X-gene product of hepatitis B virus induces apoptosis in liver cells.
Hepatitis B virus is a causative agent of hepatocellular carcinoma, and in the course of tumorigenesis, the X-gene product (HBx) is known to play important roles. Here, we investigated the transforming potential of HBx by conventional focus formation assay in NIH3T3 cells. Cells were cotransfected with the HBx expression plasmid along with other oncogenes including Ha-ras, v-src, v-myc, v-fos, and E1a. Unexpectedly, the introduction of HBx completely abrogated the focus-forming ability of all five tested oncogenes. In addition, the cotransfection of Bcl-2, an apoptosis inhibitor, reversed the HBx-mediated inhibition of focus formation, suggesting that the observed repression of focus formation by HBx is through the induction of apoptosis. Next, to test unequivocally whether HBx induces apoptosis in liver cells, we established stable Chang liver cell lines expressing HBx under the control of a tetracycline-inducible promoter. Induction of HBx in these cells in the presence of 1% calf serum resulted in typical apoptosis phenomena such as DNA fragmentation, nuclear condensation, and fragmentation. Based on these results, we propose that HBx sensitizes liver cells to apoptosis upon hepatitis B virus infection, contributing to the development of hepatitis and the subsequent generation of hepatocellular carcinoma.
Kim
H
H
Signal Transduction Laboratory, Mogam Biotechnology Research Institute, 341 Pojungri, Koosungmyon, Yonginsi, Kyunggido 449-910, Korea.
Lee
H
H
Yun
Y
Y
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D053938:DNA Fragmentation; D011905:Genes, ras; D008099:Liver / Q000473:pathology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D013752:Tetracycline