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Analysis of the Regulatory Mechanism and Function of a Novel Class of Phospholipase C, PLCε

Research Project

Project/Area Number 15390093
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  Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40144472)

Co-Investigator(Kenkyū-buntansha) SATOH Takaya  Kobe University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (20251655)
SHIMA Fumi  Kobe University, Graduate School of Medicine, Instructor, 大学院・医学系研究科, 助手 (60335445)
EDAMATSU Hironori  Kobe University, Graduate School of Medicine, Instructor, 大学院・医学系研究科, 助手 (70335438)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2004: ¥6,200,000 (Direct Cost: ¥6,200,000)
Fiscal Year 2003: ¥9,200,000 (Direct Cost: ¥9,200,000)
Keywordsphospholipase C / small G protein / Ras protein / phosphoinositide signaling / ventricular dilation / semilunar valve disease / knockout mice / nematodes / Rap1蛋白質 / 半月弁逆流 / 半月弁狭窄
Research Abstract

1, We constructed phospholipase C_ε(PLC_ε) knockout mice and showed that the hearts of these mice develop ventricular dilation, which is caused by a volume overload resulting from marked regurgitation and mild stenosis of the semilunar (aortic and pulmonic) valves. We analysed the mechanism of the congenital semilunar valvulogenesis defect causing these phenotypes and concluded that the abnormal thickening and morphology of the semilunar valve leaflets in PLC_ε knockout mice were caused by aberrant cellular proliferation in valve remodeling at the late stages of semilunar valvulogenesis. By analogy with the phenotypes of mice carrying an attenuated epidermal growth factor (EGF) receptor or deficient in heparin-binding EGF, we speculated a crucial role of PLC_ε, as a Ras effector downstream of the EGF receptor, in inhibition of valvular cell proliferation. In fact, we observed increased phosphorylation of Smad1/5/8, which induce valvular cell proliferation downstream of the BMP receptor, in PLC_ε knockout mice.
2, By applying the two stage skin chemical carcinogenesis protocol using DMBA as an initiator and a phorbor ester TPA as a promoter to PLC_ε knockout mice, we showed that PLC_ε plays a crucial role in ras oncogene-induced development of benign tumors as well as in their malignant progression. We further analysed the mechanism of action of PLC_ε. PLC_ε knockout mice showed marked reduction in proliferation of basal layer cells and epidermal hyperplasia induced by TPA, suggesting a crucial role of PLC_ε in downstream signaling from TPA.
3, We disrupted the PLC_ε gene in a model organism Caenorhabditis elegans and observed a sterile phenotype, caused by abnormal contraction of sphincter muscles of the spermatheca.
4, By using BaF3 cells expressing a PDGF receptor mutant lacking the PLC_γ-binding sites, we showed the importance of PH and RA domains by establishing an assay system for Ca^<2+> increase induced by PDGF-dependent PLC_ε activation.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (33 results)

All 2005 2004 2003 Other

All Journal Article (28 results) Patent(Industrial Property Rights) (1 results) Publications (4 results)

  • [Journal Article] Congenital semilunar valvulogenesis defect in mice deficient in phospholipase Cε.2005

    • Author(s)
      Makoto Tadano et al.
    • Journal Title

      Molecular and Cellular Biology 25巻6号

      Pages: 2191-2199

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Congenital semilunar valvulogenesis defect in mice deficient in phospholipase C_ε.2005

    • Author(s)
      Makoto Tadano et al.
    • Journal Title

      Mol.Cell.Biol. 25(6)

      Pages: 2191-2199

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Congenital semilunar valvulogenesis defect in mice deficient in phospholipase Cε2005

    • Author(s)
      Makoto Tadano, et al.
    • Journal Title

      Molecular and Cellular Biology 25巻・6号

      Pages: 2191-2199

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of a novel domain of Ras and Rap1 that directs their differential subcellular localizations.2004

    • Author(s)
      Kazuhiro Nomura et al.
    • Journal Title

      The Journal of Biological Chemistry 279巻21号

      Pages: 22664-22673

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of the Sec14-like domain of Db1 family exchange factors in the regulation of Rho family GTPases in different subcellular sites2004

    • Author(s)
      Shuji Ueda et al.
    • Journal Title

      Cellular Signalling 16巻8号

      Pages: 899-906

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phospholipase Cε regulates ovulation in Caenorhabditis elegans.2004

    • Author(s)
      Ken-ichi Kariya et al.
    • Journal Title

      Developmental Biology 274巻1号

      Pages: 201-210

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Crucial role of phospholipase Cε in chemical carcinogen-induced skin tumor development.2004

    • Author(s)
      Yunfeng Bai et al.
    • Journal Title

      Cancer Research 64巻24号

      Pages: 8808-8810

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Direct activation of fission yeast adenylyl cyclase by heterotrimeric G protein gpa2.2004

    • Author(s)
      Hideki Ogihara et al.
    • Journal Title

      Kobe Journal of Medical Sciences 50巻4号

      Pages: 111-122

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of a novel domain of Ras and Rap 1 that directs their differential subcellular localizations.2004

    • Author(s)
      Kazuhiro Nomura et al.
    • Journal Title

      J.Biol.Chem. 279(21)

      Pages: 22664-22673

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of the Sec 14-like domain of Dbl family exchange factors in the regulation of Rho family GTPases in different subcellular sites.2004

    • Author(s)
      Shuji Ueda et al.
    • Journal Title

      Cell.Signal. 16(8)

      Pages: 899-906

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phospholipase C_ε regulates ovulation in Caenorhabditis elegans.2004

    • Author(s)
      Ken-ichi Kariya et al.
    • Journal Title

      Dev.Biol. 274(1)

      Pages: 201-210

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Crucial role of phospholipase C_ε in chemical carcinogen-induced skin tumor development.2004

    • Author(s)
      Yunfeng Bai et al.
    • Journal Title

      Cancer Res. 64(24)

      Pages: 8808-8890

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Direct activation of fission yeast adenylyl cyclase by heterotrimeric G protein gpa2.2004

    • Author(s)
      Hideki Ogihara et al.
    • Journal Title

      Kobe J.Med.Sci. 50(4)

      Pages: 111-122

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of a novel domain of Ras and Rap1 that directs their differential subcellular localizations2004

    • Author(s)
      Kazuhiro Nomura, et al.
    • Journal Title

      The Journal of Biological Chemistry 279巻・21号

      Pages: 22664-22673

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of the Sec14-like domain of DbI family exchange factors in the regulation of Rho family GTPases in different subcellular sites2004

    • Author(s)
      Shuji Ueda, et al.
    • Journal Title

      Cellular Signalling 16巻・8号

      Pages: 899-906

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Phospholipase Cε regulates ovulation in Caenorhabditis elegans2004

    • Author(s)
      Ken-ichi Kariya, et al.
    • Journal Title

      Developmental Biology 274巻・1号

      Pages: 201-210

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Crucial role of phospholipase Cε in chemical carcinogen-induced skin tumor development2004

    • Author(s)
      Yunfeng Bai, et al.
    • Journal Title

      Cancer Research 64巻・24号

      Pages: 8808-8810

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Direct activation of fission yeast adenylyl cyclase by heterotrimeric G protein gpa22004

    • Author(s)
      Hideki Ogihara, et al.
    • Journal Title

      Kobe Journal of Medical Sciences 50巻・4号(印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Neuronal lineage-specific induction of phospholipase Cε expression in the developing mouse brain.2003

    • Author(s)
      Dongmei Wu et al.
    • Journal Title

      European Journal of Neuroscience 17巻8号

      Pages: 1571-1580

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Single- and multiple-molecule dynamics of the signaling from H-Ras to c Raf-1 visualized on the plasma membrane of living cells.2003

    • Author(s)
      Kayo Hibino et al.
    • Journal Title

      Chemphyschem 4巻7号

      Pages: 748-753

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Neuronal lineage-specific induction of phospholipase C_ε expression in the developing mouse brain.2003

    • Author(s)
      Dongmei Wu et al.
    • Journal Title

      Eur.J.Neurosci. 17(8)

      Pages: 1571-1580

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Single- and multiple-molecule dynamics of the signaling from H-Ras to c Raf-1 visualized on the plasma membrane of living cells.2003

    • Author(s)
      Kayo Hibino et al.
    • Journal Title

      Chemphyschem. 4(7)

      Pages: 748-753

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ras and Rap1 activation of PLCε lipase activity.

    • Author(s)
      Hironori Edamatsu et al.
    • Journal Title

      Methods in Enzymology (未定)(印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phospholipase Cε guanine nucleotide exchange factor activity and activation of Rap1.

    • Author(s)
      Takaya Satoh et al.
    • Journal Title

      Methods in Enzymology (未定)(印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Posttranslational modifications of Ras essential for activation of its effectors.

    • Author(s)
      Fumi Shima et al.
    • Journal Title

      Seikagaku (未定)(印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ras and Rap1 activation of PLCε lipase activity.

    • Author(s)
      Hironori Edamatsu et al.
    • Journal Title

      Methods Enzymol. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phospholipase C_ε guanine nucleotide exchange factor activity and activation of Rap 1.

    • Author(s)
      Takaya Satoh et al.
    • Journal Title

      Methods Enzymol. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Posttranslational modifications of Ras essential for activation of its effectors.

    • Author(s)
      Fumi Shima et al.
    • Journal Title

      Seikagaku (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] ホスホリパーゼCεを分子標的とした新規抗がん剤のスクリーニング方法2004

    • Inventor(s)
      片岡 徹, 枝松 裕紀
    • Industrial Property Rights Holder
      神戸大学
    • Industrial Property Number
      2004-022308
    • Filing Date
      2004-01-29
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Publications] Kazuhiro Nomura, et al.: "Identification of a novel domain of Ras and Rap1 that directs their differential subcellular localizations"The Journal of Biological Chemistry. 279・(未定)(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shuji Ueda, et al.: "Role of the Sec14-like domain of Dbl and Ost guanine nucleotide exchange factors in the regulation of Rho family GTP-binding proteins in different subcellular compartments"Cellular Signalling. 16・(未定)(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Dongmei Wu, et al.: "Neuronal lineage-specific induction of phospholipase Cε expression in the developing mouse brain"European Journal of Neuroscience. 17・8. 1571-1580 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kayo Hibino, et al.: "Single- and multiple-molecule dynamics of the signaling from H-Ras to c Raf-1 visualized on the plasma membrane of living cells"Chemphyschem. 4・7. 748-753 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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