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2012 Fiscal Year Annual Research Report

脂質代謝酵素がストレス応答を制御する新規機構の解析

Research Project

Project/Area Number 23659033
Research InstitutionThe University of Tokyo

Principal Investigator

一條 秀憲  東京大学, 薬学研究科(研究院), 教授 (00242206)

Keywordsストレス応答 / シグナル伝達 / 線虫 / 緑膿菌感染 / MAPキナーゼ
Research Abstract

われわれは、様々なストレスに対して鋭敏に応答して活性化するp38に注目し、その活性化状態を生きた線虫の個体において可視化できる系を構築し、p38の活性化に必要なシグナル分子群を、ゲノムワイドスクリーニングにより同定してきた。線虫における全遺伝子の86%に相当する16,757クローンのスクリーニングを行った結果、55の候補因子を単離した。脂質代謝酵素Xはこのスクリーニングで単離された候補因子の一つである。線虫における脂質代謝酵素Xの機能を主にスクリーニングに用いたレポーターを指標として解析した。指標はレポーター線虫の蛍光強度(線虫p38活性依存的に転写誘導される遺伝子のプロモーター下流にGFPをもつ)を用いた。線虫における脂質代謝酵素Xの欠失変異体は機能解析において必須であるが、これまでに酵素ドメインを欠失する変異体は単離されていないため、紫外線とテトラメチルスルホン酸を組み合わせたUV/TMP法を用いることで、欠失変異体を単離した。単離した欠失変異体に関しては、表現型に関する情報を収集した。表現型に関しては、線虫p38欠失変異体と共通する表現型、これまでに報告されている神経細胞の分化、自然免疫応答、酸化ストレス応答などを中心とした解析を行った。また、われわれはすでに線虫のNSY-1–PMK-1経路(哺乳類でのASK1–p38経路に相当する)を構成する分子の各種変異体を所有していたため、それらの変異体との遺伝学的相互関係を調べることで、既知のp38活性化経路との相対的な関係について解析を行った結果、XがNSY-1の上流活性化因子であることを明らかにした。今後は哺乳動物におけるシグナルの保存性ならびに機能の解析が重要と考えられる。

  • Research Products

    (29 results)

All 2013 2012

All Journal Article (18 results) (of which Peer Reviewed: 17 results) Presentation (11 results) (of which Invited: 9 results)

  • [Journal Article] Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling2013

    • Author(s)
      Shiizaki, S., Naguro, I. and Ichijo, H
    • Journal Title

      Adv. Biol. Regul., (review article)

      Volume: 53 Pages: 135-144

    • DOI

      doi:10.1016/j.jbior.2012.09.006

    • Peer Reviewed
  • [Journal Article] Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury2013

    • Author(s)
      Katome, T., Namekata, K., Guo, X., Semba, K.,Kittaka, D., Kawamura, K., Kimura, A., Harada, C., Ichijo, H., Mitamura, Y. and Harada, T
    • Journal Title

      Cell Death Differ

      Volume: 20 Pages: 270-280

    • DOI

      doi:10.1038/cdd.2012.122

    • Peer Reviewed
  • [Journal Article] Apoptosis Signal-regulating Kinase 1 deficiency attenuates vascular injury-induced neointimal hyperplasia by suppressing apoptosis in smooth muscle cells2013

    • Author(s)
      Tasaki, T. et al.
    • Journal Title

      Am. J. Pathol.

      Volume: 182 Pages: 597-609

    • DOI

      doi: 10.1016/j.ajpath.2012.10.008

  • [Journal Article] Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ß cell exhaustion2013

    • Author(s)
      Yamaguchi, K. et al.
    • Journal Title

      Biochim. Biophys. Acta,

      Volume: 1830 Pages: 3656-3663

    • DOI

      doi: 10.1016/j.bbagen.2013.01.029

    • Peer Reviewed
  • [Journal Article] Integration of the Apoptosis signal-regulating kinase 1-mediated stress signaling with the Akt/PKB-IκB kinase cascade2013

    • Author(s)
      Puckett, M.C. et al.
    • Journal Title

      Mol.Cell. Biol.,

      Volume: in press Pages: in press

    • Peer Reviewed
  • [Journal Article] ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney2012

    • Author(s)
      Naguro, I., Umeda, T., Kobayashi, Y., Maruyama, J., Hattori, K., Shimizu, Y., Kataoka, K., Kim-Mitsuyama, S., Uchida, S., Vandewalle, A., Noguchi, T., Nishitoh, H., Matsuzawa, A., Takeda, K. and Ichijo, H
    • Journal Title

      Nat. Commun.

      Volume: 3 Pages: 1285

    • DOI

      doi:10.1038/ncomms2283

    • Peer Reviewed
  • [Journal Article] The Phosphorylation-Dependent Regulation of Mitochondrial Proteins in Stress Responses2012

    • Author(s)
      Kanamaru, Y., Sekine S., Ichijo, H. and Takeda, K
    • Journal Title

      J. Signal Transduc. (review article)

      Volume: 2012 Pages: 12

    • DOI

      doi:10.1155/2012/931215

    • Peer Reviewed
  • [Journal Article] ASK1 promotes apoptosis of normal and malignant plasma cells2012

    • Author(s)
      Lin, F.R., Huang, S.Y., Hung, K.H., Su, S.T., Chung, C.H., Matsuzawa, A., Hsiao, M., Ichijo, H. and Lin, K.I
    • Journal Title

      Blood

      Volume: 120 Pages: 1039-1047

    • DOI

      doi:10.1182/blood-2011-12-399808

    • Peer Reviewed
  • [Journal Article] Prevention of apoptosis by mitochondrial phosphatase PGAM5 in the mushroom body is crucial for heat shock resistance in Drosophila melanogaster2012

    • Author(s)
      Ishida, Y., Sekine, Y., Oguchi, H., Chihara, T., Miura, M., Ichijo, H. and Takeda, K
    • Journal Title

      PloS ONE

      Volume: 7 Pages: e30265

    • DOI

      doi:10.1371/journal.pone.0030265

    • Peer Reviewed
  • [Journal Article] Apoptosis Signal-Regulating Kinase 1 Mediates MPTP Toxicity and Regulates Glial Activation2012

    • Author(s)
      Lee, K.W., Zhao, X., Im, J.Y., Grosso, H., Jang, W.H., Chan, T.W., Sonsalla, P.K., German, D.C., Ichijo, H., Junn, E., and Mouradian, M.M
    • Journal Title

      PloS ONE

      Volume: 7 Pages: e29935

    • DOI

      doi:10.1371/journal.pone.0029935

    • Peer Reviewed
  • [Journal Article] ER stress activates the NLRP3 inflammasome via an UPR-independent pathway.2012

    • Author(s)
      Menu, P. et al.
    • Journal Title

      Cell Death & Disease

      Volume: 3 Pages: e261

    • DOI

      doi: 10.1038/cddis.2011.132

    • Peer Reviewed
  • [Journal Article] Novel mechanism of angiotensin II-induced cardiacinjury in hypertensive rats: the critical role of ASK12012

    • Author(s)
      Nako, H. et al.
    • Journal Title

      Hypertens. Res.

      Volume: 35 Pages: 194-200

    • DOI

      doi: 10.1038/hr.2011.175

    • Peer Reviewed
  • [Journal Article] A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.2012

    • Author(s)
      Fujisawa, T. et al.
    • Journal Title

      Ann. Neurol.

      Volume: 72 Pages: 739-749

    • DOI

      doi: 10.1002/ana.23668

    • Peer Reviewed
  • [Journal Article] Oxidative Stress-Induced Diseases via the ASK1 Signaling Pathway2012

    • Author(s)
      Soga, M. et al.
    • Journal Title

      Int. J. Cell Biol.

      Volume: 2012 Pages: 439587

    • DOI

      doi: 10.1155/2012/439587

    • Peer Reviewed
  • [Journal Article] Therapeutic targets in the ASK1-dependent stress signalling pathways2012

    • Author(s)
      Hayakawa, R. et al.
    • Journal Title

      Proc. Jpn. Acad. Ser. B: Phys. Biol. Sci.

      Volume: 88 Pages: 434-453

    • Peer Reviewed
  • [Journal Article] Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM52012

    • Author(s)
      Sekine,S. et al.
    • Journal Title

      J. Biol. Chem.

      Volume: 287 Pages: 34635-34645

    • DOI

      doi: 10.1074/jbc.M112.357509

    • Peer Reviewed
  • [Journal Article] The kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP52012

    • Author(s)
      Sekine, Y. et al.
    • Journal Title

      Mol. Cell

      Volume: 48 Pages: 692-704

    • DOI

      doi: 10.1016/j.molcel.2012.09.018

    • Peer Reviewed
  • [Journal Article] Apoptosis signal-regulating kinase-1 inhibitor as a potent therapeutic drug for the treatment of gastric cancer.2012

    • Author(s)
      Hayakawa, Y. et al.
    • Journal Title

      Cancer Sci.

      Volume: 103 Pages: 2181-2185

    • DOI

      doi: 10.1111/cas.12024

    • Peer Reviewed
  • [Presentation] 細胞がストレスを感じる仕組みと疾患2013

    • Author(s)
      一條秀憲
    • Organizer
      第37回皮膚科免疫セミナー
    • Place of Presentation
      東京
    • Year and Date
      20130302-20130302
    • Invited
  • [Presentation] Redox control of cell death2012

    • Author(s)
      Hidenori Ichijo
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡
    • Year and Date
      20121214-20121216
  • [Presentation] ASK Family Kinases in Stress Response and Disease2012

    • Author(s)
      Ichijo, H
    • Organizer
      The 4th Takeda Science Foundation Symposium on PharmaSciences "On the Frontiers of Chemical Biology"
    • Place of Presentation
      東京
    • Year and Date
      20121203-04
  • [Presentation] SOD1 as a molecular switch to initiate the homeostatic ER stress response2012

    • Author(s)
      Hidenori Ichijo
    • Organizer
      The 2nd International Symposium by JSPS Core-to-Core Program “Cooperative International Framework in TGF-β Family Signaling” TGF-β Family: Signal Network and Tumor Microenvironment
    • Place of Presentation
      東京
    • Year and Date
      20121028-20121030
    • Invited
  • [Presentation] ストレス応答の破綻と神経変性疾患2012

    • Author(s)
      一條秀憲
    • Organizer
      第39回日本脳科学会
    • Place of Presentation
      小倉
    • Year and Date
      20121006-20121007
    • Invited
  • [Presentation] Stress signaling in cell death, inflammation and disease2012

    • Author(s)
      Hidenori Ichijo
    • Organizer
      Fifty-third International Symposium on Biological Regulation and Enzyme Activity in Normal and Neoplastic Tissues
    • Place of Presentation
      Bologna, Italy
    • Year and Date
      20120917-20120918
    • Invited
  • [Presentation] SOD1 as a molecular switch to initiate homeostatic ER stress response under conditions of zinc deficiency2012

    • Author(s)
      Hidenori Ichijo
    • Organizer
      第33回内藤コンファレンス The 33rd Naito Conference: Oxygen Biology: Hypoxia, Oxidative Stress and Diseases
    • Place of Presentation
      札幌
    • Year and Date
      20120626-20120629
    • Invited
  • [Presentation] ALS発症のメカニズム2012

    • Author(s)
      一條秀憲
    • Organizer
      第5回東京アンチエイジングアカデミー
    • Place of Presentation
      大手町、東京
    • Year and Date
      20120621-20120621
    • Invited
  • [Presentation] SOD1 as a molecular switch to evoke ER stress in ALS and Zinc deficiency2012

    • Author(s)
      Hidenori Ichijo
    • Organizer
      Program for Young Researcher Symposium in Europe'  supported by Graduate School of Pharmaceutical Sciences, U-Tokyo Joint International Symposium
    • Place of Presentation
      ケンブリッジ大学、イギリス
    • Year and Date
      20120607-20120612
    • Invited
  • [Presentation] Stress signaling in human diseases2012

    • Author(s)
      Hidenori Ichijo
    • Organizer
      Program for Young Researcher Symposium in Europe'  supported by Graduate School of Pharmaceutical Sciences, U-Tokyo Joint International Symposium
    • Place of Presentation
      ボン大学、ドイツ
    • Year and Date
      20120607-20120612
    • Invited
  • [Presentation] 細胞がストレスを感じるシグナル伝達の仕組みと疾患2012

    • Author(s)
      一條秀憲
    • Organizer
      日本分子生物学会第12回春季シンポジウム
    • Place of Presentation
      石和温泉 慶山
    • Year and Date
      20120425-20120426
    • Invited

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Published: 2014-07-24  

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