Abstract
The X-gene product of hepatitis B virus (HBx) has been implicated in hepatitis B virus (HBV)-mediated hepatocellular carcinoma through its ability to induce liver cancer in some transgenic mice and to transactivate a variety of viral and cellular promoters. In this study, we demonstrated that the level of p21(waf1) RNA was decreased in the HBx-expressing cells and this effect was due to the transcriptional repression of the p21(waf1) gene by HBx via a p53-independent pathway. As the Sp1 binding sites of the p21(waf1) promoter were sufficient to confer HBx responsiveness to a previously non-responsive promoter, we suggested that HBx represses the transcription of p21(waf1) by downregulating the activity of Sp1. Because the tumor repressor p21(waf1) protein is a universal inhibitor of cyclin-CDK complexes and DNA replication that induces cell cycle arrest at the G1-S checkpoint, the repression of p21(waf1) by HBx might play an important role in a HBV-mediated pathogenesis.
MeSH terms
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3T3 Cells
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Animals
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Base Sequence
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Binding Sites / genetics
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics*
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DNA / genetics
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DNA / metabolism
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Down-Regulation
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Gene Expression Regulation
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Humans
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Luciferases / genetics
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Luciferases / metabolism
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Mice
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Molecular Sequence Data
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Mutation
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Plasmids / genetics
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Promoter Regions, Genetic / genetics*
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Protein Binding
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Deletion
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Signal Transduction
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Sp1 Transcription Factor / genetics
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Sp1 Transcription Factor / metabolism
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription, Genetic
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / physiology*
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Viral Regulatory and Accessory Proteins
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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RNA, Messenger
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Recombinant Fusion Proteins
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Sp1 Transcription Factor
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Trans-Activators
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Tumor Suppressor Protein p53
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Viral Regulatory and Accessory Proteins
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hepatitis B virus X protein
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DNA
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Luciferases