Skip to main content

Advertisement

SpringerLink
Log in

The Anti-Death Machinery in IKK/NF-κB Signaling

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

The most extensively studied function of NF-κB is its ability to promote cell survival through induction of target genes, whose products inhibit various aspects of the apoptotic machinery in both normal and malignant cells. Recent studies, however, indicate that NF-κB activation can also suppress programmed necrosis through induction of genes encoding anti-oxidant proteins. Since tumor cells often use NF-κB pathway as a shield to escape the killing of conventional anti-cancer therapies, intervention of IKK/NF-κB signaling would be a promising option to improve the efficacy of cancer treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ghosh S, Karin M: Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96, 2002

    Article  PubMed  CAS  Google Scholar 

  2. Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol 3:221–227, 2002

    Article  PubMed  CAS  Google Scholar 

  3. Karin M, Delhase M: The I kappa B kinase (IKK) and NF-kappa B: Key elements of proinflammatory signalling. Semin Immunol 12:85–98, 2000

    Article  PubMed  CAS  Google Scholar 

  4. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R, Karin M: The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189:1839–1845, 1999

    PubMed  CAS  Google Scholar 

  5. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M: Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293:1495–1499, 2001

    Article  PubMed  CAS  Google Scholar 

  6. Senftleben U, Karin M: The IKK/NF-kappa B pathway. Crit Care Med 30:S18–S26, 2002

    CAS  Google Scholar 

  7. Bonizzi G, Karin M: The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288, 2004

    Article  PubMed  CAS  Google Scholar 

  8. Varfolomeev EE, Ashkenazi A: Tumor necrosis factor: An apoptosis JuNKie? Cell 116:491–497, 2004

    Article  PubMed  CAS  Google Scholar 

  9. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M: Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661, 2005

    Article  PubMed  CAS  Google Scholar 

  10. Maeda S, Chang L, Li ZW, Luo JL, Leffert H, Karin M: IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 19:725–737, 2003

    Article  PubMed  CAS  Google Scholar 

  11. Weil R, Israel A: T-cell-receptor- and B-cell-receptor-mediated activation of NF-kappaB in lymphocytes. Curr Opin Immunol 16:374–381, 2004

    Article  PubMed  CAS  Google Scholar 

  12. Hsu LC, Park JM, Zhang K, Luo JL, Maeda S, Kaufman RJ, Eckmann L, Guiney DG, Karin M: The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428:341–345, 2004

    Article  PubMed  CAS  Google Scholar 

  13. Kerr JF, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257, 1972

    PubMed  CAS  Google Scholar 

  14. Wyllie AH, Kerr JF, Currie AR: Cell death: The significance of apoptosis. Int Rev Cytol 68:251–306, 1980

    Article  PubMed  CAS  Google Scholar 

  15. Danial NN, Korsmeyer SJ: Cell death: Critical control points. Cell 116:205–219, 2004

    Article  PubMed  CAS  Google Scholar 

  16. Hengartner MO: The biochemistry of apoptosis. Nature 407:770–776, 2000

    Article  PubMed  CAS  Google Scholar 

  17. Leist M, Jaattela M: Four deaths and a funeral: From caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598, 2001

    Article  PubMed  CAS  Google Scholar 

  18. Jaattela M, Tschopp J: Caspase-independent cell death in T lymphocytes. Nat Immunol 4:416–423, 2003

    PubMed  Google Scholar 

  19. Perfettini JL, Kroemer G: Caspase activation is not death. Nat Immunol 4:308–310, 2003

    Article  PubMed  CAS  Google Scholar 

  20. Abraham MC, Shaham S: Death without caspases, caspases without death. Trends Cell Biol 14:184–193, 2004

    Article  PubMed  CAS  Google Scholar 

  21. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ: Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304:1500–1502, 2004

    Article  PubMed  CAS  Google Scholar 

  22. Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, Waisman A, Brenner O, Haffner R, Gustafsson E, Ramakrishnan P, Lapidot T, Wallach D: Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol, 173: 2976–2984, 2004.

    PubMed  CAS  Google Scholar 

  23. Fiers W, Beyaert R, Declercq W, Vandenabeele P: More than one way to die: Apoptosis, necrosis and reactive oxygen damage. Oncogene 18:7719–7730, 1999

    PubMed  CAS  Google Scholar 

  24. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D: Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376:167–170, 1995

    Article  PubMed  CAS  Google Scholar 

  25. Doi TS, Marino MW, Takahashi T, Yoshida T, Sakakura T, Old LJ, Obata Y: Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA 96:2994–2999, 1999

    Article  PubMed  CAS  Google Scholar 

  26. Makris C, Godfrey VL, Krahn-Senftleben G, Takahashi T, Roberts JL, Schwarz T, Feng L, Johnson RS, Karin M: Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 5:969–979, 2000

    Article  PubMed  CAS  Google Scholar 

  27. Chaisson ML, Brooling JT, Ladiges W, Tsai S, Fausto N: Hepatocyte-specific inhibition of NF-kappaB leads to apoptosis after TNF treatment, but not after partial hepatectomy. J Clin Invest 110:193–202, 2002

    Google Scholar 

  28. Lavon I, Goldberg I, Amit S, Landsman L, Jung S, Tsuberi BZ, Barshack I, Kopolovic J, Galun E, Bujard H, Ben-Neriah Y: High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappaB activation. Nat Med 6:573–577, 2000

    PubMed  CAS  Google Scholar 

  29. Voll RE, Jimi E, Phillips RJ, Barber DF, Rincon M, Hayday AC, Flavell RA, Ghosh S: NF-kappa B activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13:677–689, 2000

    Article  PubMed  CAS  Google Scholar 

  30. Boothby MR, Mora AL, Scherer DC, Brockman JA, Ballard DW: Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-kappaB. J Exp Med 185:1897–1907, 1997

    Article  PubMed  CAS  Google Scholar 

  31. Esslinger CW, Wilson A, Sordat B, Beermann F, Jongeneel CV: Abnormal T lymphocyte development induced by targeted overexpression of IkappaB alpha. J Immunol 158:5075–5078, 1997

    PubMed  CAS  Google Scholar 

  32. Green DR: Death and NF-kappaB in T cell activation: Life at the edge. Mol Cell 11:551–552, 2003

    PubMed  CAS  Google Scholar 

  33. Gilmore TD, Kalaitzidis D, Liang MC, Starczynowski DT: The c-Rel transcription factor and B-cell proliferation: A deal with the devil. Oncogene 23:2275–2286, 2004

    Article  PubMed  CAS  Google Scholar 

  34. Zhang JY, Green CL, Tao S, Khavari PA: NF-kappaB RelA opposes epidermal proliferation driven by TNFR1 and JNK. Genes Dev 18:17–22, 2004

    PubMed  Google Scholar 

  35. Schmidt-Ullrich R, Aebischer T, Hulsken J, Birchmeier W, Klemm U, Scheidereit C: Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. Development 128:3843–3853, 2001

    PubMed  CAS  Google Scholar 

  36. Mattson MP, Camandola S: NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107:247–254, 2001

    Article  PubMed  CAS  Google Scholar 

  37. Baldwin AS: Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 107:241–246, 2001

    PubMed  CAS  Google Scholar 

  38. Liu ZG, Hsu H, Goeddel DV, Karin M: Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87:565–576, 1996

    Article  PubMed  CAS  Google Scholar 

  39. Kucharczak J, Simmons MJ, Fan Y, Gelinas C: To be, or not to be: NF-kappaB is the answer-role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22:8961–8982, 2003

    Article  PubMed  CAS  Google Scholar 

  40. French LE, Tschopp J: Protein-based therapeutic approaches targeting death receptors. Cell Death Differ 10:117–123, 2003

    Article  PubMed  CAS  Google Scholar 

  41. Lavrik I, Golks A, Krammer PH: Death receptor signaling. J Cell Sci 118:265–267, 2005

    Article  PubMed  CAS  Google Scholar 

  42. Peter ME, Krammer PH: The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 10:26–35, 2003

    Article  PubMed  CAS  Google Scholar 

  43. Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P, Wallach D: Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:267–276, 1998

    Article  PubMed  CAS  Google Scholar 

  44. Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS, Lowe SW, Goeddel DV, Mak TW: FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279:1954–1958, 1998

    Article  PubMed  CAS  Google Scholar 

  45. Harper N, Hughes M, MacFarlane M, Cohen GM: Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. J Biol Chem 278:25534–25541, 2003

    PubMed  CAS  Google Scholar 

  46. Micheau O, Tschopp J: Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–190, 2003

    Article  PubMed  CAS  Google Scholar 

  47. Devin A, Cook A, Lin Y, Rodriguez Y, Kelliher M, Liu Z: The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity 12:419–429, 2000

    Article  PubMed  CAS  Google Scholar 

  48. Zhang SQ, Kovalenko A, Cantarella G, Wallach D: Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity 12:301–311, 2000

    Article  PubMed  CAS  Google Scholar 

  49. Chen G, Cao P, Goeddel DV: TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Mol Cell 9:401–410, 2002

    Article  PubMed  CAS  Google Scholar 

  50. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME: Two CD95 (APO-1/Fas) signaling pathways. Embo J 17:1675–1687, 1998

    Article  PubMed  CAS  Google Scholar 

  51. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X: Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490, 1998

    Article  PubMed  CAS  Google Scholar 

  52. Li H, Zhu H, Xu CJ, Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501, 1998

    Article  PubMed  CAS  Google Scholar 

  53. Deng Y, Ren X, Yang L, Lin Y, Wu X: A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell 115:61–70, 2003

    Article  PubMed  CAS  Google Scholar 

  54. Davis RJ: Signal transduction by the JNK group of MAP kinases. Cell 103:239–252, 2000

    Article  PubMed  CAS  Google Scholar 

  55. Chang L, Karin M: Mammalian MAP kinase signalling cascades. Nature 410:37–40, 2001

    PubMed  CAS  Google Scholar 

  56. Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May WS Jr: Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 276:23681–23688, 2001

    PubMed  CAS  Google Scholar 

  57. Maundrell K, Antonsson B, Magnenat E, Camps M, Muda M, Chabert C, Gillieron C, Boschert U, Vial-Knecht E, Martinou JC, Arkinstall S: Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Rac1. J Biol Chem 272:25238–25242, 1997

    Article  PubMed  CAS  Google Scholar 

  58. Yamamoto K, Ichijo H, Korsmeyer SJ: BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 19:8469–8478, 1999

    PubMed  CAS  Google Scholar 

  59. Lei K, Davis RJ: JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 100:2432–2437, 2003

    PubMed  CAS  Google Scholar 

  60. Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y: JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. Embo J 23:1889–1899, 2004

    Article  PubMed  CAS  Google Scholar 

  61. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL: Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102:43–53, 2000

    Article  PubMed  CAS  Google Scholar 

  62. Lamb JA, Ventura JJ, Hess P, Flavell RA, Davis RJ: JunD mediates survival signaling by the JNK signal transduction pathway. Mol Cell 11:1479–1489, 2003

    Article  PubMed  CAS  Google Scholar 

  63. Kallunki T, Deng T, Hibi M, Karin M: c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions. Cell 87:929–939, 1996

    Article  PubMed  CAS  Google Scholar 

  64. Nishina H, Vaz C, Billia P, Nghiem M, Sasaki T, De la Pompa JL, Furlonger K, Paige C, Hui C, Fischer KD, Kishimoto H, Iwatsubo T, Katada T, Woodgett JR, Penninger JM: Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development 126:505–516, 1999

    PubMed  CAS  Google Scholar 

  65. Wada T, Joza N, Cheng HY, Sasaki T, Kozieradzki I, Bachmaier K, Katada T, Schreiber M, Wagner EF, Nishina H, Penninger JM: MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nat Cell Biol 6:215–226, 2004

    Article  PubMed  CAS  Google Scholar 

  66. Liu J, Minemoto Y, Lin A: c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis. Mol Cell Biol 24:10844–10856, 2004

    PubMed  CAS  Google Scholar 

  67. Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF: Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell 15:713–725, 2004

    Article  PubMed  CAS  Google Scholar 

  68. Natoli G, Costanzo A, Ianni A, Templeton DJ, Woodgett JR, Balsano C, Levrero M: Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science 275:200–203, 1997

    Article  PubMed  CAS  Google Scholar 

  69. Zhang Y, Chen F: Reactive oxygen species (ROS), troublemakers between nuclear factor-kappaB (NF-kappaB) and c-Jun NH(2)-terminal kinase (JNK). Cancer Res 64:1902–1905, 2004

    PubMed  CAS  Google Scholar 

  70. Papa S, Zazzeroni F, Pham CG, Bubici C, Franzoso G: Linking JNK signaling to NF-kappaB: A key to survival. J Cell Sci 117:5197–5208, 2004

    Article  PubMed  CAS  Google Scholar 

  71. Chen F, Castranova V, Li Z, Karin M, Shi X: Inhibitor of nuclear factor kappaB kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic. Cancer Res 63:7689–7693, 2003

    PubMed  CAS  Google Scholar 

  72. De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, Jones J, Cong R, Franzoso G: Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414:308–313, 2001

    Article  PubMed  CAS  Google Scholar 

  73. Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, Lin A: Inhibition of JNK activation through NF-kappaB target genes. Nature 414:313–317, 2001

    Article  PubMed  CAS  Google Scholar 

  74. Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, Piao JH, Yagita H, Okumura K, Doi T, Nakano H: NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. Embo J 22:3898–3909, 2003

    Article  PubMed  CAS  Google Scholar 

  75. Schwabe RF, Bradham CA, Uehara T, Hatano E, Bennett BL, Schoonhoven R, Brenner D: A. c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration. Hepatology 37:824–832, 2003

    Article  PubMed  CAS  Google Scholar 

  76. Yamada Y, Kirillova I, Peschon JJ, Fausto N: Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci USA 94:1441–1446, 1997

    PubMed  CAS  Google Scholar 

  77. Park JM, Brady H, Ruocco MG, Sun H, Williams D, Lee SJ, Kato T Jr, Richards N, Chan K, Mercurio F, Karin M, Wasserman SA: Targeting of TAK1 by the NF-kappa B protein Relish regulates the JNK-mediated immune response in Drosophila. Genes Dev 18:584–594, 2004

    Article  PubMed  CAS  Google Scholar 

  78. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, Nguyen DU, Pham CG, Nelsbach AH, Melis T, De Smaele E, Tang WJ, D'Adamio L, Franzoso G: Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nat Cell Biol 6:146–153, 2004

    Article  PubMed  CAS  Google Scholar 

  79. Tang G, Yang J, Minemoto Y, Lin A: Blocking caspase-3-mediated proteolysis of IKKbeta suppresses TNF-alpha-induced apoptosis. Mol Cell 8:1005–1016, 2001

    Article  PubMed  CAS  Google Scholar 

  80. Amanullah A, Azam N, Balliet A, Hollander C, Hoffman B, Fornace A, Liebermann D: Cell signalling: Cell survival and a Gadd45-factor deficiency. Nature 424:741; discussion 742, 2003

    Article  PubMed  CAS  Google Scholar 

  81. Kamata H, Hirata H: Redox regulation of cellular signalling. Cell Signal 11:1–14, 1999

    Article  PubMed  CAS  Google Scholar 

  82. Takeda K, Matsuzawa A, Nishitoh H, Ichijo H: Roles of MAPKKK ASK1 in stress-induced cell death. Cell Struct Funct 28:23–29, 2003

    Article  PubMed  CAS  Google Scholar 

  83. Salmeen A, Andersen JN, Myers MP, Meng TC, Hinks JA, Tonks NK, Barford D: Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423:769–773, 2003

    Article  PubMed  CAS  Google Scholar 

  84. van Montfort RL, Congreve M, Tisi D, Carr R, Jhoti H: Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 423:773–777, 2003

    PubMed  Google Scholar 

  85. Lee SR, Kwon KS, Kim SR, Rhee SG: Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem 273:15366–15372, 1998

    PubMed  CAS  Google Scholar 

  86. Meng TC, Fukada T, Tonks NK: Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 9:387–399, 2002

    Article  PubMed  CAS  Google Scholar 

  87. Meng TC, Buckley DA, Galic S, Tiganis T, Tonks NK: Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B. J Biol Chem 279:37716–37725, 2004

    PubMed  CAS  Google Scholar 

  88. Sasazuki T, Okazaki T, Tada K, Sakon-Komazawa S, Katano M, Tanaka M, Yagita H, Okumura K, Tominaga N, Hayashizaki Y, Okazaki Y, Nakano H: Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS. Mol Immunol 41:547–551, 2004

    Article  PubMed  CAS  Google Scholar 

  89. Wong GH, Elwell JH, Oberley LW, Goeddel DV: Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell 58:923–931, 1989

    Article  PubMed  CAS  Google Scholar 

  90. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH Jr, Scott RW, Snider WD: Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47, 1996

    Article  PubMed  CAS  Google Scholar 

  91. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, Beaumont C, Torti FM, Torti SV, Franzoso G: Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 119:529–542, 2004

    Article  PubMed  CAS  Google Scholar 

  92. Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P: Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat Immunol 4:387–393, 2003

    Article  PubMed  CAS  Google Scholar 

  93. Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W: Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 267:5317–5323, 1992

    CAS  Google Scholar 

  94. Goossens V, Grooten J, De Vos K, Fiers W: Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci USA 92:8115–8119, 1995

    PubMed  CAS  Google Scholar 

  95. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G: Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182:367–377, 1995

    Article  PubMed  CAS  Google Scholar 

  96. Chang TS, Cho CS, Park S, Yu S, Kang SW, Rhee SG: Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria. J Biol Chem 279:41975–41984, 2004

    PubMed  CAS  Google Scholar 

  97. Newmeyer DD, Ferguson-Miller S: Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112:481–490, 2003

    PubMed  CAS  Google Scholar 

  98. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J: Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1:489–495, 2000

    Article  PubMed  CAS  Google Scholar 

  99. Lin Y, Choksi S, Shen HM, Yang QF, Hur GM, Kim YS, Tran JH, Nedospasov SA, Liu ZG: Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J Biol Chem 279:10822–10828, 2004

    PubMed  CAS  Google Scholar 

  100. Liu CY, Takemasa A, Liles WC, Goodman RB, Jonas M, Rosen H, Chi E, Winn RK, Harlan JM, Chuang PI: Broad-spectrum caspase inhibition paradoxically augments cell death in TNF-alpha -stimulated neutrophils. Blood 101:295–304, 2003

    PubMed  CAS  Google Scholar 

  101. Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, Grooten J, Fiers W, Vandenabeele P: Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med 187:1477–1485, 1998

    Article  PubMed  CAS  Google Scholar 

  102. Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y, Nagata S: Caspase-independent cell killing by Fas-associated protein with death domain. J Cell Biol 143:1353–1360, 1998

    Article  PubMed  CAS  Google Scholar 

  103. Bossy-Wetzel E, Green DR: Caspases induce cytochrome c release from mitochondria by activating cytosolic factors. J Biol Chem 274:17484–17490, 1999

    Article  PubMed  CAS  Google Scholar 

  104. Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR: The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2:156–162, 2000

    Google Scholar 

  105. Waterhouse NJ, Goldstein JC, von Ahsen O, Schuler M, Newmeyer DD, Green DR: Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J Cell Biol 153:319–328, 2001

    Article  PubMed  CAS  Google Scholar 

  106. Ricci JE, Munoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, Scheffler IE, Ellisman MH, Green DR: Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117:773–786, 2004

    Article  PubMed  CAS  Google Scholar 

  107. Ventura JJ, Cogswell P, Flavell RA, Baldwin AS Jr, Davis RJ: JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species. Genes Dev 18:2905–2915, 2004

    Article  PubMed  CAS  Google Scholar 

  108. Cardone MH, Salvesen GS, Widmann C, Johnson G, Frisch SM: The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell 90:315–323, 1997

    Article  PubMed  CAS  Google Scholar 

  109. Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ: Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288:870–874, 2000

    Article  PubMed  CAS  Google Scholar 

  110. Levkau B, Scatena M, Giachelli CM, Ross R, Raines EW: Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kappa B loop. Nat Cell Biol 1:227–233, 1999

    Article  PubMed  CAS  Google Scholar 

  111. Reuther JY, Baldwin AS Jr: Apoptosis promotes a caspase-induced amino-terminal truncation of IkappaBalpha that functions as a stable inhibitor of NF-kappaB. J Biol Chem 274:20664–20670, 1999

    Article  PubMed  CAS  Google Scholar 

  112. Toledano MB, Leonard WJ: Modulation of transcription factor NF-kappa B binding activity by oxidation-reduction in vitro. Proc Natl Acad Sci USA 88:4328–4332, 1991

    PubMed  CAS  Google Scholar 

  113. Kapahi P, Takahashi T, Natoli G, Adams SR, Chen Y, Tsien RY, Karin M: Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J Biol Chem 275:36062–36066, 2000

    Article  PubMed  CAS  Google Scholar 

  114. Denecker G, Vercammen D, Steemans M, Vanden Berghe T, Brouckaert G, Van Loo G, Zhivotovsky B, Fiers W, Grooten J, Declercq W, Vandenabeele P: Death receptor-induced apoptotic and necrotic cell death: Differential role of caspases and mitochondria. Cell Death Differ 8:829–840, 2001

    Article  PubMed  CAS  Google Scholar 

  115. Vanden Berghe T, van Loo G, Saelens X, Van Gurp M, Brouckaert G, Kalai M, Declercq W, Vandenabeele P: Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD. J Biol Chem 279:7925–7933, 2004

    PubMed  CAS  Google Scholar 

  116. Frelin C, Imbert V, Griessinger E, Loubat A, Dreano M, Peyron JF: AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-alpha in Jurkat leukemic cells. Oncogene 22:8187–8194, 2003

    Article  PubMed  CAS  Google Scholar 

  117. Frelin C, Imbert V, Griessinger E, Peyron AC, Rochet N, Philip P, Dageville C, Sirvent A, Hummelsberger M, Berard E, Dreano M, Sirvent N, Peyron JF: Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells. Blood 105:804–811, 2005

    Article  PubMed  CAS  Google Scholar 

  118. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296, 2004

    Article  PubMed  CAS  Google Scholar 

  119. Wong GH, Kaspar RL, Vehar G: Tumor necrosis factor and lymphotoxin: Protection against oxidative stress through induction of MnSOD. Exs 77:321–333, 1996

    PubMed  CAS  Google Scholar 

  120. Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W: Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407:390–395, 2000

    Article  PubMed  CAS  Google Scholar 

  121. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M: Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6:297–305, 2004

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, Gilman Drive, La Jolla, San Diego, CA

    Jun-Li Luo, Hideaki Kamata & Michael Karin1

  2. Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093, USA

    Michael Karin1

Authors
  1. Jun-Li Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideaki Kamata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Karin1
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Karin1.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, JL., Kamata, H. & Karin1, M. The Anti-Death Machinery in IKK/NF-κB Signaling. J Clin Immunol 25, 541–550 (2005). https://doi.org/10.1007/s10875-005-8217-6

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-005-8217-6

Key Words

Search

Navigation