Presentation
      東京
    • Related Report
      2011 Research-status Report
  • [Presentation] 実測パラメーターに基づく細胞内シグナル伝達系の定量的シミュレーション2011

    • Author(s)
      青木一洋
    • Organizer
      第6回トランスポーター研究会(招待講演)
    • Place of Presentation
      宮城県仙台市
    • Related Report
      2011 Research-status Report
  • [Presentation] 定量的な細胞シグナル伝達モデルの構築にむけて2011

    • Author(s)
      青木一洋
    • Organizer
      細胞システムの動態と論理(招待講演)
    • Place of Presentation
      埼玉県和光市
    • Related Report
      2011 Research-status Report
  • [Remarks] フィードフォワードとフィードバック制御 および分子標的薬の感受性についての定量解析

    • URL

      https://sites.google.com/site/qsimulationproject/project-definition/fb

    • Related Report
      2014 Annual Research Report
  • [Remarks] 定量細胞シミュレーションプロジェクト

    • URL

      https://sites.google.com/site/qsimulationproject/

    • Related Report
      2012 Research-status Report

URL: 

Published: 2011-08-05   Modified: 2019-07-29  

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