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Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1alpha through activation of mitogen-activated protein kinase pathway.

Yoo, YG; Oh, SH; Park, ES; Cho, H; Lee, N; Park, H; Kim, DK; Yu, DY; Seong, JK; Lee, MO
The Journal of biological chemistry, 278(40):39076-39084, 2003
Journal Title
The Journal of biological chemistry
Hepatitis B virus X protein (HBx) of the hepatitis B virus was strongly implicated in angiogenesis and metastasis during hepatocarcinogenesis. Here, we explored the possibility of cross-talk between HBx and hypoxia-inducible factor-1alpha (HIF-1alpha), a potent transcriptional inducer of angiogenic factors. First, we showed that stability of HIF-1alpha protein was increased by HBx in HBx-inducible Chang liver cells as well as in transient HBx expression system of non-hepatic cells. Immunofluorescence studies revealed that the HBx-induced HIF-1alpha was partially translocated into the nucleus in majority of cells while additional CoCl2-induced hypoxic condition caused complete nuclear translocation. Second, HBx induced both phosphorylation of HIF-1alpha and activation of p42/p44 mitogen-activated protein kinases (MAPKs), which were synergistically enhanced in the presence of CoCl2. Furthermore, HBx enhanced transcriptional activity of HIF-1alpha in the reporter genes encoding hypoxia response element or VEGF promoter. Either treatment of MEK inhibitor PD98059 or coexpression of dominant-negative MAPK mutants abolished the HBx-induced transcriptional activity and protein stability as well as nuclear translocation of HIF-1alpha, suggesting that HBx activates HIF-1alpha through MAPK pathway. Third, the association of HIF-1alpha with von Hippel-Lindau was decreased but the association with CREB-binding protein was enhanced in the presence of HBx, suggesting the molecular mechanism by which HBx enhances the protein stability and transactivation function of HIF-1alpha. Finally, we demonstrated that expression of HIF-1alpha and vascular endothelial growth factor was increased in the liver of HBx-transgenic mice, suggesting that the cross-talk between HIF-1alpha and HBx may lead to transcriptional activation of HIF-1alpha target genes, which play a critical role in hepatocarcinogenesis.
MeSH terms
Active Transport, Cell NucleusAndrostadienes/pharmacologyAnimalsAnoxiaBlotting, WesternCell LineCell Nucleus/metabolismCobalt/pharmacologyEndothelial Growth Factors/metabolismEnzyme Inhibitors/pharmacologyFlavonoids/pharmacologyFlow CytometryGenes, ReporterHela CellsHumansHypoxia-Inducible Factor 1, alpha SubunitImmunohistochemistryIntercellular Signaling Peptides and Proteins/metabolisLigases/metabolismLymphokines/metabolismMAP Kinase Signaling System*MiceMice, TransgenicMicroscopy, FluorescenceMitogen-Activated Protein Kinase 1/metabolismMitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinases/metabolismPhosphorylationPlasmids/metabolismPrecipitin TestsPromoter Regions, GeneticProtein TransportReverse Transcriptase Polymerase Chain ReactionSignal TransductionTime FactorsTrans-Activators/metabolismTrans-Activators/physiology*Transcription Factors/metabolism*Transcription, Genetic*Transcriptional ActivationTransfectionTumor Cells, CulturedTumor Suppressor Proteins*Ubiquitin-Protein Ligases*Vascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVon Hippel-Lindau Tumor Suppressor Protein
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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조, 혜성
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