• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Mechanism of hepatocyte injury via survival and death signaling induced by hepatitis viruses

Research Project

Project/Area Number 13307019
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

OMATA Masao  The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (90125914)

Co-Investigator(Kenkyū-buntansha) KATO Naoya  The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (90313220)
OTSUKA Motoyuki  The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
TANIGUCHI Hiroyoshi  The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
TANAKA Yasuo  The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
Project Period (FY) 2001 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥52,390,000 (Direct Cost: ¥40,300,000、Indirect Cost: ¥12,090,000)
Fiscal Year 2004: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
Fiscal Year 2003: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2002: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2001: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000)
KeywordsHepatitis B virus / Hepatitis C virus / Hepatitis delta virus / Signal transduction / Apoptosis / Innate Immunity / Persistent infection / NF-κB / A型肝炎ウイルス / 線維化 / TGF-β / インターフェロン / p53 / cDNA array / シグナル伝導 / NF-KB / Bcl-Xr / SRF
Research Abstract

In this study, we aimed to clarify the mechanism of hepatocyte injury via survival and death signaling induced by hepatitis viruses. 1)Hepatitis C virus(HCV) core protein activated NF-κB-dependent signaling pathway through tumor necrosis factor receptor-associated factor. This function of HCV core protein may play an important role in the inflammatory reaction induced by this virus. In fact, HCV core protein activated also interteukin(IL)-8 promoter through NF-κB. Moreover, differences in the amino acid sequence of HCV core protein correlates with hepatitis activity through modulation of IL-8 induction in HCV infected patients. In addition, HCV core protein upregulated transforming growth factor(TGF)β-1 expression, suggesting a new paradigm for exacerbation of liver fibrosis by HCV infection. 2)HCV NS3 protein interacts directly with TBK1,and that this binding results in the inhibition of the association between TBK1 and IRF-3,a key transcriptional factor to produce interferon-b, which … More leads to the inhibition of IRF-3 activation. This might show the mechanisms in the inhbition of innate immune responses and in the persistence of HCV infection by NS3 protein. 3)HCV NS4A and NS4B proteins inhibited cellular protein synthesis by targeting the process of translation. HCV NS4A and NS4B proteins have an effect of translational inhbition. This novel function may be involved in HCV infection and help its survival in host cells. 4)HCV NS5A protein interacts with and partially sequestrates p53 and hTAFII32,a component of TFIID and an essential coactivator of p53, in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection. 5)Uncerstanding the function of hepatitis B virus(HBV) X protein(HBx) is fundamental to elucidating the underlying mechanisms of hepatitis and hepatocarcinogenesis caused by HBV infection. We identified heat shock protein 60(Hsp60) as a novel cellular target of HBx by the combination of affinity purification and mass spectrometry. Confocal laser microscopy demonstrated that HBx and Hsp60 colocalized in mitochondria. Furthermore, TUNEL revealed that the introduction of HspGO into cells facilitated HBx-induced apoptosis. These findings suggest the importance of the molecular chaperon protein Hsp60 to the function of HBV viral proteins. 6)Hepatitis delta virus(HDV) is a naturally occurring satellite of HBV. HBx, alone or with the large isoform of HDV antigens(LHDAg), synergistically activated the serum response element(SRE)-dependent pathway. HBx activated the transcriptional ability of Elk-1,whereas LHDAg activated the transcritional ability of serum response factor(SRF). Thus, HBx and LHDAg synergistically activated the SRE-dependent pathway. These results may help us understand clinical phenomena in patients coinfected with HBV and HDV. Less

Report

(5 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (38 results)

All 2005 2004 2002 2001 Other

All Journal Article (18 results) Publications (20 results)

  • [Journal Article] Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses.2005

    • Author(s)
      Otsuka M, Kato N, Moriyama M, Taniguchi H, Wang Y, Narayan D, Kawabe T, Omata M.
    • Journal Title

      Hepatology (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] Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways.2005

    • Author(s)
      Shao RX et al.
    • Journal Title

      Gastroenterology 128

      Pages: 86-95

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hepatic gene expression profiles associated with fibrosis progression and hepatocarcinogenesis in hepatitis C patients.2005

    • Author(s)
      Shao RX et al.
    • Journal Title

      World J Gastroenterol 11

      Pages: 1995-1999

    • Related Report
      2004 Annual Research Report
  • [Journal Article] HCV core protein upregulates TGF-β1 transcription.2004

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

      J Med Virol 72

      Pages: 52-59

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interaction of HBx with heat shock protein 60 enhances HBx-mediated apoptosis.2004

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

      Biochem Biophys Res Commun 318

      Pages: 461-469

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription.2004

    • Author(s)
      Taniguchi H, Kato N, Otsuka M, Goto T, Yoshida H, Shiratori Y, Omata M.
    • Journal Title

      J Med Virol 72

      Pages: 52-59

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interaction of the hepatitis B virus X protein(HBx) with heat shock protein 60 enhances HBx-mediated apoptosis.2004

    • Author(s)
      Tanaka Y, Kanai F, Kawakami T, Tateishi K, Ijichi H, Kawabe T, Arakawa Y, Kawakami T, Nishimura T, Shirakata Y, Koike K, Omata M.
    • Journal Title

      Biochem Biophys Res Commun 318

      Pages: 461-469

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interaction of hepatitis B virus X protein (HBx) with heat shock protein 60 enhances HBx-mediated apoptosis.2004

    • Author(s)
      Tanaka Y et al.
    • Journal Title

      Biochem Biophys Res Commun 318

      Pages: 461-469

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A simple combination of serum type IV collagen and PT to diagnose cirrhosis in patients with chronic active hepatitis C.2004

    • Author(s)
      Qui Y et al.
    • Journal Title

      Hepatol Res 30

      Pages: 214-220

    • Related Report
      2004 Annual Research Report
  • [Journal Article] HCV core protein inhibits apoptosis via enhanced Bcl-xL expression.2002

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

      Virology 296

      Pages: 84-93

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis.2002

    • Author(s)
      Lan KH, et al.
    • Journal Title

      Oncogene 21

      Pages: 4801-4811

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core protein inhibits apoptosis via enhanced Bcl-x(L) expression.2002

    • Author(s)
      Otsuka M, Kato N, Taniguchi H, Yoshida H, Goto T, Shiratori Y, Omata M.
    • Journal Title

      Virology 296

      Pages: 84-93

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis.2002

    • Author(s)
      Lan KH, Sheu ML, Hwang SJ, Yen SH, Chen SY, Wu JC, Wang YJ, Kato N, Omata M, Chang FY, Lee SD.
    • Journal Title

      Oncogene 21

      Pages: 4801-4811

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HCV core protein activate NP-κB-dependent signaling through TRAF.2001

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

      J Biol Chem 276

      Pages: 16399-16405

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core protein activates nuclear factor κB-dependent signaling through tumor necrosis factor receptor-associated factor.2001

    • Author(s)
      Yoshida H, Kato N, Shiratori Y, Otsuka M, Maeda S, Kato J, Omata M.
    • Journal Title

      J Biol Chem 276

      Pages: 16399-16405

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses.

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

      Hepatology (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] Interaction between HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses.

    • Author(s)
      Otsuka M et al.
    • Journal Title

      Hepatology (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] HCV core protein and hepatitis activity are associated through transactivation of interleukin-8.

    • Author(s)
      Hoshida Y et al.
    • Journal Title

      J Infect Dis (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Publications] Otsuka M: "Liver chip and gene shaving"J Gastroenterol. 38 (Suppl15). 89-92 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanda T: "Hepatitis A virus VP3 may activate serum response element associated transcription"Scand J Gastroenterol. 38. 307-313 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Otsuka M: "Comparing gene expression profiles in human liver, gastric, and pancreatic tissues using full-length-enriched cDNA libraries"Hepatol Res. 27. 76-82 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Moriyama M: "Relevance network between chemosensitivity and transcriptome in human hepatoma cells"Mol Cancer Ther. 2. 199-205 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Taniguchi H: "Hepatitis C virus core protein upregulates transforming growth factor-β1 transcription"J Med Virol. 72. 52-59 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Wang Y: "UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma in japanese patients with hepatitis C virus infection"Clin Cancer Res. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Otsuka M: "Differential cellular gene expression induced by hepatitis B and C viruses"Biophys Biochem Res Commun. 300. 443-447 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Goto T: "Hepatitis B virus HBX and the large hepatitis Delta antigen synergistically activate the SRE dependent pathway"J Infect Dis. 187. 820-828 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Wang Y: "Interleukin-1β gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection"Hepatology. 37. 65-71 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Lan KH: "HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis"Oncogene. 21. 4801-4811 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato J: "Interferons Specifically Suppress the Translation from the Internal Ribosome Entry Site of Hepatitis C Virus through a Double-Standard RNA-Activated Protein Kinase-Independent Pathway"J Infect Dis. 186. 155-163 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ono-Nita SK: "Novel Nucleoside Analogue MCC-478 (LY582563) Is Effective against Wild-Type or Lamivudine-Resistant Hepatitis B Virus"Antimicrob Agents Chemother.. 46. 2602-2605 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Otsuka M: "In Okita K. ed : Hepatitis C Virus/Oxidative Stress and Liver Diseases"Springer-Verlag Tokyo. (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Otsuka M. et al.: "Hepatitis C Virus core protein inhibits apoptosis via enhanced Bcl-Xr expression"Virology. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato J. et al.: "Hepatitis C virus NS4A and NS4B proteins supress translation in vivo"J Med Virol. 66. 187-199 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshida H. et al.: "Hepatitis C Virus core protein activates NF-κB dependent signaling through tumor necrosis factor receptor-associated factor"J Biol Chem. 276. 16399-16405 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ono-Nita SK, et al.: "The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B Virus replication and drug resistance"J Clin Invest. 107. 449-455 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ono-Nita SK, et al.: "Current options for the Harpy of durnic hepatitis B infection"Curr Infect Dis Rep. 3. 137-142 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Goto T, et al.: "Large Isoform of hepatitis delta antigen activates the rat smooth muscle (SM) 22α promoter via enhancement of transcriptional ability of serum response factor"Cells of the Hepatic sinusoid. 8. 223-224 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato N, et al.: "Induction of proliferation-related signals by hepatitis C virus In : Okita K, ed. Growth, Proliferation, and apoptosis in Hepatocytes"Springer-Verlag Tokyo. 81-98 (2002)

    • Related Report
      2001 Annual Research Report

URL: 

Published: 2001-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi