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2013 Fiscal Year Final Research Report

Elucidation of a novel signaling pathway responsible for the roles of phospholipase Cepsilon in augmentation of inflammation and carcinogenesis

Research Project

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Project/Area Number 23390071
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKobe University

Principal Investigator

KATAOKA TOHRU  神戸大学, 医学(系)研究科(研究院), 教授 (40144472)

Co-Investigator(Kenkyū-buntansha) SHIMA Fumi  神戸大学, 医学研究科, 准教授 (60335445)
EDAMATSU Hironori  神戸大学, 医学研究科, 助教 (70335438)
Project Period (FY) 2011-04-01 – 2014-03-31
KeywordsホスホリパーゼC / シグナル伝達 / 炎症 / 発癌 / サイトカイン / Ras蛋白質 / 低分子量G蛋白質 / 表皮角化細胞
Research Abstract

We investigated the molecular mechanisms underlying the augmentation of inflammation by phospholipase Cepsilon (PLCepsilon), an effector of the small GTPases Ras and Rap, as well as its function in whole animals. We found that PLCepsilon plays a role in induction of the proinflammatory cytokine expression by facilitating the nuclear translocation of the transcription factor NF-kappaB upon stimulation of cells with tumor necrosis factor (TNF)-alpha. A candidate of the endogenous ligand was identified that is secreted from TNF-alpha-stimulated cells and induces the PLCepsilon-dependent cytokine expression in an autocrine manner. Moreover, we identified a protein kinase which is activated in a PLCepsilon-dependent manner and presumably involved in the induction of the cytokine expression. Furthermore, from the studies using PLCepsilon knockout mice, we clarified the crucial roles of PLCepsilon in the colitis-induced intestinal carcinogenesis and the pathogenesis of bronchial asthma.

  • Research Products

    (25 results)

All 2014 2013 2012 2011 Other

All Journal Article (11 results) (of which Peer Reviewed: 11 results) Presentation (11 results) Book (2 results) Remarks (1 results)

  • [Journal Article] Critical function of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in mouse spermatogenesis2014

    • Author(s)
      Okada, K., Miyake, H., Yamaguchi, K., Chiba, K., Maeta, K., Bilasy, S. A., Edamatsu, H., Kataoka, T., and Fujisawa, M
    • Journal Title

      Biochem. Biophys. Res. Comm

      Volume: 445 Pages: 89-94

    • DOI

      10.1016/j.bbrc.2014.01.149

    • Peer Reviewed
  • [Journal Article] In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction2013

    • Author(s)
      Shima, F., Yoshikawa, Y., Ye, M., Araki, M., Matsumoto, S., Liao, J., Hu, L., Sugimoto, T., Ijiri, Y., Takeda, A., Nishiyama, Y., Sato, C., Muraoka, S., Tamura, A., Osoda, T., Tsuda, K., Miyakawa, T., Fukunishi, H., Shimada, J., Kumasaka, T., Yamamoto, M., and Kataoka, T
    • Journal Title

      Proc. Natl. Acad. Sci. USA

      Volume: 110 Pages: 8182-8187

    • DOI

      10.1073/pnas.1217730110

    • Peer Reviewed
  • [Journal Article] Akt2 regulates Rac1 activity in the insulin-dependent signaling pathway leading to GLUT4 translocation to the plasma membrane in skeletal muscle cells2013

    • Author(s)
      Nozaki, S., Takeda, T., Kitaura, T., Takenaka, N., Kataoka, T., and Satoh, T.
    • Journal Title

      Cell. Signal

      Volume: 25 Pages: 1361-1371

    • DOI

      10.1016/j.cellsig.2013.02.023

    • Peer Reviewed
  • [Journal Article] Role of RalA downstream of Rac1 in insulin-dependent glucose uptake in muscle cells2012

    • Author(s)
      Nozaki, S., Ueda, S., Takenaka, N., Kataoka, T., and Satoh, T
    • Journal Title

      Cell. Signal

      Volume: 24 (11) Pages: 2111-2117

    • DOI

      10.1016/j.cellsig.2012.07.013

    • Peer Reviewed
  • [Journal Article] Crystal structures of the state 1 conformations of the GTP-bound H-Ras protein and its oncogenic G12V and Q61L mutants2012

    • Author(s)
      Muraoka, S., Shima, F., Araki, M., Inoue, T., Yoshimoto, A., Ijiri, Y., Seki, N., Tamura, A., Kumasaka, T., Yamamoto, M., and Kataoka, T
    • Journal Title

      FEBS Lett

      Volume: 586 Pages: 1715-1718

    • DOI

      10.1016/j.febslet.2012.04.058

    • Peer Reviewed
  • [Journal Article] PLCepsilon cooperates with the NF-kappaB pathway to augment TNFalpha-stimulated CCL2/MCP1 expression in human keratinocyte2011

    • Author(s)
      Harada, Y., Edamatsu, H., and Kataoka, T
    • Journal Title

      Biochem. Biophys. Res. Commun

      Volume: 414 Pages: 106-111

    • DOI

      10.1016/j.bbrc.2011.09.032

    • Peer Reviewed
  • [Journal Article] Phospholipase Cepsilon as a potential molecular target for anti-inflammatory therapy and cancer prevention2011

    • Author(s)
      Edamatsu, H., Takenaka, N., Hu, L., and Kataoka, T
    • Journal Title

      Inflamm. Regen

      Volume: 31 Pages: 370-374

    • URL

      http://www.jsir.gr.jp/journal/Vol31No4/pdf/08_M6_370.pdf

    • Peer Reviewed
  • [Journal Article] Solution structure of the state 1 conformer of GTP-bound H-Ras protein and distinct dynamic properties between the state 1 and state 2 conformers2011

    • Author(s)
      Araki, M., Shima, F., Yoshikawa, Y., Muraoka, S., Ijiri, Y., Nagahara, Y., Shirono, T., Kataoka, T., and Tamura, A
    • Journal Title

      J. Biol. Chem

      Volume: 286 Pages: 39644-39653

    • DOI

      10.1074/jbc.M111.227074

    • Peer Reviewed
  • [Journal Article] RA-GEF-1 (Rapgef2) is essential for proper development of the midline commissures2011

    • Author(s)
      Bilasy, S. E., Satoh, T., Terashima, T., and Kataoka, T
    • Journal Title

      Neurosci. Res.

      Volume: 71 Pages: 200-209

    • DOI

      10.1016/j.neures.2011.08.004

    • Peer Reviewed
  • [Journal Article] Phospholipase Cepsilon has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC2011

    • Author(s)
      Oka, M., Edamatsu, H., Kunisada, M., Hu, L., Takenaka, N., Sakaguchi, M., Kataoka, T., and Nishigori, C
    • Journal Title

      Lab. Invest

      Volume: 91 Pages: 711-718

    • DOI

      10.1038/labinvest.2011.10

    • Peer Reviewed
  • [Journal Article] Critical roles of interactions among switch I- preceding residues and between switch II and its neighboring alpha-helix in conformational dynamics of the GTP- bound Ras family small GTPases2011

    • Author(s)
      Matsumoto, K., Shima, F., Muraoka, S., Araki, M., Hu, L., Ijiri, Y., Hirai, R., Liao, J., Yoshioka, T., Kumasaka, T., Yamamoto, M., Tamura, A., and Kataoka, T
    • Journal Title

      J. Biol. Chem

      Volume: 286 Pages: 15403-15412

    • DOI

      10.1074/jbc.M110.204933

    • Peer Reviewed
  • [Presentation] New strategies for development of anti-cancer drugs targeting the Ras family signaling pathway2013

    • Author(s)
      Kataoka, T
    • Organizer
      WINPTech 2012 : Recent Development in Drug Discovery Sciences
    • Place of Presentation
      神戸大学統合拠点
    • Year and Date
      20130218-19
  • [Presentation] In silico discovery of novel Ras inhibitors that display anti-tumor activity by blocking the Ras-effector interaction2013

    • Author(s)
      Shima, F
    • Organizer
      WINPTech 2012 : Recent Development in Drug Discovery Sciences
    • Place of Presentation
      神戸大学統合拠点
    • Year and Date
      20130218-19
  • [Presentation] 癌の発生機構の基礎研究に基づく新しい癌治療薬の創薬2013

    • Author(s)
      片岡 徹
    • Organizer
      第23回生物試料分析化学会年次学術集会
    • Place of Presentation
      新梅田研修センター
    • Year and Date
      20130210-11
  • [Presentation] ras がん遺伝子産物の分子標的薬のインシリコ創薬2013

    • Author(s)
      片岡 徹
    • Organizer
      平成25年度臨床研究総合センターシンポジウム~がん治療最前線 : ゲノム創薬と免疫治療~
    • Place of Presentation
      千葉県がんセンター
    • Year and Date
      2013-12-07
  • [Presentation] Ras シグナル伝達系を標的とした抗がん剤の開発2013

    • Author(s)
      片岡 徹
    • Organizer
      大阪大学産学連携プロジェクト MEET 医学研究コロキウム・1-がんの分子標的治療を考える-
    • Place of Presentation
      大阪大学大学院医学研究科
    • Year and Date
      2013-10-07
  • [Presentation] 気道炎症におけるホスホリパーゼCεの役割2013

    • Author(s)
      永野達也,枝松裕紀,小林和幸,西村善博,片岡 徹
    • Organizer
      第4回IAA学術集会
    • Place of Presentation
      東京国際フォーラム
    • Year and Date
      2013-04-21
  • [Presentation] Crucial role of phospholipase Cepsilon in colitis-induced colon tumor formation in ApcMin mice(日本語演題名 : ApcMin マウスの腸炎誘発性大腸腺腫発生におけるホスホリパーゼ Cεの重要な役割)2012

    • Author(s)
      脇田将裕,枝松裕紀,北澤荘平,片岡 徹
    • Organizer
      第35回日本分子生物学会年会
    • Place of Presentation
      福岡国際会議場
    • Year and Date
      2012-12-11
  • [Presentation] New strategies for development of anti-cancer drugs targeting the Ras pathway2012

    • Author(s)
      Kataoka, T
    • Organizer
      The 2nd International Symposium on Cancer and Cancer Stem Cells Research in Toyama
    • Place of Presentation
      富山大学
    • Year and Date
      2012-02-28
  • [Presentation] Universal roles of phospholipase Cepsilon in de novo carcinogenesis and inflammation2011

    • Author(s)
      Kataoka, T
    • Organizer
      2011 Taiwan-Japan Joint Symposium on Cell Signaling and Gene Regulation
    • Place of Presentation
      National Cheng Kung University (台湾)
    • Year and Date
      2011-11-20
  • [Presentation] Crucial role of phospholipase Cepsilon in the development of asthma in mice2011

    • Author(s)
      Nagano, T., Edamatsu, H., Kobayashi, K., Nishimura, Y., and Kataoka, T.
    • Organizer
      European Respiratory Society Annual Congress(欧州呼吸器学会年会)
    • Place of Presentation
      Amsterdam RAI( オランダ)
    • Year and Date
      2011-09-25
  • [Presentation] Overexpression of phospholipase Cepsilon in keratinocytes results in IL-23 production leading to skin inflammation accompanied by IL-22-producing T cell infiltration2011

    • Author(s)
      Edamatsu, H., Takenaka, N., and Kataoka, T.
    • Organizer
      10th World Congress on Inflammation
    • Place of Presentation
      Paris Convention Centre(フランス)
    • Year and Date
      2011-06-27
  • [Book] がん基盤生物学-革新的シーズ育成に向けて-2013

    • Author(s)
      枝松裕紀,片岡 徹
    • Total Pages
      142-146
    • Publisher
      南山堂
  • [Book] The Enzymes Vol. 34 Inhibitors of the Ras superfamily G-proteins2013

    • Author(s)
      Shima, F., Yoshikawa, Y., Matsumoto, S., and Kataoka, T
    • Total Pages
      1-23
    • Publisher
      Part B (Elsevier)
  • [Remarks]

    • URL

      http://www.med.kobe-u.ac.jp/molbiol/

URL: 

Published: 2015-06-25  

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