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

• Project/Area Number: 23390071
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kobe 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,760,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥4,560,000); Fiscal Year 2013: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2012: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2011: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• 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 / ホスホリパーゼＣ

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

• [Journal Article] Critical function of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in mouse spermatogenesis (2014)
  • 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 Issue: 1 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 interaction (2013)
  • 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 Issue: 20 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 cells (2013)
  • Author(s): Nozaki, S., Takeda, T., Kitaura, T., Takenaka, N., Kataoka, T., and Satoh, T.
  • Journal Title: Cell. Signal Volume: 25 Issue: 6 Pages: 1361-1371
  • DOI: 10.1016/j.cellsig.2013.02.023
  • NAID: 120006895711
  • 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 cells (2013)
  • Author(s): Shinsuke Nozaki
  • Journal Title: Cellular Signalling Volume: -
  • Peer Reviewed
• [Journal Article] In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction (2013)
  • Author(s): Fumi Shima
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: -
  • Peer Reviewed
• [Journal Article] Role of RalA downstream of Rac1 in insulin-dependent glucose uptake in muscle cells (2012)
  • Author(s): Nozaki, S., Ueda, S., Takenaka, N., Kataoka, T., and Satoh, T
  • Journal Title: Cell. Signal Volume: 24 (11) Issue: 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 mutants (2012)
  • Author(s): 村岡 真
  • Journal Title: FEBS Letters Volume: 586巻・12号 Issue: 12 Pages: 1715-1718
  • DOI: 10.1016/j.febslet.2012.04.058
  • Peer Reviewed
• [Journal Article] PLCε cooperates with the NF-κB pathway to augment TNFα-stimulated CCL2/MCP1 expression in human keratinocyte (2011)
  • Author(s): Harada, Y., Edamatsu, H., Kataoka, T.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 414 Issue: 1 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 prevention (2011)
  • 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 conformers (2011)
  • Author(s): 荒木望嗣
  • Journal Title: The Journal of Biological Chemistry Volume: 286巻・45号 Issue: 45 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 commissures (2011)
  • Author(s): Bilasy SE, Satoh T, Terashima T, Kataoka T.
  • Journal Title: Neuroscience Research Volume: 71(3) Issue: 3 Pages: 200-9
  • DOI: 10.1016/j.neures.2011.08.004
  • Peer Reviewed
• [Journal Article] Phospholipase Cε has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC (2011)
  • Author(s): Oka, M., Edamatsu, H., et al
  • Journal Title: Lab.Invest. Volume: 91 Issue: 5 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 α-helix on Conformational Dynamics of the GTP-bound Ras Family Small GTPases (2011)
  • Author(s): 松本耕祐
  • Journal Title: The Journal of Biological Chemistry Volume: 286巻・17号 Issue: 17 Pages: 15403-15412
  • DOI: 10.1074/jbc.m110.204933
  • Peer Reviewed
• [Journal Article] Phospholipase Cε as a potential molecular target for anti-inflammatory therapy and cancer prevention (2011)
  • Author(s): Hironori Edamatsu, et al
  • Journal Title: Inflammation and Regeneration Volume: 31巻 Pages: 370-374
  • NAID: 130004482284
  • Peer Reviewed
• [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] 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
• [Presentation] New strategies for development of anti-cancer drugs targeting the Ras family signaling pathway (2013)
  • Author(s): Kataoka, T
  • Organizer: WINPTech 2012 : Recent Development in Drug Discovery Sciences
  • Place of Presentation: 神戸大学統合拠点
• [Presentation] In silico discovery of novel Ras inhibitors that display anti-tumor activity by blocking the Ras-effector interaction (2013)
  • Author(s): Shima, F
  • Organizer: WINPTech 2012 : Recent Development in Drug Discovery Sciences
  • Place of Presentation: 神戸大学統合拠点
• [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回生物試料分析科学会年次学術集会
  • Place of Presentation: 新梅田研修センター(大阪市)
  • Invited
• [Presentation] New strategies for development of anti-cancer drugs targeting the Ras signaling pathway (2013)
  • Author(s): Tohru Kataoka
  • Organizer: WINPTech 2012: Recent Development in Drug Discovery Sciences
  • Place of Presentation: 神戸大学統合拠点(神戸市)
  • Invited
• [Presentation] In silico discovery of novel Ras inhibitors that display anti-tumor activity by blocking the Ras-effector interaction (2013)
  • Author(s): Fumi Shima
  • Organizer: WINPTech 2012: Recent Development in Drug Discovery Sciences
  • Place of Presentation: 神戸大学統合拠点(神戸市)
  • Invited
• [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 pathway (2012)
  • 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] New strategies for development of anti-cancer drugs targeting the Ras pathway (2012)
  • Author(s): Tohru Kataoka
  • Organizer: The 2^<nd> International Symposium on Cancer and Cancer Stem Cells Research in Toyama
  • Place of Presentation: 富山大学(富山県)(招待講演)
  • Year and Date: 2012-02-28
• [Presentation] Universal roles of phospholipase Cepsilon in de novo carcinogenesis and inflammation (2011)
  • 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] Universal roles of phospholipase Cε in de novo carcinogenesis and inflammation (2011)
  • Author(s): Tohru Kataoka
  • Organizer: 2011 Taiwan-Japan Joint Symposium on Cell Signaling and Gene Regulation
  • Place of Presentation: National Cheng Kung University (台湾)(招待講演)
  • Year and Date: 2011-11-20
• [Presentation] Crucial role of phospholipase Cepsilon in the development of asthma in mice (2011)
  • 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] Crucial role of phospholipase Cε in the development of asthma in mice (2011)
  • Author(s): Tatsuya Nagano, et al
  • Organizer: European Respiratory Society Annual Congress
  • 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 infiltration (2011)
  • 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
• [Presentation] Overexpression of phospholipase Cε in keratinocytes results in IL-23 production leading to skin inflammation accompanied by IL-22-producing T cell infiltration (2011)
  • Author(s): Hironori Edamatsu, et al
  • Organizer: 10^<th> World Congress on Inflammation
  • Place of Presentation: Paris Convention Centre(フランス)
  • Year and Date: 2011-06-27
• [Presentation] rasがん遺伝子産物の分子標的薬のインシリコ創薬
  • 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
  • Invited
• [Presentation] Rasシグナル伝達系を標的とした抗がん剤の開発
  • 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
  • Invited
• [Presentation] 気道炎症におけるホスホリパーゼＣεの役割
  • 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 (Innovative Asthma Association) 学術集会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Crucial role of phospholipase Cepsilon in colitis-induced colon tumor formation in ApcMin mice
  • Author(s): 脇田将裕
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場(福岡市)
• [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
  • Publisher: 南山堂
• [Book] The Enzymes Vol. 34 Inhibitors of the Ras superfamily G-proteins (2013)
  • Author(s): Shima, F., Yoshikawa, Y., Matsumoto, S., and Kataoka, T
  • Publisher: Part B (Elsevier)
• [Book] The Enzymes Vol. 34 Inhibitors of the Ras superfamily G-proteins, Part B (2013)
  • Author(s): Fumi Shima, Yoko Yoshikawa, Shigeyuki Matsunoto, Tohru Kataoka
  • Publisher: Elsevier Inc.
• [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
  • Publisher: 南山堂
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/molbiol/
• [Remarks] 神戸大学大学院医学研究科分子生物学分野ホームページ
  • URL: http://www.med.kobe-u.ac.jp/molbiol/index.html
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/molbiol/index.html
• [Patent(Industrial Property Rights)] Ras機能阻害剤のスクリーニング方法 (2012)
  • Inventor(s): 片岡徹、島扶美、田村厚夫、荒木望嗣
  • Industrial Property Rights Holder: 神戸大学
  • Filing Date: 2012-01-31
  • Overseas