Katsuyuki Yaginuma

The X gene of hepatitis B virus induced growth stimulation and tumorigenic transformation of mouse NIH3T3 cells.

To examine the transforming potential of the × gene product of hepatitis B virus (HBV), the X‐gene‐containing region (referred to as the HBx region) was introduced into mouse NIH3T3 cells. Each transformed cell line expressed X‐coding mRNA at a different level. A positive correlation was found between the level of X‐coding mRNA and the saturation density of the cells. The HBx‐transformed cell lines exhibited × protein production and tumor formation in nude mice. The function of HBV in oncogenesis may involve the continuous expression of the X‐gene‐coded product in the HBV DNA‐integrated cells.

Contribution of HBV X Gene Expression to Hepatic Carcinogenesis

The X protein of the hepatitis B virus transactivates various viral and cellular genes and has unique amino acid sequences, homologous to the functionally essential domain of Kunitz-type serine protease inhibitors and indispensable for its transactivation function. Here we present that the X protein inhibited major serine proteases in the hepatic cells and that it regulates its own gene transcription in HepG2 cells in a transactivational manner. Analysis using several CAT constructs with a normal or mutant X promoter region localized the X responsive element in the promoter region within the BalI/MboI fragment. We also found that the suppressor oncogene product p53, but not mutant p53, markedly reduced transcription from the X gene promoter. Results suggest that the X protein activates the X gene promoter by inhibiting proteolysis of the transcription factor(s) in the transcriptional machinery, and that the X protein directly or indirectly renders wild-type p53 ineffective for blocking transcription of the X gene and other cellular genes.