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Study on the function of receptor for Helicobacter pylori VacA and the mechanism of its intoxication

Research Project

Project/Area Number 17209015
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Bacteriology (including Mycology)
Research InstitutionNagasaki University

Principal Investigator

HIRAYAMA Toshiya  Nagasaki university, Tropical Medicine, Professor, 熱帯医学研究所, 教授 (50050696)

Co-Investigator(Kenkyū-buntansha) WADA Akihiro  Nagasaki University, Institute of Tropical Medicine, Lecturer, 熱帯医学研究所, 講師 (70253698)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥50,050,000 (Direct Cost: ¥38,500,000、Indirect Cost: ¥11,550,000)
Fiscal Year 2006: ¥26,390,000 (Direct Cost: ¥20,300,000、Indirect Cost: ¥6,090,000)
Fiscal Year 2005: ¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000)
KeywordsHelicobacter pylori / VacA / AZ-521 cells / COX-2 / PGE_2 / p38 MAP kinase / ATF-2 cascade / Bacterial toxin / Pathogenesis
Research Abstract

By 2006 budget, we found that VacA increases PGE_2 production by AZ-521 cells by up-regulation of COX-2 expression through a signaling pathway involving the p38 MAP kinase/ATF-2 cascade, leading to activation of the CRE element on the COX-2 promoter.
Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase-2 (COX-2) mRNA in a time-and dose-dependent manner. A p38 MAP kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erkl/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased PGE_2 production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-kB or NF-IL6 sites, but not a mutated CRE site, suggesting direct involvement of the ATF-2/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-siRNA resulted in suppression of COX-2 expression. Thus, we found that VacA enhances PGE_2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK /ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (15 results)

All 2006 2005

All Journal Article (15 results)

  • [Journal Article] Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation2006

    • Author(s)
      Yamasaki E., et al.
    • Journal Title

      J. Biol. Chem. 281

      Pages: 11250-11259

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Endoscope disinfection using chlorine dioxide in an automated washer-disinfector2006

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

      J. Hosp. Infect. 63

      Pages: 298-305

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Helicobacter pylori VacA clustering in lipid rafts, mediated by receptor, RPTP, is required for intoxication in AZ-521 cells.2006

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

      Infectlmmun. 74

      Pages: 6571-6580

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation2006

    • Author(s)
      Yamasaki E., Wada A., Kumatori A., Nakagawa I., Funao J., Nakayama M., Hisatsune J., Kimura M., Moss J., Hirayama T.
    • Journal Title

      J. Biol. Chem. 281

      Pages: 11250-11259

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Endoscope disinfection using chlorine dioxide in an automated washer-disinfector.2006

    • Author(s)
      Isomoto H., Urata M, Kawazoe K, Matsuda J, Nishi Y, Wada A, Ohnita K, Hirakata Y, Matsuo N, Inoue K, Hirayama T, Kamihira S, Kohno S.
    • Journal Title

      J. Hosp. Infect 63

      Pages: 298-305

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Helicobacter pylori VacA clustering in lipid rafts, mediated by receptor, RPTP β, is required for intoxication in AZ-521 cells.2006

    • Author(s)
      Nakayama M, Hisatsune J, Yamasaki E, Nishi Y, Wada A, Kurazono H, Sap J, Yahiro K, Moss J, Hirayama T
    • Journal Title

      Infect Immun 74

      Pages: 6571-6580

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation2006

    • Author(s)
      Yamasaki E., et al.
    • Journal Title

      J.Biol.Chem. 281

      Pages: 11250-11259

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Endoscope disinfection using chlorine dioxide in an automated washer-disinfector2006

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

      J.Hosp.Infect. 63

      Pages: 298-305

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Helicobacter pylori VacA clustering in lipid rafts, mediated by receptor, RPTP is required for intoxication in AZ-521 cells.2006

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

      Infect Immun. 74

      Pages: 6571-6580

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation2006

    • Author(s)
      Yamasaki E., et al.
    • Journal Title

      J Biol Chem (印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Cytotoxicity and recognition of receptor-like protein tyrosine phosphatases, RPTPα and RPTPβ, by Helicobacter pylori m2VacA.2005

    • Author(s)
      De Guzman, B.B et al.
    • Journal Title

      Cell Microbiol 7

      Pages: 1285-1293

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Functional antagonism between Helicobacter pylori CagA and VacA in control of the NFAT signaling pathway in gastric epithelial cells2005

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

      Proc.Natl.Acad.Sci.USA. 102

      Pages: 9661-9666

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inhibitory effects of polyphenols on gastric injury by Helicobacter pylori VacA toxin2005

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

      Helicobacter 10

      Pages: 231-239

    • Related Report
      2005 Annual Research Report
  • [Journal Article] High concentrations of human beta-defensin 2 in gastric juice of patients with Helicobacter pylori infection2005

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

      World J Gastroenterol 11

      Pages: 4782-4787

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Vacuolating cytotoxin A is associated with increased thrombin generation in gastric mucosa2005

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

      Helicobacter 10

      Pages: 323-331

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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