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TAK1 prevents TRAIL‐induced cell death through an NF‐κB‐independent mechanism
Author(s) -
Morioka Sho,
Omori Emily,
Kajino Taisuke,
KajinoSakamoto Rie,
Matsumoto Kunihiro,
NinomiyaTsuji Jun
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1050.2
Subject(s) - programmed cell death , apoptosis , tumor necrosis factor alpha , microbiology and biotechnology , nf κb , mapk/erk pathway , necrosis , cell , biology , cancer research , chemistry , kinase , signal transduction , immunology , biochemistry , genetics
TAK1 functions downstream of several cytokines such as TNF, and activates both MAPK and NF‐κB pathways. We have previously determined that TAK1 is essential for preventing TNF‐induced cell death in epithelial tissues such as skin epidermis and intestinal epithelium. Deletion of TNF receptor I (TNFRI) largely rescued cell death caused by TAK1 deletion; however, dead cells in double (TNFRI and TAK1)‐deficient epithelial tissues were still increased compared to TNFRI knockout tissues. Here, we attempted to determine the TNF‐independent mechanism of cell death in TAK1‐deficient cells. TNF‐Related Apoptosis‐Inducing Ligand (TRAIL) belongs to TNF family, and is also known to induce cell death. We found that TAK1 deletion increased sensitivity to TRAIL‐killing. Although NF‐κB is one of the most important cell survival factors, we found that TRAIL did not induce NF‐κB activation even in TAK1 wild type cells, and that NEMO/IKKγ deletion did not increase sensitivity to TRAIL. In contrast, we found that expressions of several antioxidant genes were reduced in TAK1‐deficient cells, and that treatment of exogenous antioxidant butylated hydroxyanisole (BHA) rescued TRAIL‐killing. These results suggest that TAK1 regulates antioxidant gene expression and contributes to TRAIL‐resistance independently of NF‐κB activity. This work was supported by grants from Crohn's and Colitis Foundation of America and NIH (GM68812).