TRAF6 upregulates expression of HIF-1α and promotes tumor angiogenesis.
TNF receptor (TNFR)-associated factor TRAF6 is a key activator of NF-κB, playing a critical role in the regulation of innate immune responses and their connection to adaptive immune responses. TRAF6 interactions determine receptor-induced cell death versus survival. TRAF6 has been implicated in cancer but its contributions have not been investigated ... deeply. In this study, we show that TRAF6 upregulates expression of hypoxia-inducible factor (HIF)-1α. TRAF6 affects HIF-1α protein levels but has little effect on mRNA level. TRAF6 increases HIF-1α protein independent of oxygen. We found that TRAF6 binds HIF-1α and mediates its K63-linked polyubiquitination. The E3 ligase activity of TRAF6 was required to increase HIF-1α protein levels. Finally, we showed that TRAF6 promoted tumor angiogenesis and growth. Our results reveal how TRAF6 functions to upregulate HIF-1α expression and promote tumor angiogenesis.
Mesh Terms:
Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoprecipitation, Neovascularization, Pathologic, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 6, Transfection, Up-Regulation
Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoprecipitation, Neovascularization, Pathologic, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 6, Transfection, Up-Regulation
Cancer Res.
Date: Aug. 01, 2013
PubMed ID: 23722539
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