title: TRAF6 upregulates expression of HIF-1α and promotes tumor angiogenesis.
abstract: 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.
authors.affiliation: The Key Lab of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Sun
authors.forename: Xue-Bing
authors.initials: XB
authors.lastname: Li
authors.forename: Ya
authors.initials: Y
authors.lastname: Meng
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D015151:Immunoblotting; D047468:Immunoprecipitation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6