Hepatitis B virus surface (S) transactivator with DNA-binding properties

Abstract

Chronic infection with hepatitis B virus (HBV) in humans is strongly linked to the development of hepatocellular carcinoma (HCC). Activation of growth-regulatory genes may play a crucial role in carcinogenesis. Proto-oncogene expression has been shown to be higher in HCC tissue with integrated HBV DNA than in the normal liver. Earlier, we showed that the 3' end of the HBV major surface gene (S) (426-855 nucleotides of the S region) is a transactivator of the X promoter-enhancer regulatory element in co-transfection experiments. This region expresses a truncated carboxy terminal S protein extending from amino acid residues 102 to 226. In this study, the truncated S protein (trc-S) was examined for its enhancing activity on several viral and cellular regulatory elements. The results indicate that trc-S activates rous sarcoma virus long terminal repeat (LTR), human T-lymphotropic virus 2 LTR, human immunodeficiency virus 1 LTR, and the c-jun and c-fos promoters. Electrophoretic mobility shift assays carried out to investigate its DNA-binding properties established that trc-S binds to HBV X promoter and oligonucleotides representing binding sites for the AP1 and TFIID transcription factors. The specificity of this interaction was confirmed by using competition experiments and supershift assays. These experiments suggest that trc-S is a transactivator of several cellular and viral promoters and that this activity is mediated by direct interaction with DNA.

Hepatitis B Virus preS2 Domain Promotes Angiogenesis in Hepatocellular Carcinoma via Transcriptional Activation of VEGFA Promoter

“…Our study showed that the preS2 domain upregulated the VEGFA promoter activity dose-dependently. As described previously, an SHBs protein with an N-terminal truncation leaving a fragment of aa 102 -226 without any preS2 domain had DNA-binding properties (22). Given all the above studies, we speculate that the HBV preS2 domain may activate the VEGFA promoter by enhancing HIF-1 stability or expression levels.…”

Molecular characterization of hepatitis B virus surface antigen mutants in Singapore patients with hepatocellular carcinoma and hepatitis B virus carriers negative for HBsAg but positive for anti‐HBs and anti‐HBc

“…Mutations of the a‐determinant could have functional impacts on the cellular function of HBsAg as a transcriptional activator 28 . The generation of ground glass hepatocytes and subsequent development of HCC has been shown by overexpression of the large HBsAg in transgenic mice, probably mediated by the transcriptional activity of the large surface antigen (LHBsAg) 29 .…”