EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells.

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.
Mesh Terms:
Breast Neoplasms, Cell Line, Tumor, Cell Nucleus, Cytoplasm, Down-Regulation, Epithelial Cells, Epstein-Barr Virus Infections, Hela Cells, Herpesvirus 4, Human, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Nasopharynx, Nuclear Proteins, Procollagen-Proline Dioxygenase, Transfection, Ubiquitin-Protein Ligases, Up-Regulation, Viral Matrix Proteins
Cancer Res.
Date: Oct. 15, 2006
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