Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts.
Epidemiology shows a clear correlation between chronic infection with the hepatitis B virus (HBV) and development of hepatocellular carcinoma (HCC). The potential role of the transactivating hepatitis B virus X protein (HBx) in transformation by HBV is controversial. Here we report that HBx suppresses transformation of primary rat embryo fibroblasts (REFs). Cooperating oncogenes like c-Ha-ras and c-myc transform REF very efficiently but cotransfection with HBx suppressed transformation of REFs down to 5%. Similarly, transfection of HBx together with the cooperating oncogenes Ha-ras and SV40 LTAg or c-Ha-ras and mutant p53 reduced the number of foci to 13%. Comparable results were obtained with HBx in the context of the whole HBV. Suppression of focus formation in REF could be partly relieved by cotransfection of apoptosis inhibitors Bcl-2 or E1B. However, cotransfection of apoptosis inhibitors crmA and p35 did not influence the proapoptotic functions of HBx. Thus, HBx may specifically activate the Bcl-2 sensitive pathway leading to apoptosis. Experiments with 13 HBx linker scanning mutants revealed that the domains necessary for HBx dependent transactivation overlap with the domains needed for the apoptotic/growth arrest functions of HBx.
Schuster
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Institut für Medizinische Virologie, Justus-Liebig-Universität, Frankfurter Str. 107, D-35392 Giessen, Germany.
Gerlich
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Schaefer
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D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics*; D002999:Clone Cells; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000821:virology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005814:Genes, Viral / Q000502:physiology*; D016679:Genome, Viral; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology; D008668:Metallothionein / Q000235:genetics / Q000502:physiology; D009857:Oncogenes / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins; D015678:Viral Structural Proteins / Q000235:genetics*
D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D015678:Viral Structural Proteins; C057628:hepatitis B virus X protein; D008668:Metallothionein