Disruption of the function of tumor-suppressor gene p53 by the hepatitis B virus X protein and hepatocarcinogenesis.
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.
Takada
S
S
Department of Gene Research, Cancer Institute (JFCR), Tokyo, Japan.
Tsuchida
N
N
Kobayashi
M
M
Koike
K
K
D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D016158:Genes, p53; D006509:Hepatitis B / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D015183:Restriction Mapping; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins; D016662:Virus Integration
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein