NF-kappaB Inhibits TNF-induced Accumulation of ROS That Mediate Prolonged MAPK Activation and Necrotic Cell Death

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2003 Jul 26

PMID 12881424

Citations 183

Authors

Sachiko Sakon

Xin Xue

Mutsuhiro Takekawa

Tomonari Sasazuki

Tatsuma Okazaki

Yuko Kojima

Jian-hu Piao

Hideo Yagita

Ko Okumura

Takahiro Doi

Hiroyasu Nakano

Affiliations

Soon will be listed here.

Abstract

NF-kappaB downregulates tumor necrosis factor (TNF)-induced c-Jun N-terminal kinase (JNK) activation that promotes cell death, but the mechanism is not yet fully understood. By using murine embryonic fibroblasts (MEFs) that are deficient in TNF receptor-associated factor (TRAF) 2 and TRAF5 (DKO) or p65 NF-kappaB subunit (p65KO), we demonstrate here that TNF stimulation leads to accumulation of reactive oxygen species (ROS), which is essential for prolonged mitogen-activated protein kinase (MAPK) activation and cell death. Interestingly, dying cells show necrotic as well as apoptotic morphological changes as assessed by electron microscopy and flow cytometry, and necrotic, but not apoptotic, cell death is substantially inhibited by antioxidant. Importantly, TNF does not induce ROS accumulation or prolonged MAPK activation in wild-type MEFs, indicating that TRAF-mediated NF-kappaB activation normally suppresses the TNF-induced ROS accumulation that subsequently induces prolonged MAPK activation and necrotic cell death

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References

Fiers W, Beyaert R, Declercq W, Vandenabeele P . More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene. 2000; 18(54):7719-30. DOI: 10.1038/sj.onc.1203249. View

Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K . Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells. 1999; 4(6):353-62. DOI: 10.1046/j.1365-2443.1999.00265.x. View

Davis R . Signal transduction by the JNK group of MAP kinases. Cell. 2000; 103(2):239-52. DOI: 10.1016/s0092-8674(00)00116-1. View

Thannickal V, Fanburg B . Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000; 279(6):L1005-28. DOI: 10.1152/ajplung.2000.279.6.L1005. View

Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S . Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2001; 1(6):489-95. DOI: 10.1038/82732. View

Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K . ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2001; 2(3):222-8. PMC: 1083842. DOI: 10.1093/embo-reports/kve046. View

Chen K, Vita J, Berk B, Keaney Jr J . c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation. J Biol Chem. 2001; 276(19):16045-50. DOI: 10.1074/jbc.M011766200. View

Javelaud D, BESANCON F . NF-kappa B activation results in rapid inactivation of JNK in TNF alpha-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-kappa B. Oncogene. 2001; 20(32):4365-72. DOI: 10.1038/sj.onc.1204570. View

Tada K, Okazaki T, Sakon S, Kobarai T, Kurosawa K, Yamaoka S . Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death. J Biol Chem. 2001; 276(39):36530-4. DOI: 10.1074/jbc.M104837200. View

10.

Ichijo H . From receptors to stress-activated MAP kinases. Oncogene. 1999; 18(45):6087-93. DOI: 10.1038/sj.onc.1203129. View

11.

Adler V, Yin Z, Tew K, Ronai Z . Role of redox potential and reactive oxygen species in stress signaling. Oncogene. 1999; 18(45):6104-11. DOI: 10.1038/sj.onc.1203128. View

12.

Barkett M, Gilmore T . Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene. 1999; 18(49):6910-24. DOI: 10.1038/sj.onc.1203238. View

13.

De Smaele E, Zazzeroni F, Papa S, Nguyen D, Jin R, Jones J . Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature. 2001; 414(6861):308-13. DOI: 10.1038/35104560. View

14.

Tang G, Minemoto Y, Dibling B, Purcell N, Li Z, Karin M . Inhibition of JNK activation through NF-kappaB target genes. Nature. 2001; 414(6861):313-7. DOI: 10.1038/35104568. View

15.

Kitagawa D, Tanemura S, Ohata S, Shimizu N, Seo J, Nishitai G . Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation. Its implication in an anti-apoptotic function. J Biol Chem. 2001; 277(1):366-71. DOI: 10.1074/jbc.M107110200. View

16.

Chung J, Park Y, Ye H, Wu H . All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 2002; 115(Pt 4):679-88. DOI: 10.1242/jcs.115.4.679. View

17.

Karin M, Lin A . NF-kappaB at the crossroads of life and death. Nat Immunol. 2002; 3(3):221-7. DOI: 10.1038/ni0302-221. View

18.

Tanaka H, Matsumura I, Ezoe S, Satoh Y, Sakamaki T, Albanese C . E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell. 2002; 9(5):1017-29. DOI: 10.1016/s1097-2765(02)00522-1. View

19.

Wallach D, Arumugam T, Boldin M, Cantarella G, Ganesh K, Goltsev Y . How are the regulators regulated? The search for mechanisms that impose specificity on induction of cell death and NF-kappaB activation by members of the TNF/NGF receptor family. Arthritis Res. 2002; 4 Suppl 3:S189-96. PMC: 3240160. DOI: 10.1186/ar585. View

20.

Mak T, Yeh W . Signaling for survival and apoptosis in the immune system. Arthritis Res. 2002; 4 Suppl 3:S243-52. PMC: 3240145. DOI: 10.1186/ar569. View