Abstract
Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit alpha. Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1alpha and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1alpha activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1alpha for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1alpha complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1alpha and is involved in a recently appreciated aspect of EBV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Breast Neoplasms / metabolism
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Breast Neoplasms / virology
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cytoplasm / metabolism
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Down-Regulation
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Epithelial Cells / enzymology
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Epstein-Barr Virus Infections / metabolism
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HeLa Cells
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Herpesvirus 4, Human
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Nasopharynx / cytology
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Nasopharynx / enzymology*
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Nasopharynx / metabolism
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Procollagen-Proline Dioxygenase / metabolism*
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Transfection
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Ubiquitin-Protein Ligases / biosynthesis
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Up-Regulation
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / metabolism*
Substances
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EBV-associated membrane antigen, Epstein-Barr virus
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Viral Matrix Proteins
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Procollagen-Proline Dioxygenase
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Ubiquitin-Protein Ligases
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seven in absentia proteins