The hepatitis B virus preS2/St transactivator utilizes AP-1 and other transcription factors for transactivation.
Integrated hepatitis B virus DNA cloned from hepatitis B virus-associated hepatocellular carcinoma frequently contains 3'-truncated middle surface genes (preS2/St), which were recently found to have a transcriptional transactivator function. Because preS2/St, among others, is able to transactivate the promoters of the cellular oncogenes c-myc and c-fos, it has been speculated that integrated preS2/St genes might contribute to hepatitis B virus-associated liver carcinogenesis. In this study, we investigated the mechanism of target gene stimulation by preS2/St. It was found that deletion of a fragment containing the binding site for transcription factor AP-1 (Jun-Fos) substantially decreases inducibility of the human c-myc promoter by preS2/St. A subsequent investigation of AP-1 activation by preS2/St revealed the following: (a) insertion of multimeric AP-1 binding sites confers inducibility to an otherwise unstimulatable test promoter; (b) transactivation of AP-1 sites is dramatically increased when Jun and Fos are overexpressed by cotransfected expression plasmids; and (c) inhibitors of AP-1 activation also impair transactivation by preS2/St. Besides AP-1, preS2/St was also able to utilize the unrelated transcription factors NF-kappa B and AP-2 for transactivation, suggesting that the gene product of preS2/St acts indirectly through one or several general cellular pathways rather than as a bona fide transcription factor. Because AP-1 conveys induction of a large panel of tumor-relevant genes, its preS2/St-dependent activation implies a possible causative role in hepatitis B virus-associated hepatocarcinogenesis.
Lauer
U
U
Max-Planck-Institut für Biochemie, Martinsried, Germany.
Weiss
L
L
Lipp
M
M
Hofschneider
P H
PH
Kekulé
A S
AS
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000382:microbiology; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics; D005814:Genes, Viral / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000382:microbiology; D016328:NF-kappa B / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D014157:Transcription Factors