HBV transcription repression in response to genotoxic stress is p53-dependent and abrogated by pX.
Transcription of hepatitis B Virus (HBV), an important risk factor of hepatocellular carcinoma (HCC), is controlled by cellular transcription activators including some of the cellular signaling targets. Consequently, HBV transcription rate changes in response to the cellular physiological conditions. In this report we investigated HBV gene expression and the role of physiological levels of the viral X protein (pX) under cisplatin induced genotoxic stress. We show that under these conditions the RNA level of an HBV mutant which does not express pX is sharply reduced. Studies revealed that transcription repression is responsible for the observed reduction in HBV RNA level. Repression of HBV transcription was obtained only in the p53 proficient cells. Furthermore, HBV transcription rate is recovered by the cotransfected p53 dominant negative plasmid, indicating that p53 is directly responsible for HBV transcription repression. Unexpectedly, p73, the recent p53 homologue, does not repress but rather activates HBV transcription. Interestingly, pX produced either by the HBV genome or by a cotransfected plasmid, relieves the p53 mediated repression. Collectively, these results attribute a physiological role to p53-inactivation by pX, and explain how pX may support HCC development.
Doitsh
G
G
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Shaul
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D002945:Cisplatin / Q000494:pharmacology; D004279:DNA, Viral / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000187:drug effects; D013312:Stress, Physiological; D013489:Suppression, Genetic; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D054334:Viral Regulatory and Accessory Proteins
D000970:Antineoplastic Agents; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012367:RNA, Viral; C000606460:TP73 protein, human; D015534:Trans-Activators; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D002945:Cisplatin