The hepatitis B virus PreS2/S t 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 /S t ), which were recently found to have a transcriptional transactivator function. Because preS2 /S t , among others, is able to transactivate the promoters of the cellular oncogenes c‐ myc and c‐ fos , it has been speculated that integrated preS2 /S t genes might contribute to hepatitis B virus‐associated liver carcinogenesis. In this study, we investigated the mechanism of target gene stimulation by preS2 /S t . 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 /S t . A subsequent investigation of AP‐1 activation by preS2 /S t 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 /S t . Besides AP‐1, preS2 /S t was also able to utilize the unrelated transcription factors NF‐kB and AP‐2 for transactivation, suggesting that the gene product of preS2 /S t 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 /S t ‐dependent activation implies a possible causative role in hepatitis B virus‐associated hepatocarcinogenesis. (Hepatology 1994;19:23–31).