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Hepatitis B Virus X Protein Modulates the Expression of PTEN by Inhibiting the Function of p53, a Transcriptional Activator in Liver Cells¹

National Research Laboratory for Glycobiology, MOST, Korean Government, Kyungju 780-714, South Korea [T-W. C., C-H. K.]; Department of Biochemistry and Molecular Biology, Dongguk University COM, Kyungju 780-714, South Korea [T-W. C., C-H. K.]; Faculty of Natural Resources and Life Science, Dong-A University, Pusan 604-714, South Korea [Y-C. L.]; and Proteome Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejon 305-333, South Korea [J-H. K.]

The Hepatitis B Virus X (HBx) protein of hepatitis B virus plays a major role in hepatocellular carcinoma. It has been reported that the mutation and disruption of PTEN, a known tumor suppressor and a negative regulator of phosphatidylinositol 3'-kinase/AKT might be involved in tumor progression. However, the relationship between HBx and PTEN expression in hepatocellular carcinoma (HCC) development is not fully understood. This study reports on an investigation of whether PTEN expression in HBx-transfected cells is modulated by HBx or not. HBx decreased the expression of PTEN in HBx-transfected cells, as evidenced by Western as well as Northern blot analysis. In addition, AKT was found to be activated by HBx, as evidenced by not only the phosphorylation of AKT at serine 473 but by the phosphorylation of the exogenous substrate histone H2B as well, and these were specifically blocked by the presence of wortmannin. Moreover, The growth rate of HBx-transfected liver cells was higher than that of Chang and Chang-pEGFP cells. HBx had no effect on the expression of p53, a known transcriptional activator of PTEN. However, we confirmed that the binding of the p53 protein to p53 binding site-oligo of PTEN promoter is decreased in HBx-transfected liver cells by electrophoretic mobility shift analysis and, in addition, that HBx disrupts p53-mediated PTEN transcription, as evidenced by a PTEN promoter assay. Therefore, we conclude that HBx in liver cells down-regulates the expression of PTEN and activates AKT. This constitutes the first report to demonstrate that HBx has an effect on the p53-mediated transcription of PTEN, which, in turn, is associated with tumor suppression.

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