Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis
| Autor: | Christian Bréchot, Teh Ia Huo, Carlo Giannini, Xin Wei Wang, Elisa A. Spillare, Marshonna Forgues, Chuan Ging Wu, Curtis C. Harris |
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| Rok vydání: | 2000 |
| Předmět: |
Transcriptional Activation
Cancer Research Hepatitis B virus Carcinoma Hepatocellular Molecular Sequence Data Apoptosis Biology medicine.disease_cause Virus Cell Line Hepatitis B Chronic Orthohepadnavirus Genes Reporter Chlorocebus aethiops Genetics medicine Animals Humans Viral Regulatory and Accessory Proteins Amino Acid Sequence Luciferases Molecular Biology Glutathione Transferase Liver Neoplasms NF-kappa B biology.organism_classification medicine.disease digestive system diseases HBx Hepadnaviridae Hepatocellular carcinoma Protein Biosynthesis COS Cells Mutation Cancer research Trans-Activators Tumor Suppressor Protein p53 Carcinogenesis |
| Zdroj: | Oncogene. 20(28) |
| ISSN: | 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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