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Biochem Biophys Res Commun. 2006 Dec 8;351(1):93-8. Epub 2006 Oct 11.

TNF-receptor associated factor 6-deficient fibroblast is sensitive to the TNF-alpha-induced cell death: involvement of reactive oxygen species.

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Department of Biochemistry, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.


Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) has mainly been involved in signaling from CD40 and IL-1 receptor family. While TNF-alpha exerts various biological effects including cell death, the role of TRAF6 in the TNF-alpha signaling remains to be unclear. Here, we demonstrated that murine embryonic fibroblasts (MEFs) derived from TRAF6 knockout (TRAF6KO) mice have increased sensitivity to actinomycin D plus TNF-alpha-induced cell death compared with wild-type MEF. Reactive oxygen species (ROS) were accumulated more in TRAF6KO MEF than in wild-type MEF. An antioxidant, butylated hydroxyanisole (BHA) completely inhibited TNF-alpha-induced cell death and DNA fragmentation. Thus, the TNF-alpha-induced cell death in TRAF6KO MEF was ROS-dependent. Reconstitution of full-length TRAF6 but not N-terminal-deleted TRAF6 constructs in TRAF6KO MEF reversed TNF-alpha-induced cell death, ROS accumulation, and DNA fragmentation completely. Thus, we concluded that resistance against TNF-alpha-induced cell death is rendered by TRAF6, which regulates ROS accumulation.

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