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PMID: 11053079 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB.

Annals of the rheumatic diseases ·Vol. 59 Suppl 1 ·2000-11-00 ·Pages i6-16

Aggarwal BB

Abstract

Tumour necrosis factor (TNF) is a pleiotropic cytokine that mediates apoptosis, cell proliferation, immunomodulation, inflammation, viral replication, allergy, arthritis, septic shock, insulin resistance, autoimmune diseases, and other pathological conditions. TNF transduces these cellular responses through two distinct receptors: type I, which are expressed on all cell types, and type II, which are expressed only on cells of the immune system and endothelial cells. At the cellular level, these receptors activate the pathways leading to the activation of transcription factors NF-kappaB and AP-1, apoptosis and proliferation, and mitogen activated protein kinases. None of these receptors exhibit any enzymatic activity but the signals are transmitted through the recruitment of more than a dozen different signalling proteins, which together form signalling cascades. Inhibitors of TNF signalling have therapeutic value as indicated by the approval of the soluble TNF receptors and anti-TNF antibodies for rheumatoid arthritis and for inflammatory bowl disease.

MeSH Terms
Apoptosis/physiology Cell Division/physiology Humans JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases/metabolism NF-kappa B/metabolism Proteins/physiology Receptors, Tumor Necrosis Factor/physiology Signal Transduction/physiology TNF Receptor-Associated Factor 1
Chemicals
NF-kappa B Proteins Receptors, Tumor Necrosis Factor TNF Receptor-Associated Factor 1 JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Aggarwal B B
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, PO Box 143, Houston, Texas 77030, USA. [email protected]
References (108)
108 references, click to expand
  1. Activation of caspase-2 in apoptosis.
    J Biol Chem. 1997 Aug 22;272(34):21010-7 PMID: 9261102
  2. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.
    Cell. 1997 Aug 8;90(3):405-13 PMID: 9267021
  3. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme.
    J Biol Chem. 1994 Dec 9;269(49):30761-4 PMID: 7983002
  4. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice.
    Nature. 1994 Dec 8;372(6506):560-3 PMID: 7990930
  5. Lymphoid expression and regulation of A20, an inhibitor of programmed cell death.
    J Immunol. 1995 Feb 15;154(4):1699-706 PMID: 7836754
  6. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme.
    Science. 1995 Mar 31;267(5206):2000-3 PMID: 7535475
  7. Defects in regulation of apoptosis in caspase-2-deficient mice.
    Genes Dev. 1998 May 1;12(9):1304-14 PMID: 9573047
  8. RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis.
    J Biol Chem. 1998 May 15;273(20):12296-300 PMID: 9575181
  9. RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase.
    J Biol Chem. 1998 Jul 3;273(27):16968-75 PMID: 9642260
  10. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation.
    Cell. 1998 Jun 26;93(7):1231-40 PMID: 9657155
  11. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9.
    Cell. 1998 Aug 7;94(3):325-37 PMID: 9708735
  12. Differential requirement for caspase 9 in apoptotic pathways in vivo.
    Cell. 1998 Aug 7;94(3):339-52 PMID: 9708736
  13. Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38.
    J Biol Chem. 1998 Aug 28;273(35):22681-92 PMID: 9712898
  14. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1.
    Curr Biol. 1998 Jul 16;8(15):885-8 PMID: 9705938
  15. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
    Cell. 1998 Aug 21;94(4):481-90 PMID: 9727491
  16. 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. 1998 Aug;9(2):267-76 PMID: 9729047
  17. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.
    Science. 1998 Sep 11;281(5383):1680-3 PMID: 9733516
  18. BRE: a modulator of TNF-alpha action.
    FASEB J. 1998 Sep;12(12):1101-8 PMID: 9737713
  19. RIP2 is a Raf1-activated mitogen-activated protein kinase kinase.
    J Biol Chem. 1999 Nov 19;274(47):33684-90 PMID: 10559258
  20. 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. 2000 Apr;12(4):419-29 PMID: 10795740
  21. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin.
    Nature. 1984 Dec 20-1985 Jan 2;312(5996):724-9 PMID: 6392892
  22. Human tumor necrosis factor. Production, purification, and characterization.
    J Biol Chem. 1985 Feb 25;260(4):2345-54 PMID: 3871770
  23. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon.
    Nature. 1985 Dec 19-1986 Jan 1;318(6047):665-7 PMID: 3001529
  24. Tumor necrosis factors: gene structure and biological activities.
    Cold Spring Harb Symp Quant Biol. 1986;51 Pt 1:597-609 PMID: 3472740
  25. Human tumor necrosis factor-alpha receptor. Purification by immunoaffinity chromatography and initial characterization.
    J Biol Chem. 1988 Dec 15;263(35):19098-104 PMID: 2848815
  26. Isolation and characterization of a tumor necrosis factor binding protein from urine.
    Eur J Haematol. 1989 Mar;42(3):270-5 PMID: 2924890
  27. Purification and biologic characterization of a specific tumor necrosis factor alpha inhibitor.
    J Biol Chem. 1989 Jul 15;264(20):11966-73 PMID: 2545692
  28. A tumor necrosis factor-binding protein purified to homogeneity from human urine protects cells from tumor necrosis factor toxicity.
    J Biol Chem. 1989 Jul 15;264(20):11974-80 PMID: 2545693
  29. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2.
    Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9792-6 PMID: 9275204
  30. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death.
    Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11333-8 PMID: 9326610
  31. Tumor necrosis factor (TNF) receptor 1 signaling downstream of TNF receptor-associated factor 2. Nuclear factor kappaB (NFkappaB)-inducing kinase requirement for activation of activating protein 1 and NFkappaB but not of c-Jun N-terminal kinase/stress-activated protein kinase.
    J Biol Chem. 1997 Oct 17;272(42):26079-82 PMID: 9334169
  32. FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b.
    J Biol Chem. 1997 Oct 24;272(43):26953-8 PMID: 9341131
  33. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation.
    Cell. 1997 Oct 17;91(2):243-52 PMID: 9346241
  34. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK.
    Science. 1997 Oct 31;278(5339):866-9 PMID: 9346485
  35. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis.
    Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10717-22 PMID: 9380701
  36. TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival.
    Immunity. 1997 Nov;7(5):703-13 PMID: 9390693
  37. Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice.
    Immunity. 1997 Nov;7(5):715-25 PMID: 9390694
  38. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD.
    Nature. 1998 Jan 1;391(6662):43-50 PMID: 9422506
  39. Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death signal.
    J Biol Chem. 1998 Feb 20;273(8):4345-9 PMID: 9468483
  40. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis.
    Science. 1998 Mar 20;279(5358):1954-8 PMID: 9506948
  41. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1.
    Nature. 1998 Mar 19;392(6673):296-300 PMID: 9521326
  42. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes.
    Genes Dev. 1998 Mar 15;12(6):806-19 PMID: 9512515
  43. The death domain kinase RIP mediates the TNF-induced NF-kappaB signal.
    Immunity. 1998 Mar;8(3):297-303 PMID: 9529147
  44. NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176.
    Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3792-7 PMID: 9520446
  45. Overexpression of the p80 TNF receptor leads to TNF-dependent apoptosis, nuclear factor-kappa B activation, and c-Jun kinase activation.
    J Immunol. 1998 Apr 1;160(7):3152-62 PMID: 9531270
  46. Depressed Langerhans cell migration and reduced contact hypersensitivity response in mice lacking TNF receptor p75.
    J Immunol. 1997 Dec 15;159(12):6148-55 PMID: 9550416
  47. Apaf1 is required for mitochondrial pathways of apoptosis and brain development.
    Cell. 1998 Sep 18;94(6):739-50 PMID: 9753321
  48. A critical role of the p75 tumor necrosis factor receptor (p75TNF-R) in organ inflammation independent of TNF, lymphotoxin alpha, or the p55TNF-R.
    J Exp Med. 1998 Oct 5;188(7):1343-52 PMID: 9763613
  49. ASK1 is essential for JNK/SAPK activation by TRAF2.
    Mol Cell. 1998 Sep;2(3):389-95 PMID: 9774977
  50. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains.
    Science. 1999 Jan 22;283(5401):543-6 PMID: 9915703
  51. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation.
    Science. 1999 Apr 9;284(5412):309-13 PMID: 10195894
  52. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase.
    Science. 1999 Apr 9;284(5412):316-20 PMID: 10195896
  53. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene.
    Science. 1999 Apr 9;284(5412):321-5 PMID: 10195897
  54. A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'.
    EMBO J. 1999 Apr 15;18(8):2119-26 PMID: 10205166
  55. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9.
    J Biol Chem. 1999 Apr 23;274(17):11549-56 PMID: 10206961
  56. Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice.
    Immunity. 1999 Apr;10(4):421-9 PMID: 10229185
  57. Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice.
    EMBO J. 1999 May 4;18(9):2472-9 PMID: 10228161
  58. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase.
    Nat Genet. 1999 May;22(1):74-7 PMID: 10319865
  59. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain.
    Genes Dev. 1999 May 15;13(10):1297-308 PMID: 10346818
  60. RIP3, a novel apoptosis-inducing kinase.
    J Biol Chem. 1999 Jun 11;274(24):16871-5 PMID: 10358032
  61. Identification of Grb2 as a novel binding partner of tumor necrosis factor (TNF) receptor I.
    J Exp Med. 1999 Jun 7;189(11):1707-14 PMID: 10359574
  62. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis.
    J Exp Med. 1999 Jun 7;189(11):1839-45 PMID: 10359587
  63. TANK potentiates tumor necrosis factor receptor-associated factor-mediated c-Jun N-terminal kinase/stress-activated protein kinase activation through the germinal center kinase pathway.
    Mol Cell Biol. 1999 Oct;19(10):6665-72 PMID: 10490605
  64. Caspase activation: the induced-proximity model.
    Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10964-7 PMID: 10500109
  65. Soluble forms of tumor necrosis factor receptors (TNF-Rs). The cDNA for the type I TNF-R, cloned using amino acid sequence data of its soluble form, encodes both the cell surface and a soluble form of the receptor.
    EMBO J. 1990 Oct;9(10):3269-78 PMID: 1698610
  66. A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor.
    Proc Natl Acad Sci U S A. 1990 Nov;87(21):8331-5 PMID: 2172983
  67. Characterization in vitro of a human tumor necrosis factor-binding protein. A soluble form of a tumor necrosis factor receptor.
    J Clin Invest. 1990 Nov;86(5):1396-1402 PMID: 2173717
  68. The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity.
    J Biol Chem. 1992 Jun 25;267(18):12424-7 PMID: 1618749
  69. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection.
    Cell. 1993 May 7;73(3):457-67 PMID: 8387893
  70. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes.
    Nature. 1993 Aug 26;364(6440):798-802 PMID: 8395024
  71. A novel domain within the 55 kd TNF receptor signals cell death.
    Cell. 1993 Sep 10;74(5):845-53 PMID: 8397073
  72. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor.
    Cell. 1994 Aug 26;78(4):681-92 PMID: 8069916
  73. Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor.
    Cell. 1990 Apr 20;61(2):351-9 PMID: 2158862
  74. Molecular cloning and expression of a receptor for human tumor necrosis factor.
    Cell. 1990 Apr 20;61(2):361-70 PMID: 2158863
  75. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins.
    Science. 1990 May 25;248(4958):1019-23 PMID: 2160731
  76. Characterization of a tumor necrosis factor alpha (TNF-alpha) inhibitor: evidence of immunological cross-reactivity with the TNF receptor.
    Proc Natl Acad Sci U S A. 1990 Jul;87(13):5188-92 PMID: 2164226
  77. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.
    J Biol Chem. 1995 Apr 7;270(14):7795-8 PMID: 7536190
  78. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation.
    Cell. 1995 May 19;81(4):495-504 PMID: 7758105
  79. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.
    Cell. 1995 May 19;81(4):505-12 PMID: 7538907
  80. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death.
    Cell. 1995 May 19;81(4):513-23 PMID: 7538908
  81. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.
    Cell. 1995 Jun 2;81(5):801-9 PMID: 7774019
  82. TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40.
    Science. 1995 Sep 8;269(5229):1424-7 PMID: 7544915
  83. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.
    Cell. 1995 Dec 29;83(7):1243-52 PMID: 8548810
  84. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.
    Cell. 1996 Jan 26;84(2):299-308 PMID: 8565075
  85. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex.
    Immunity. 1996 Apr;4(4):387-96 PMID: 8612133
  86. Tumor necrosis factors: developments during the last decade.
    Eur Cytokine Netw. 1996 Apr-Jun;7(2):93-124 PMID: 8688493
  87. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation.
    Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6721-5 PMID: 8692885
  88. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.
    Cell. 1996 Jun 14;85(6):803-15 PMID: 8681376
  89. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex.
    Cell. 1996 Jun 14;85(6):817-27 PMID: 8681377
  90. I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction.
    Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8241-6 PMID: 8710854
  91. FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase.
    Cell. 1996 Sep 20;86(6):937-47 PMID: 8808629
  92. Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin.
    J Immunol. 1996 Nov 15;157(10):4277-81 PMID: 8906799
  93. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice.
    Nature. 1996 Nov 28;384(6607):368-72 PMID: 8934524
  94. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13973-8 PMID: 8943045
  95. RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis.
    EMBO J. 1996 Nov 15;15(22):6189-96 PMID: 8947041
  96. RAIDD is a new 'death' adaptor molecule.
    Nature. 1997 Jan 2;385(6611):86-9 PMID: 8985253
  97. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1.
    Nature. 1997 Feb 6;385(6616):540-4 PMID: 9020361
  98. CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP.
    Cancer Res. 1997 Feb 15;57(4):615-9 PMID: 9044836
  99. A novel interaction between the juxtamembrane region of the p55 tumor necrosis factor receptor and phosphatidylinositol-4-phosphate 5-kinase.
    J Biol Chem. 1997 Feb 28;272(9):5861-70 PMID: 9038203
  100. A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis.
    J Biol Chem. 1997 Apr 11;272(15):9621-4 PMID: 9092488
  101. TRAF-interacting protein (TRIP): a novel component of the tumor necrosis factor receptor (TNFR)- and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation.
    J Exp Med. 1997 Apr 7;185(7):1275-85 PMID: 9104814
  102. MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase.
    J Biol Chem. 1997 May 2;272(18):12069-75 PMID: 9115275
  103. TNF receptor p55 controls early acute graft-versus-host disease.
    J Immunol. 1997 Jun 1;158(11):5185-90 PMID: 9164935
  104. Casper is a FADD- and caspase-related inducer of apoptosis.
    Immunity. 1997 Jun;6(6):751-63 PMID: 9208847
  105. Inhibition of death receptor signals by cellular FLIP.
    Nature. 1997 Jul 10;388(6638):190-5 PMID: 9217161
  106. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis.
    J Biol Chem. 1997 Jul 25;272(30):18542-5 PMID: 9228018
  107. X-linked IAP is a direct inhibitor of cell-death proteases.
    Nature. 1997 Jul 17;388(6639):300-4 PMID: 9230442
  108. Identification and characterization of an IkappaB kinase.
    Cell. 1997 Jul 25;90(2):373-83 PMID: 9244310
Article Info
Journal
Annals of the rheumatic diseases
Abbr.
Ann Rheum Dis
ISSN
0003-4967
DOI
10.1136/ard.59.suppl_1.i6
Email
[email protected]
Published
2000-11-00
Pages
i6-16
Language
English
Region
England
NLM ID
0372355
PMCID
PMC1766635
Subset
IM
External Links
PubMed source DOI: 10.1136/ard.59.suppl_1.i6 PMC Full Text View journal details
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