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HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

Oncogene volume 21, pages 4801–4811 (2002)Cite this article

Abstract

Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis and hepatocellular carcinoma. HCV NS5A, one of non-structural proteins of HCV, was suggested to play a role in oncogenic transformation. Since the tumor suppressor p53 is important for preventing neoplastic transformation, we investigated the functional effects of HCV NS5A on p53. In vitro and in vivo coimmunoprecipitation and confocal microscopy were used to determine the interaction of NS5A and p53. HCV NS5A binds directly to p53 and colocalizes p53 in the perinuclear region. NS5A inhibits transcriptional transactivation by p53 in a dose-dependent manner by use of a reporter assay. Down regulation of endogenous p21/waf1 expression, which is activated by p53 in Hep3B cells, by NS5A was demonstrated by using FLAG- and FLAG-NS5A Hep3B stable cell lines. The effect of NS5A on p53-mediated apoptosis was determined by flow cytometry in both NS5A permanently and transiently transfected Hep3B cells with exogenous p53. The p53-induced apoptosis was abrogated by NS5A and the inhibition effect correlates well with the binding ability of NS5A to p53. In addition, HCV NS5A protein interacts with and colocalizes hTAFII32, a component of TFIID and an essential coactivator of p53, in vivo. These results suggest that HCV NS5A interacts with and partially sequestrates p53 and hTAFII32 in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection.

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Acknowledgements

We thank Junichi Miyazaki, Yan-Hwa Wu Lee, Robert Tijin for their gifts of plasmids and Xin Wei Wang (NCI, NIH, USA) for reviewing this manuscript. The study was partially supported by grants from the National Science Council, Taiwan (NSC 89-2315-B-075-002 and NSC 90-2314-B-075-037-MH).

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 11217, Taiwan, Republic of China

    Keng-Hsin Lan, Jaw-Ching Wu, Yuan-Jan Wang, Full-Young Chang & Shou-Dong Lee

  2. Department of Family Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 11217, Taiwan, Republic of China

    Shinn-Jang Hwang

  3. Cancer Center, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 11217, Taiwan, Republic of China

    Meei-Ling Sheu & Sang-Hue Yen

  4. Department and Institute of Pharmacology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 11217, Taiwan, Republic of China

    Keng-Hsin Lan

  5. Institute of Biochemistry, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 11217, Taiwan, Republic of China

    Shiow-Yi Chen

  6. Department of Gastroenterology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan

    Naoya Kato & Masao Omata

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  1. Keng-Hsin Lan
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Correspondence to Shou-Dong Lee.

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Lan, KH., Sheu, ML., Hwang, SJ. et al. HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis. Oncogene 21, 4801–4811 (2002). https://doi.org/10.1038/sj.onc.1205589

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