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Disruption of the function of tumor-suppressor gene p53 by the hepatitis B virus X protein and hepatocarcinogenesis

  • Original Paper
  • Experimental Oncology
  • Published:
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Abstract

The X gene of the hepatitis B virus codes for a small basic protein and is able to transactivate viral and cellular genes, although the X protein exhibits no DNA-binding activity. The mechanism of transactivation by X protein has been suggested to be via protein-protein interaction(s). We first demonstrated that X protein had amino acid sequences homologous to the functionally essential domain of Kunitz-type serine protease inhibitors and that those sequences were indispensable for the transactivation function. We demonstrated that X protein exhibited an inhibitor activity against hepatic serine proteases, and subsequently found that the protein activated X gene transcription in HepG2 cells and that the X responsive element was localized in the minimal promoter of the X gene. In contrast, the tumor-suppressor gene p53, but not mutant p53, remarkably reduced transcription from the minimal promoter. This p53 repression on the X gene promoter was cancelled by X gene co-expression, probably indicating that the X protein disrupts the p53 tumor suppressor function in the nucleus. All data suggest that X protein leads to transactivation of cellular oncogenes by preventing an interaction between p53 and cellular transcription factor(s) consisting of the basal transcriptional machinery.

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Abbreviations

HBV :

hepatitis B virus

HCC :

hepatocellular carcinoma

ORF :

open-reading frame

X-PBP :

x-promoter binding protein

CAT :

chloramphenicol acetyltransferase

PCR :

polymerase chain reaction

GSHV :

ground squirrel hepatitis virus

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Authors and Affiliations

  1. Department of Gene Research, The Cancer Institute (JFCR), Kami-Ikebukuro, Toshima-ku, 170, Tokyo, Japan

    Shinako Takada, Midori Kobayashi & Katsuro Koike

  2. Department of Molecular and Cellular Oncology, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, 113, Tokyo, Japan

    Nobuo Tsuchida

Authors
  1. Shinako Takada
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  2. Nobuo Tsuchida
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  3. Midori Kobayashi
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  4. Katsuro Koike
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Additional information

Work dedicated to Dr. Haruo Sugano on the occasion of his 70th birthday. The material of this paper was essentially presented at the 60th Anniversary Symposium of the Cancer Institute and the Cancer Institute Hospital, Tokyo, held in September 1994

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Takada, S., Tsuchida, N., Kobayashi, M. et al. Disruption of the function of tumor-suppressor gene p53 by the hepatitis B virus X protein and hepatocarcinogenesis. J Cancer Res Clin Oncol 121, 593–601 (1995). https://doi.org/10.1007/BF01197776

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  • DOI: https://doi.org/10.1007/BF01197776

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