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

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Title
Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1α through activation of mitogen-activated protein kinase pathway
Author(s)
Y G Yoo; S H Oh; E S Park; H S Cho; N R Lee; H S Park; D K Kim; Dae Yeul Yu; J K Seong; M O Lee
Bibliographic Citation
Journal of Biological Chemistry, vol. 278, no. 40, pp. 39076-39084
Publication Year
2003
Abstract
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-1α (HIF-1α), a potent transcriptional inducer of angiogenic factors. First, we showed that stability of HIF-1α 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-1α 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-1α 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-1αa 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-1α, suggesting that HBx activates HIF-1α through MAPK pathway. Third, the association of HIF-1α 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-1α. Finally, we demonstrated that expression of HIF-1α and vascular endothelial growth factor was increased in the liver of HBx-transgenic mice, suggesting that the cross-talk between HIF-1α and HBx may lead to transcriptional activation of HIF-1α target genes, which play a critical role in hepatocarcinogenesis.
ISSN
0021-9258
Publisher
Amer Soc Biochemistry Molecular Biology Inc
DOI
http://dx.doi.org/10.1074/jbc.M305101200
Type
Article
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1. Journal Articles > Journal Articles
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