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Molecular basis for Epstein-Barr virus genome DNA replication

Research Project

Project/Area Number 12470073
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Virology
Research InstitutionDivision of Virology Aichi Cancer Center Research Institute

Principal Investigator

TSURUMI tatsuya  Aichi Cancer Center Research Institute, Division of Virology, Chief, 腫瘍ウイルス学部, 部長 (90172072)

Co-Investigator(Kenkyū-buntansha) NAKASU Shou  Division of Virology Senior Researcher, 腫瘍ウイルス学部, 主任研究員 (50198107)
SUGAYA Yutaka  Division of Virology Research Resident, 腫瘍ウイルス学部, リサーチレジデント
FUJITA Masatoshi  Division of Virology Senior Resercher, 腫瘍ウイルス学部, 主任研究員 (30270713)
中村 普武  愛知県がんセンター, 腫瘍ウイルス学部, 室長 (30109938)
葛島 清隆  愛知県がんセンター, 腫瘍ウイルス学部, 室長 (30311442)
横山 直明  愛知県がんセンター, 腫瘍ウイルス学部, 主任研究員 (80301802)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥8,400,000 (Direct Cost: ¥8,400,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2001: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2000: ¥3,500,000 (Direct Cost: ¥3,500,000)
KeywordsDNA replication / Epstein-Barr virus / helicase / primase / protein-protein interaction / 癌 / 酵素 / ゲノム / Epstein-Barrウイルス / ヘリカーゼ / プライマーゼ
Research Abstract

Productive infection/replication of herpesviruses usually occurs in growth arrested cells but there has been no direct evidence in case of Epstein-Barr virus (EBV) since an efficient lytic replication system without external stimuli does not exist for the virus. Expression of EBV lytic switch transactivator BZLF1 protein in EBV-negative epithelial tumor cell lines, however, is known to arrest cell cycle in G0/G1 by induction of the tumor suppressor protein, p53 and the cyclin dependent kinase inhibitors, p21WAF-1/CIP-1 and p27KIP-1 followed by the accumulation of hypophosphorylated form of Rb protein. In order to determine the effect of onset of the lytic viral replication on cellular events in EBV-latently infected B lymphoblastoid cell lines, a tightly controlled induction system of the EBV lytic replication program by inducible BZLF1 protein expression was established in B95-8 cells. The induction of the lytic replication completely arrested cell cycle progression and cellular DNA replication. Surprisingly, the levels of p53, p21WAF-1/CIP-1, and p27KIP-1 were constant before and after the lytic program induction, indicating that the cell cycle arrest induced by the lytic program is not mediated through p53 and the CDK inhibitors. Furthermore, although cellular DNA replication was blocked, elevation of cyclin E/A expression and accumulation of hyperphosphorylated forms of Rb protein were observed, being a post-G1/S phase characteristics of cells. Thus, while the EBV lytic program promoted specific cell cycle associated activities involved in the progression from G1 to S phase, it inhibited cellular DNA synthesis. Such cellular condition appears to most favors viral lytic replication.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (37 results)

All Other

All Publications (37 results)

  • [Publications] Fujita M: "Nuclear organization of DNA replication initiation proteins in mammalian cells"J.Biol.Chem.. 277. 10354-10361 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuzushima K: "Tetramer-assisted identification and characterization of epitopes recognized by HLA A^*2402-restricted Epstein-Barr virus -specific CD8_+ T cells"Blood. 101. 1460-1468 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kudoh A: "Reactivation of lytic replication from Epstein-Barr virus latently infected B-cells occurs with high S-phase CDK activity while inhibiting cellular DNA replication"J.Virol.. 77. 851-861 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M: "Establishment of latrunculin-A resistance in HeLa cells by expression of R183A D184A mutant beta-actin"Oncogene. 22. 627-631 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 鶴見達也: "Epstein-Barrウイルスの増殖機構:ウイルスゲノム複製を中心として"ウイルス. 52. 191-201 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsurumi T: "Molecular basis for Epstein-Barr virus DNA replication"Curr.Tops.Virol.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuzushima, K, et.al.: "Increased frequency of antigen-specific CD8+ cytotoxic T lymphocytes infiltrating an Epstein-Barr virus-associated gastric carcinoma"J.Clin.Invest.. 104. 163-171 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuzushima, K, et. al.: "Rapid determination of Epstein-Barr virus-specific CD8+T cell frequencies by flow cytometry"Blood. 94. 3094-3100 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita,M., et.al.: "Cell cycle regulataion of human CDC6 protein : intracellular localization, interaction with the human MCM complex and cdc2 kinase-mediated hyperphosphorylation"J.Biol.Chem.. 274. 25927-25932 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokoyama N. et.al.: "Assembly of the Epstein-Barr Virus BBLF4, BSLF1, and BBLF2/3 Proteins and Their Interactive Properties"J.Gen.Virol.. 80. 2879-2887 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hoshino Y. et.al.: "Antigen-driven expansion and contraction of CD8+ activated T cells in primary EBV infection"J.Immunol.. 163. 5735-5740 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujii K. et.al.: "The Epstein-Barr virus Pol catalytic subunit physically interacts with the BBLF4-BSLF1-BBLF2/3 complex"J.Virol.. 74. 2550-2557 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuzushima K., et. al.: "Longitudinal Dynamics of Epstein-Barr Virus-Specific Cytotoxic T Lymphocytes during The Posttransplant Lymphoproliferative Disorder"J.Infec.Dis.. 182. 937-940 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hoshino Y, et.al.: "Early intervention in post-transplant lymphoprolioferative disorders based on Epstein-Barr viral load"Bone Marrow Transplant.. 26. 199-202 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokoyama,N., et.al.: "Co-expression of human chaperone Hsp70 and Hsdj or Hsp40 Co-factor, increases solubility of overexpressed target proteins in insect cells"Biochim.Biophys.Acta. 1493. 119-124 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuzushima,K et. al.: "Efficient identification of HLA A^*2402-restricted cytomegalovirus- specific CD8+ T cell epitopes by a computer algorithm and an enzyme-linked immunospot assay"Blood. 98. 1872-1881 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M, et. al.: "Nuclear organization of DNA replication initiation proteins in mammalian cells"J.Biol.Chem.. 277. 10354-10361 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuzushima K, et.al.: "Tetramer-assisted identification and characterization of epitopes recognized by HLA A^*2402-restricted Epstein-Barr virus -specific CD8+ T cells"Blood. 101. 1460-1468 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kudoh A., et.al.: "Reactivation of lytic replication from Epstein-Barr virus latently infected B-cells occurs with high S-phase CDK activity while inhibiting cellular DNA replication"J.Virol.. 77. 851-861 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M, et.al.: "Establishment of latrunculin-A resistance in HeLa cells by expression of R183A D184A mutant beta-actin"Oncogene.. 22. 627-31 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsurumi T.: "Epstein-Barr Virus and Human Cancer : EBV replication enzymes"Curr.Top.MicrobioLImmunol.. 258. 65-83 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuzushima K and Tsurumi T.: "The CD8+ T cell response to Epstein-Barr Virus (EBV) : Development of an efficient method to detect EBV-specific CD8+ T cells by flow cytometry and its clinical application"Curr.Tops.Virol.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsurumi T and Fujita M.: "Molecular basis for Epstein-Barr virus DNA replication"Curr.Tops.Virol.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M: "Nuclear organization of DNA replication initiation proteins in mammalian cells"J.Biol.Chem.. 277. 10354-10361 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuzushima K: "Tetramer-assisted identification and characterization of epitopes recognized by HLA A^*2402-restricted Epstein-Barr virus -specific CD8+ T cells"Blood. 101. 1460-1468 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kudoh A: "Reactivation of lytic replication from Epstein-Barr virus latently infected B-cells occurs with high S-phase CDK activity while inhibiting cellular DNA replication"J. Virol.. 77. 851-861 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujita M: "Establishment of latrunculin-A resistance in HeLa cells by expression of R183A D184A mutant beta-actin"Oncogene. 22. 627-631 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 鶴見達也: "Epstein-Barrウイルスの増殖機構:ウイルスゲノム複製を中心として"ウイルス. 52. 191-201 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsurumi T: "Molecular basis for Epstein-Barr virus DNA replication"Curr. Tops. Virol.. (In press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuzushima, K: "Efficient identification of HLA A^*2402-restricted cytomegalovirus specific CD8+ T cell epitopes by a computer algorithm and an enzyme-linked immunospot assay"Blood. 98. 1872-1881 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujita M: "Nuclear organization of DNA replication initiation proteins in mammalian cells"J.Biol.Chem.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsurumi T: "Epstein-Barr Virus and Human Cancer : EBV replication enzymes"Curr.Top.Microbiol.Immunol.. 258. 65-83 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujii K. et al: "The Epstein-Barr virus Pol catalytic subunit physically interacts with the BBLF4-BSLF1-BBLF2/3 complex."Journal of Virology. 74. 2550-2557 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kuzushima K et al: "Longitudinal Dynamics of Epstein-Barr virus-specific cytotoxie T lymphocytes during the Posttrunsplant Lymphoproliferative Disorder"Journal of Infectious Disease. 182. 937-940 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hoshino Y. et al: "Early intervention in post-transplant lymphoproliferative dosorders based on Eqstein-Barr riral load."Bone Marrow Transplant. 26. 199-202 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yokoyama N. et al: "Co-expression of human chaperone Hsp70 and Hsdj or Hsp40 Co-factor, increases solubility of overexpressed target proteins in insect cells"biochim Biophys.Acta. 1493. 119-124 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsurumi T: "Epstein-Barr virus and human cancer : EBV replication enzymes"Curr.Top.Microbiol.Immunol.. 19 (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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