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: Heng Sun, Xue-Bing Li, Ya Meng, Li Fan, Min Li, Jing Fang
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 15 Pg. 4950-9 (Aug 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23722539 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Small Interfering
• TNF Receptor-Associated Factor 6

Topics

• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis)
• Immunoblotting
• Immunoprecipitation
• Neovascularization, Pathologic (metabolism)
• RNA, Small Interfering
• Real-Time Polymerase Chain Reaction
• Signal Transduction (physiology)
• TNF Receptor-Associated Factor 6 (metabolism)
• Transfection
• Up-Regulation