Molecular mechanism of p73-mediated regulation of hepatitis B virus core promoter/enhancer II: implications for hepatocarcinogenesis.
Hepatitis B virus (HBV) is a causative agent of chronic hepatitis and hepatocellular carcinoma. Recent findings demonstrating p73 and specifically N-terminally truncated p73 (DeltaTAp73) accumulation in hepatocellular carcinoma suggest that p73 plays a role in the malignant phenotype. Here, we investigated the mechanism of HBV pregenomic core promoter/enhancer II (cp/EII) regulation by full-length TAp73 and its oncogenic counterpart DeltaTAp73. Ectopic and endogenous expression of TAp73 leads to a significant downregulation of cp/EII activity in p53-deficient hepatoma cell lines. In contrast, overexpression of DeltaTAp73 results in significant cp/EII activation and increased HBV core (HBc) expression. TAp73-mediated repression of HBV transcription was substantially abolished by DeltaTAp73. We show that both TAp73 and DeltaTAp73 proteins directly bind to the Sp1 transcription factor, a key stimulator of HBV gene expression. However, only TAp73 abolishes Sp1 binding to cp/EII, whereas the DeltaTAp73-Sp1 complex further persists on the DNA. The inhibitory effect of p53/p73 on HBc expression is associated with the inhibition of viral replication, while DeltaTAp73 is not. These data strongly support the fact that the p73-isoform-related interaction with Sp1 is the underlying mechanism of the diverse outcome on HBc expression, suggesting a new mechanism by which oncogenic DeltaTAp73 could enhance the carcinogenic process in liver cells.
Buhlmann
Sven
S
Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock, Schillingallee 69, D-18057 Rostock, Germany.
Racek
Tomas
T
Schwarz
Alexandra
A
Schaefer
Stephan
S
Pützer
Brigitte M
BM
D002472:Cell Transformation, Viral / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000821:virology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014758:Viral Core Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016329:Sp1 Transcription Factor; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D014758:Viral Core Proteins