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1999 Fiscal Year Final Research Report Summary

Cloning of human proteins which interact with heaptitis C virus proteins

Research Project

Project/Area Number 09670518
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

YOSHI Haruhiko  University of Tokyo Faculty of Medicine, Assistant, 医学部・附属病院, 助手 (60240305)

Co-Investigator(Kenkyū-buntansha) KATO Naoya  University of Tokyo Faculty of Medicine, Assistant, 医学部・附属病院, 助手 (90313220)
SHIRATORI Yasushi  University of Tokyo Faculty of Medicine, Lecturer, 医学部・附属病院, 講師 (70196624)
OMATA Masao  University of Tokyo Faculty of Medicine, Professor, 医学部・附属病院, 教授 (90125914)
Project Period (FY) 1997 – 1999
KeywordsHepatitis C virus (HCV) / NS5A / Transcription / TBP / TAF / Core / NF-κB / p53
Research Abstract

In this study, it was revealed that the NS5A protein, without its 146 N-terminal amino acids and fused to the DNA-binding domain of GAL4 strongly activates transcription in yeast and human hepatoma cells. Analysis of NS5A protein deletion mutants revealed that the domain of transcriptional activation exists in the central region of the NS5A protein. This region contains two acidic regions and one proline-rich region. Because NS5A protein is revealed to be a potent transcriptional transactivator, we examined the interaction of NS5A with general transcription factors in vivo to investigate how NS5A stimulates transcription. We found that NS5A binds to the human TATA box-binding protein (TBP). a major component of transcription factor for RNA polymerase II D (TFIID). We also observed an interaction between NS5A and a group of human TBP-associated factors (hTAFs), including TAFィイD2IIィエD270, hTAFィイD2IIィエD232/31, hTAFィイD2IIィエD228, hTAFィイD2IIィエD220, and hTAFィイD2IIィエD218. Further deletion analysis of NS5A revealed that the C-terminus of NS5A, ranging from amino acids 2153 to 2449, is important for its interactions with TFIID components. To clarify the effects of HCV infection on hepatocytes, we analyzed the influence of 7 HCV (core, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins on 5 well-defined intracellular signaling pathways associated with cell proliferation, differentiation, and apoptosis by use of a reporter assay. Of 7 HCV proteins, core protein had the strongest influence on intracellular signals, especially NF-κB-, AP-1-, and SRE-associated pathways. HCV NS4B also activated NF-κB pathway. Moreover, we found that core protein interacts with p53 and modulates p53-dependent promoter activities during HCV infection.

  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Shiratori, Y., Kato, N., et al.: "Quantative Assays for HCV in serum as predictors of the long-term response to IFN"J. Hepatol. 27. 437-444 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiratori, Y., Kato, N., et al.: "Predictors of the efficacy of IFN therapy in chronic HCV infection"Gastroenterology. 113. 558-566 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, N., Shiratori, Y., et al.: "HCV NS5A is a potent transcriptional activator"J. Virol. 71. 8856-8859 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiratori, Y., Kato, N., et al.: "Does dual infection by HBV & HCV play an important role in the pathogenesis of HCL in Japan?"Cancer. 80. 2060-2067 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kanda, T., Shiratori, Y., et al.: "Detection of GBV-L RNA in patients with nonA-E fulminant hepatitis by RT PCR"Hepatology. 25. 1261-1265 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiratori, Y., Yoshida, H., et al.: "How soon can a virological sustained response be determined after withdrawal of IFN therapy in chronic hepatitis c"J. Gastroenterol. Hepatol. 14. 79-84 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ono, E., Shiratori, Y., et al.: "Platelet count reflects stage of chronic hepatitis c"Hepatol Res.. 15. 192-200 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshida, H., Shiratori, Y., et al.: "IFN therapy reduces the risk for HCV"Aun Intern Med. 131. 174-181 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiratori, Y., Kato, N., et al.: "Sustained viral response is scarcely achieved in patients with high viral load by HCV RNA by excessive IFN therapy"Dig. Dis. Sci.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiratori, Y., Yoshida, H., et al.: "Histologic improvement in fibrosis in hepatitis c patients with sustained response to IFN therapy"Aun Intern Med. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiratori Y, Kato N, Yokosuka O, Hashimoto E, Hayashi N, Nakamura A, Asada M, Kuroda H, Ohkubo H, Arakawa Y, Iwama A, Omata M.: "Quantitative assays for hepatitis C virus in serum as predictors of the long-term response to interferon."J Hepatology. 27. 437-444 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiratori Y, Kato N, Yokosuka O, Imazeki F, Hashimoto E, Hayashi N, Nakamura A, Asada M, Kuroda H, Tanaka N, Arakawa Y, Omata M: "for the Tokyo-Chiba Hepatitis Research Group. Predictors of the efficacy of interferon therapy in chronic hepatitis C virus infection."Gastroenterology. 113. 558-566 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato N, Lan K-H, Ono-Nita SK, Shiratori Y, Omata M.: "Hepatitis C virus nonstructural region 5A protein is a potent transcriptional activator"J Virol. 71. 8856-8859 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiratori Y, Shiina S, Zhang PY, Ohno E, Okudaira T, Payawal DA, Ono-Nita SK, Imamura M. Kato N. Omata M.: "Does dual infection by heatiisB and C viruses play an important role in the pathogenesis of hepatocellular carcinoma in Japan?"Cancer. 80. 2060-2067 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kanda T, Yokosuka O, Ehata T, Maru Y, Imazeki F, Saisho H, Shiratori Y. Omata M.: "Detection of GBV-C RNA in patients with non-A-E fulminant hepatitis by reverse-transcription polymerase chain reaction."Hepatology.. 25. 1261-1265 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiratori Y, Kato N, Yoshida H, Imazeki F, Okano K, Yokosuka O, Omata M.: "How soon can a virological sustained response be determined after withdrawal of interferon therapy in chronic hepatitis C?"J Gastroenterol Hepatol. 14. 79-84 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ono E, Shiratori Y, Okudaira T, Imamura M, Teratani T, Kanai F, Kato N, Yoshida H, Shiina S, Omata M.: "Platelet count reflects stage of chronic hepatitis C."Hepatol Res. 15. 192-200 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, Inoue O, Yano M, Tanaka M, Fujiyama S, Nishiguchi S, Kuroki T, Imazeki F, Yokosuka O, Kinoyama S, Yamada G, Omata M.: "Interferon therapy reduces the risk for hepatocellular carcinoma : national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan."Ann Intern Med. 131. 174-181 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiratori Y, Kato N, Yoshida H, Nakata R, Ihori M, Imazeki F, Yokosuka O, Kawase T, Katamoto T, Unuma T, Nakamura A, Ikegami F, Hirota K, Omata M.: "Sustained viral response is scarcely achieved in patients with high viral load of HCV RNA by excessive interferon therapy."Dig Dis Sci. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiratori Y, Imazeki F, Moriyama M, Yano M, Arakawa Y, Yokosuka O, Kuroki T, Sata M, Yamada G, Fujiyama S, Yoshida H, Omata M.: "Histologic improvement in fibrosis in hepatitis C patients with sustained response to interferon therapy"Ann Intern Med. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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