Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis

• Published in: Oncogene Vol. 20; no. 28; pp. 3620 - 3628
• Main Authors: HUO, Teh-La, WANG, Xin W, FORGUES, Marshonna, WU, Chuan-Ging, SPILLARE, Elisa A, GIANNINI, Carlo, BRECHOT, Christian, HARRIS, Curtis C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 21.06.2001; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animals; Apoptosis; Biological and medical sciences; Carcinogenesis; Carcinoma, Hepatocellular - virology; Cell cycle; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cercopithecus aethiops; Chronic infection; COS Cells; DNA repair; Fundamental and applied biological sciences. Psychology; Genes, Reporter; Glutathione Transferase - metabolism; Hepatitis; Hepatitis B; hepatitis B virus; Hepatitis B virus - genetics; Hepatitis B virus - metabolism; Hepatitis B, Chronic - virology; Hepatocellular carcinoma; Hepatocytes; Humans; Liver cancer; Liver Neoplasms - virology; Luciferases - genetics; Microinjection; Molecular and cellular biology; Molecular Sequence Data; Mutants; Mutation; NF-kappa B - metabolism; NF-κB protein; p53 Protein; Protein Biosynthesis; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription; Transcriptional Activation; Tumor necrosis factor-TNF; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Tumors; Viruses; X gene; United States > US; Maryland; Human; Transcription; p53 Protein; Orthohepadnavirus; Hepatic disease; Hepatocellular carcinoma; Molecular interaction; Malignant tumor; Carcinogenesis; Virus; Case study; Regulation(control); Hepadnaviridae; Mutation; Hepatitis B virus; Apoptosis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1204495

Chronic hepatitis B virus (HBV) infection and the integration of its X gene (HBx) are closely associated with the development of hepatocellular carcinoma (HCC). The integrated HBx frequently is truncated or contains point mutations. Previous studies indicated that these HBx mutants have a diminished co-transactivational activity. We have compared the effects of wild-type (wt) HBx and its naturally occurring mutants derived from human HCCs on transcriptional co-transactivation, apoptosis and interactive effects with p53. We demonstrated that overexpression of mutant, but not wt HBx, is defective in transcriptional co-transactivation of the NF-kappaB-driven luciferase reporter. By using a microinjection technique, the HBx mutants were shown to have an attenuated pro-apoptotic activity. This deficiency may be attributed to multiple mutations in the co-transactivation domain of HBx, that leads to decreased stability of the translated product. However, wt or mutant HBx bind to p53 in vitro and retain their ability to block p53-mediated apoptosis in vivo, which has been implicated as its major tumor suppressor function. The abrogation of p53-mediated apoptosis by integrated HBx mutants may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to hepatocellular carcinogenesis.