Inhibitors of NF-κB Activity

Tools for Treatment of Human Ailments
Part of the Molecular Biology Intelligence Unit book series (MBIU)


A part from being a paradigm for understanding cellular signaling, the NF-κB pathway has been thoroughly investigated over the last two decades due to its involvement in a number of human diseases. In the post genomic era, improved knowledge and novel technologies have contributed immensely to the discovery of several hitherto unknown cellular processes that regulate NF-κB. Identification of covalent modifications of many NF-κB pathway components, both in the cytoplasm and the nucleus has shed light on novel mechanisms that regulate NF-κB activity. Similarly, study of a number of cellular and viral proteins that regulate this pathway has added to our understanding of the molecular mechanisms and molecular targets in the NF-κB pathway for drug development.


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  1. 1.
    Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002; 2(10):725–734.PubMedCrossRefGoogle Scholar
  2. 2.
    Rayet B, Gelinas C. Aberrant re1/nfkb genes and activity in human cancer. Oncogene 1999; 18(49):6938–6947.PubMedCrossRefGoogle Scholar
  3. 3.
    Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity-and diet-induced insulin resistance. Int J Obes Relat Metab Disord 2003; 27(Suppl 3):S49–52.PubMedCrossRefGoogle Scholar
  4. 4.
    von Haehling S, Genth-Zotz S, Anker SD et al. Cachexia: A therapeutic approach beyond cytokine antagonism. Int J Cardiol 2002; 85(1):173–183.CrossRefGoogle Scholar
  5. 5.
    Mattson MP, Camandola S. NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 2001; 107(3):247–254.PubMedCrossRefGoogle Scholar
  6. 6.
    Tsoulfas G, Geller DA. NF-kappaB in transplantation: Friend or foe? Transpl Infect Dis 2001; 3(4):212–219.PubMedCrossRefGoogle Scholar
  7. 7.
    Valen G, Yan ZQ, Hansson GK. Nuclear factor kappa-B and the heart. J Am Coll Cardiol 2001; 38(2):307–314.PubMedCrossRefGoogle Scholar
  8. 8.
    Nichols TC, Fischer TH, Deliargyris EN et al. Role of nuclear factor-kappa B (NF-kappa B) in inflammation, periodontitis, and atherogenesis. Ann Periodontol 2001; 6(1):20–29.PubMedCrossRefGoogle Scholar
  9. 9.
    Bell S, Degitz K, Quirling M et al. Involvement of NF-kappaB signalling in skin physiology and disease. Cell Signal 2003; 15(1): 1–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Smahi A, Courtois G, Rabia SH et al. The NF-kappaB signalling pathway in human diseases: From incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet 2002; 11(20):2371–2375.PubMedCrossRefGoogle Scholar
  11. 11.
    Garg A, Aggarwal BB. Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 2002; 16(6):1053–1068.PubMedCrossRefGoogle Scholar
  12. 12.
    Karin M, Cao Y, Greten FR et al. NF-kappaB in cancer: From innocent bystander to major culprit. Nat Rev Cancer 2002; 2(4):301–310.PubMedCrossRefGoogle Scholar
  13. 13.
    Verma IM, Stevenson JK, Schwarz EM et al. Re1/NF-kappa B/I kappa B family: Intimate tales of association and dissociation. Genes Dev 1995; 9(22):2723–2735.PubMedGoogle Scholar
  14. 14.
    Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: The control of NF-[kappa] B activity. Annu Rev Immunol 2000; 18:621–663.PubMedCrossRefGoogle Scholar
  15. 15.
    Brown K, Gerstberger S, Carlson L et al. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 1995; 267(5203):1485–1488.PubMedCrossRefGoogle Scholar
  16. 16.
    Spencer E, Jiang J, Chen ZJ. Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. Genes Dev 1999; 13(3):284–294.PubMedGoogle Scholar
  17. 17.
    Deshaies RJ. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol 1999; 15:435–467.PubMedCrossRefGoogle Scholar
  18. 18.
    Winston JT, Strack P, Beer-Romero P et al. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev 1999; 13(3):270–283.PubMedGoogle Scholar
  19. 19.
    Yaron A, Hatzubai A, Davis M et al. Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature 1998; 396(6711):590–594.PubMedCrossRefGoogle Scholar
  20. 20.
    Suzuki H, Chiba T, Kobayashi M et al. IkappaBalpha ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2. Biochem Biophys Res Commun 1999; 256(1):127–132.PubMedCrossRefGoogle Scholar
  21. 21.
    Wu C, Ghosh S. beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta. J Biol Chem 1999; 274(42):29591–29594.PubMedCrossRefGoogle Scholar
  22. 22.
    Fong A, Sun SC. Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/pl00. J Biol Chem 2002; 277(25):22111–22114.PubMedCrossRefGoogle Scholar
  23. 23.
    Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109(Suppl):S81–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Ryo A, Suizu F, Yoshida Y et al. Regulation of NF-kappaB signaling by Pin 1-dependent proly1 isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 2003; 12(6):1413–1426.PubMedCrossRefGoogle Scholar
  25. 25.
    Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999; 18(49):6853–6866.PubMedCrossRefGoogle Scholar
  26. 26.
    Cheng JD, Ryseck RP, Attar RM et al. Functional redundancy of the nuclear factor kappa B inhibitors I kappa B alpha and I kappa B beta. J Exp Med 1998; 188(6):1055–1062.PubMedCrossRefGoogle Scholar
  27. 27.
    Weil R, Sirma H, Giannini C et al. Direct association and nuclear import of the hepatitis B virus X protein with the NF-kappaB inhibitor IkappaBalpha. Mol Cell Biol 1999; 19(9):6345–6354.PubMedGoogle Scholar
  28. 28.
    Prigent M, Barlat I, Langen H et al. IkappaBalpha and IkappaBalpha /NF-kappa B complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2. J Biol Chem 2000; 275(46):36441–36449.PubMedCrossRefGoogle Scholar
  29. 29.
    Fenwick C, Na SY, Voll RE et al. A subclass of Ras proteins that regulate the degradation of IkappaB. Science 2000; 287(5454):869–873.PubMedCrossRefGoogle Scholar
  30. 30.
    Gao H, Sun Y, Wu Y et al. Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways. Mol Cell 2004; 14(3):303–317.PubMedCrossRefGoogle Scholar
  31. 31.
    Delhase M, Hayakawa M, Chen Y et al. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 1999; 284(5412):309–313.PubMedCrossRefGoogle Scholar
  32. 32.
    Brummelkamp TR, Nijman SM, Dirac AM et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 2003; 424(6950):797–801.PubMedCrossRefGoogle Scholar
  33. 33.
    Kovalenko A, Chable-Bessia C, Cantarella G et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 2003; 424(6950):801–805.PubMedCrossRefGoogle Scholar
  34. 34.
    Davis M, Hatzubai A, Andersen JS et al. Pseudosubstrate regulation of the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U. Genes Dev 2002; 16(4):439–451.PubMedCrossRefGoogle Scholar
  35. 35.
    Shishodia S, Aggarwal BB. Nuclear factor-kappaB activation mediates cellular transformation, proliferation, invasion angiogenesis and metastasis of cancer. Cancer Treat Res 2004; 119:139–173.PubMedGoogle Scholar
  36. 36.
    Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol 2002; 2(9):664–674.PubMedCrossRefGoogle Scholar
  37. 37.
    Orlowski RZ, Baldwin Jr AS. NF-kappaB as a therapeutic target in cancer. Trends Mol Med 2002; 8(8):385–389.PubMedCrossRefGoogle Scholar
  38. 38.
    Haefner B. NF-kappa B: Arresting a major culprit in cancer. Drug Discov Today 2002; 7(12):653–663.PubMedCrossRefGoogle Scholar
  39. 39.
    Hinz M, Krappmann D, Eichten A et al. NF-kappaB function in growth control: Regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999; 19(4):2690–2698.PubMedGoogle Scholar
  40. 40.
    Guttridge DC, Albanese C, Reuther JY et al. NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 1999; 19(8):5785–5799.PubMedGoogle Scholar
  41. 41.
    Cao Y, Bonizzi G, Seagroves TN et al. IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 2001; 107(6):763–775.PubMedCrossRefGoogle Scholar
  42. 42.
    Perkins ND, Felzien LK, Betts JC et al. Regulation of NF-kappaB by cydin-dependent kinases associated with the p300 coactivator. Science 1997; 275(5299):523–527.PubMedCrossRefGoogle Scholar
  43. 43.
    Tergaonkar V, Bottero V, Ikawa M et al. IkappaB Kinase-independent IkappaBalpha degradation pathway: Functional NF-kappaB activity and implications for cancer therapy. Mol Cell Biol 2003; 23(22):8070–8083.PubMedCrossRefGoogle Scholar
  44. 44.
    Egan LJ, Eckmann L, Greten FR et al. IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Proc Nad Acad Sci USA 2004; 101(8):2452–2457.CrossRefGoogle Scholar
  45. 45.
    Wan YY, DeGregori J. The survival of antigen-stimulated T cells requires NFkappaB-mediated inhibition of p73 expression. Immunity 2003; 18(3):331–342.PubMedCrossRefGoogle Scholar
  46. 46.
    Stoffel A, Chaurushiya M, Singh B et al. Activation of NF-kappaB and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis. Proc Natl Acad Sci USA 2004; 101(24):9079–9084.PubMedCrossRefGoogle Scholar
  47. 47.
    Rocha S, Campbell KJ, Perkins ND. p53-and Mdm2-independent repression of NF-kappa B transactivation by the ARF tumor suppressor. Mol Cell 2003; 12(1):15–25.PubMedCrossRefGoogle Scholar
  48. 48.
    Garkavtsev I, Kozin SV, Chernova O et al. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 2004; 428(6980):328–332.PubMedCrossRefGoogle Scholar
  49. 49.
    Bignell GR, Warren W, Seal S et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 2000; 25(2):160–165.PubMedCrossRefGoogle Scholar
  50. 50.
    Webster GA, Perkins ND. Transcriptional cross talk between NF-kappaB and p53. Mol Cell Biol 1999; 19(5):3485–3495.PubMedGoogle Scholar
  51. 51.
    Wadgaonkar R, Phelps KM, Haque Z et al. CREB-binding protein is a nuclear integrator of nuclear factor-kappaB and p53 signaling. J Biol Chem 1999; 274(4):1879–1882.PubMedCrossRefGoogle Scholar
  52. 52.
    Ravi R, Mookerjee B, van Hensbergen Y et al. p53-mediated repression of nuclear factor-kappaB Re1A via the transcriptional integrator p300. Cancer Res 1998; 58(20):4531–4536.PubMedGoogle Scholar
  53. 53.
    Sosic D, Richardson JA, Yu K et al. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell 2003; 112(2):169–180.PubMedCrossRefGoogle Scholar
  54. 54.
    Lee EG, Boone DL, Chai S et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000; 289(5488):2350–2354.PubMedCrossRefGoogle Scholar
  55. 55.
    Wertz IE, O’Rourke KM, Zhou H et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004.Google Scholar
  56. 56.
    Monteleone G, Mann J, Monteleone I et al. A failure of transforming growth factor-betal negative regulation maintains sustained NF-kappaB activation in gut inflammation. J Biol Chem 2004; 279(6):3925–3932.PubMedCrossRefGoogle Scholar
  57. 57.
    Kuwata H, Watanabe Y, Miyoshi H et al. IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood 2003; 102(12):4123–4129.PubMedCrossRefGoogle Scholar
  58. 58.
    O’Connor Jr W, Harton JA, Zhu X et al. Cutting edge: CIASl/cryopyrin/PYPAFl/NALP3/ CATERPILLER 1.1 is an inducible inflammatory mediator with NF-kappa B suppressive proper ties. J Immunol 2003; 171(12):6329–6333.PubMedGoogle Scholar
  59. 59.
    Mehta VB, Besner GE. Inhibition of NF-kappa B activation and its target genes by heparin-binding epidermal growth factor-like growth factor. J Immunol 2003; 171(11):6014–6022.PubMedGoogle Scholar
  60. 60.
    Reynaert NL, Ckless K, Korn SH et al. Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation. Proc Natl Acad Sci USA 2004; 101(24):8945–8950.PubMedCrossRefGoogle Scholar
  61. 61.
    Marshall HE, Stamler JS. Inhibition of NF-kappa B by S-nitrosylation. Biochemistry 2001; 40(6):1688–1693.PubMedCrossRefGoogle Scholar
  62. 62.
    Kapahi P, Takahashi T, Natoli G et al. 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 2000; 275(46):36062–36066.PubMedCrossRefGoogle Scholar
  63. 63.
    Korn SH, Wouters EF, Vos N et al. Cytokine-induced activation of nuclear factor-kappa B is inhibited by hydrogen peroxide through oxidative inactivation of IkappaB kinase. J Biol Chem 2001; 276(38):35693–35700.PubMedCrossRefGoogle Scholar
  64. 64.
    Ji C, Kozak KR, Marnett LJ. IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal. J Biol Chem 2001; 276(21):18223–18228.PubMedCrossRefGoogle Scholar
  65. 65.
    Rossi A, Kapahi P, Natoli G et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 2000; 403(6765):103–108.PubMedCrossRefGoogle Scholar
  66. 66.
    Yang JP, Hori M, Sanda T et al. Identification of a novel inhibitor of nuclear factor-kappaB, RelA-associated inhibitor. J Biol Chem 1999; 274(22):15662–15670.PubMedCrossRefGoogle Scholar
  67. 67.
    Ganesh L, Burstein E, Guha-Niyogi A et al. The gene product Murrl restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 2003; 426(6968):853–857.PubMedCrossRefGoogle Scholar
  68. 68.
    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: Cell fate control and signal integration in development. Science 1999; 284(5415):770–776.PubMedCrossRefGoogle Scholar
  69. 69.
    Park MY, Jang HD, Lee SY et al. Fas-associated factor-1 inhibits nuclear factor-kappaB (NF-kappaB) activity by interfering with nuclear translocation of the RelA (p65) subunit of NF-kappaB. J Biol Chem 2004; 279(4):2544–2549.PubMedCrossRefGoogle Scholar
  70. 70.
    Wolff B, Naumann M. INK4 cell cycle inhibitors direct transcriptional inactivation of NF-kappaB. Oncogene 1999; 18(16):2663–2666.PubMedCrossRefGoogle Scholar
  71. 71.
    Ohata K, Ichikawa T, Nakao K et al. Interferon alpha inhibits the nuclear factor kappa B active tion triggered by X gene product of hepatitis B virus in human hepatoma cells. FEBS Lett 2003; 553(3):304–308.PubMedCrossRefGoogle Scholar
  72. 72.
    You Z, Madrid LV, Saims D et al. c-Myc sensitizes cells to tumor necrosis factor-mediated apoptosis by inhibiting nuclear factor kappa B transactivation. J Biol Chem 2002; 277(39):36671–36677.PubMedCrossRefGoogle Scholar
  73. 73.
    Manna SK, Zhang HJ, Yan T et al. Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1. J Biol Chem 1998; 273(21):13245–13254.PubMedCrossRefGoogle Scholar
  74. 74.
    Nourbakhsh M, Oumard A, Schwarzer M et al. NRF, a nuclear inhibitor of NF-kappaB proteins silencing interferon-beta promoter. Eur Cytokine Netw 2000; 11(3):500–501.PubMedGoogle Scholar
  75. 75.
    Altuwaijri S, Lin HK, Chuang KH et al. Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells. Cancer Res 2003; 63(21):7106–7112.PubMedGoogle Scholar
  76. 76.
    Steed PM, Tansey MG, Zalevsky J et al. Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science 2003; 301(5641):1895–1898.PubMedCrossRefGoogle Scholar
  77. 77.
    Van Antwerp DJ, Martin SJ, Kafri T et al. Suppression of TNF-alpha-induced apoptosis by NF-kappaB [see comments]. Science 1996; 274(5288):787–789.PubMedCrossRefGoogle Scholar
  78. 78.
    Li J, Joo SH, Tsai MD. An NF-kappaB-specific inhibitor, IkappaBalpha, binds to and inhibits cydin-dependent kinase 4. Biochemistry 2003; 42(46):13476–13483.PubMedCrossRefGoogle Scholar
  79. 79.
    Baldi L, Brown K, Franzoso G et al. Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I kappa B-alpha. J Biol Chem 1996; 271(1):376–379.PubMedCrossRefGoogle Scholar
  80. 80.
    Imbert V, Rupee RA, Livolsi A et al. Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha. Cell 1996; 86(5):787–798.PubMedCrossRefGoogle Scholar
  81. 81.
    Clohisy JC, Roy BC, Biondo C et al. Direct inhibition of NF-kappa B blocks bone erosion associated with inflammatory arthritis. J Immunol 2003; 171(10):5547–5553.PubMedGoogle Scholar
  82. 82.
    Horng T, Barton GM, Medzhitov R. TIRAP: An adapter molecule in the Toll signaling pathway. Nat Immunol 2001; 2(9):835–841.PubMedCrossRefGoogle Scholar
  83. 83.
    May MJ, D’Acquisto F, Madge LA et al. Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science 2000; 289(5484):1550–1554.PubMedCrossRefGoogle Scholar
  84. 84.
    May MJ, Marienfeld RB, Ghosh S. Characterization of the Ikappa B-kinase NEMO binding do main. J Biol Chem 2002; 277(48):45992–46000.PubMedCrossRefGoogle Scholar
  85. 85.
    Dai S, Hirayama T, Abbas S et al. The IKK inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis. J Biol Chem 2004.Google Scholar
  86. 86.
    Yaron A, Gonen H, Alkalay I et al. Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase. EMBO J 1997; 16(21):6486–6494.PubMedCrossRefGoogle Scholar
  87. 87.
    Huang TT, Feinberg SL, Suryanarayanan S et al. The zinc finger domain of NEMO is selectively required for NF-kappa B activation by UV radiation and topoisomerase inhibitors. Mol Cell Biol 2002; 22(16):5813–5825.PubMedCrossRefGoogle Scholar
  88. 88.
    Takada Y, Singh S, Aggarwal BB. Identification of a p65 peptide that selectively inhibits NF-kappa B activation induced by various inflammatory stimuli and its role in down-regulation of NF-kappaB-mediated gene expression and up-regulation of apoptosis. J Biol Chem 2004; 279(15):15096–15104.PubMedCrossRefGoogle Scholar
  89. 89.
    Kolenko V, Bloom T, Rayman P et al. Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and-3. J Immunol 1999; 163(2):590–598.PubMedGoogle Scholar
  90. 90.
    Torgerson TR, Colosia AD, Donahue JP et al. Regulation of NF-kappa B, AP-1, NFAT, and STAT1 nuclear import in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-kappa B p50. J Immunol 1998; 161(11):6084–6092.PubMedGoogle Scholar
  91. 91.
    Ducut Sigala JL, Bottero V, Young DB et al. Activation of transcription factor NF-kappaB requires ELKS, an IkappaB kinase regulatory subunit. Science 2004; 304(5679):1963–1967.PubMedCrossRefGoogle Scholar
  92. 92.
    Orth K. Function of the Yersinia effector YopJ. Curr Opin Microbiol 2002; 5(1):38–43.PubMedCrossRefGoogle Scholar
  93. 93.
    Orth K, Xu Z, Mudgett MB et al. Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease. Science 2000; 290(5496):1594–1597.PubMedCrossRefGoogle Scholar
  94. 94.
    Deng L, Wang C, Spencer E et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000; 103(2):351–361.PubMedCrossRefGoogle Scholar
  95. 95.
    Wang C, Deng L, Hong M et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001; 412(6844):346–351.PubMedCrossRefGoogle Scholar
  96. 96.
    Hajishengallis G, Genco RJ. Downregulation of the DNA-binding activity of nuclear factor-kappaB p65 subunit in Porphyromonas gingivalis fimbria-induced tolerance. Infect Immun 2004; 72(2):1188–1191.PubMedCrossRefGoogle Scholar
  97. 97.
    Alcami A, Koszinowski UH. Viral mechanisms of immune evasion. Immunol Today 2000; 21(9):447–455.PubMedCrossRefGoogle Scholar
  98. 98.
    Hiscott J, Kwon H, Genin P. Hostile takeovers: Viral appropriation of the NF-kappaB pathway. J Clin Invest 2001; 107(2):143–151.PubMedGoogle Scholar
  99. 99.
    Fennewald SM, Aronson JF, Zhang L et al. Alterations in NF-kappaB and RBP-Jkappa by arenavirus infection of macrophages in vitro and in vivo. J Virol 2002; 76(3):1154–1162.PubMedGoogle Scholar
  100. 100.
    Shao R, Karunagaran D, Zhou BP et al. Inhibition of nuclear factor-kappaB activity is involved in ElA-mediated sensitization of radiation-induced apoptosis. J Biol Chem 1997; 272(52):32739–32742.PubMedCrossRefGoogle Scholar
  101. 101.
    Friedman JM, Horwitz MS. Inhibition of tumor necrosis factor alpha-induced NF-kappa B activetion by the adenovirus E3-10.4/14.5K complex. J Virol 2002; 76(11):5515–5521.PubMedCrossRefGoogle Scholar
  102. 102.
    Browne EP, Shenk T. Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells. Proc Natl Acad Sci USA 2003; 100(20):11439–11444.PubMedCrossRefGoogle Scholar
  103. 103.
    Wang X, Li M, Zheng H et al. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J Virol 2000; 74(24):11566–11573.PubMedCrossRefGoogle Scholar
  104. 104.
    Dreyfus DH, Nagasawa M, Pratt JC et al. Inactivation of NF-kappaB by EBV BZLF-1-encoded ZEBRA protein in human T cells. J Immunol 1999; 163(11):6261–6268.PubMedGoogle Scholar
  105. 105.
    Shisler JL, Jin XL. The vaccinia virus K1L gene product inhibits host NF-kappaB activation by preventing IkappaBalpha degradation. J Virol 2004; 78(7):3553–3560.PubMedCrossRefGoogle Scholar
  106. 106.
    Besnard-Guerin C, Belaidouni N, Lassot I et al. HIV-1 Vpu sequesters beta-transducin repeat-containing protein (betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin and other SCFbetaTrCP substrates. J Biol Chem 2004; 279(1):788–795.PubMedCrossRefGoogle Scholar
  107. 107.
    Tang W, Pavlish OA, Spiegelman VS et al. Interaction of Epstein-Barr virus latent membrane protein 1 with SCFHOS/beta-TrCP E3 ubiquitin ligase regulates extent of NF-kappaB activation. J Biol Chem 2003; 278(49):48942–48949.PubMedCrossRefGoogle Scholar
  108. 108.
    Lassot I, Segeral E, Berlioz-Torrent C et al. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol 2001; 21(6):2192–2202.PubMedCrossRefGoogle Scholar
  109. 109.
    Bremner P, Heinrich M. Natural products as targeted modulators of the nuclear factor-kappaB pathway. J Pharm Pharmacol 2002; 54(4):453–472.PubMedCrossRefGoogle Scholar
  110. 110.
    Pan MH, Lin-Shiau SY, Ho CT et al. Suppression of lipopolysaccharide-induced nuclear factor-kappaB activity by theaflavin-3,3′-digallate from black tea and other polyphenols through down-regulation of IkappaB kinase activity in macrophages. Biochem Pharmacol 2000;59(4):357–367.PubMedCrossRefGoogle Scholar
  111. 111.
    Jobin C, Bradham CA, Russo MP et al. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol 1999; 163(6):3474–3483.PubMedGoogle Scholar
  112. 112.
    Straus DS, Pascual G, Li M et al. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci USA 2000; 97(9):4844–4849.PubMedCrossRefGoogle Scholar
  113. 113.
    D’Acquisto F, May MJ, Ghosh S. Inhibition of Nuclear Factor Kappa B (NF-B): An emerging theme in anti-inflammatory therapies. Mol Intervent 2002; 2(1):22–35.CrossRefGoogle Scholar
  114. 114.
    Amit S, Ben-Neriah Y. NF-kappaB activation in cancer: A challenge for ubiquitination-and proteasome-based therapeutic approach. Semin Cancer Biol 2003; 13(1):15–28.PubMedCrossRefGoogle Scholar
  115. 115.
    Magnani M, Crinelli R, Bianchi M et al. The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-κB (NF-κB). Curr Drug Targets 2000;1(4):387–399.PubMedCrossRefGoogle Scholar
  116. 116.
    Sunwoo JB, Chen Z, Dong G et al. Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 2001; 7(5):1419–1428.PubMedGoogle Scholar
  117. 117.
    Adams J. Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer. Curr Opin Chem Biol 2002; 6(4):493–500.PubMedCrossRefGoogle Scholar
  118. 118.
    Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348(26):2609–2617.PubMedCrossRefGoogle Scholar
  119. 119.
    Adams J, Kauffman M. Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 2004; 22(2):304–311.PubMedCrossRefGoogle Scholar
  120. 120.
    Tergaonkar V, Pando M, Vafa O et al. p53 stabilization is decreased upon NFkappaB activation: A role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell 2002; 1(5):493–503.PubMedCrossRefGoogle Scholar
  121. 121.
    Saklatvala J. Glucocorticoids: Do we know how they work? Arthritis Res 2002; 4(3):146–150.PubMedCrossRefGoogle Scholar
  122. 122.
    Heck S, Bender K, Kullmann M et al. I kappaB alpha-independent downregulation of NF-kappaB activity by glucocorticoid receptor. EMBO J 1997; 16(15):4698–4707.PubMedCrossRefGoogle Scholar
  123. 123.
    Auphan N, Didonato JA, Helmberg A et al. Immunoregulatory genes and immunosuppression by glucocorticoids. Arch Toxicol Suppl 1997; 19:87–95.PubMedGoogle Scholar
  124. 124.
    Doucas V, Shi Y, Miyamoto S et al. Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor [In Process Citation]. Proc Natl Acad Sci USA 2000; 97(22):11893–11898.PubMedCrossRefGoogle Scholar
  125. 125.
    Ito K, Jazrawi E, Cosio B et al. p65-activated histone acetyltransferase activity is repressed by glucocorticoids: Mifepristone fails to recruit HDAC2 to the p65-HAT complex. J Biol Chem 2001;276(32):30208–30215.PubMedCrossRefGoogle Scholar
  126. 126.
    Nissen RM, Yamamoto KR. The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev 2000;14(18):2314–2329.PubMedCrossRefGoogle Scholar
  127. 127.
    Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin [see comments]. Science 1994; 265(5174):956–959.PubMedCrossRefGoogle Scholar
  128. 128.
    Fuchs SY, Adler V, Buschmann T et al. JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev 1998; 12(17):2658–2663.PubMedGoogle Scholar
  129. 129.
    Yamamoto Y, Yin MJ, Lin KM et al. Sulindac inhibits activation of the NF-kappaB pathway. J Biol Chem 1999; 274(38):27307–27314.PubMedCrossRefGoogle Scholar
  130. 130.
    Warner TD, Mitchell JA. Cyclooxygenases: New forms, new inhibitors, and lessons from the clinic. FASEB J 2004; 18(7):790–804.PubMedCrossRefGoogle Scholar
  131. 131.
    Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420(6917):860–867.PubMedCrossRefGoogle Scholar
  132. 132.
    Kretz-Remy C, Mehlen P, Mirault ME et al. Inhibition of I kappa B-alpha phosphorylation and degradation and subsequent NF-kappa B activation by glutathione peroxidase overexpression. J Cell Biol 1996; 133(5):1083–1093.PubMedCrossRefGoogle Scholar
  133. 133.
    Carcamo JM, Pedraza A, Borquez-Ojeda O et al. Vitamin C is a kinase inhibitor: Dehydroascorbic acid inhibits I {kappa} B {alpha} kinase ta. Mol Cell Biol 2004; 24(15):6645–6652.PubMedCrossRefGoogle Scholar
  134. 134.
    Epinat JC, Gilmore TD. Diverse agents act at multiple levels to inhibit the Rel/NF-kappaB signal transduction pathway. Oncogene 1999; 18(49):6896–6909.PubMedCrossRefGoogle Scholar
  135. 135.
    Karin M, Yamamoto Y, Wang QM. The IKK NF-kappa B system: A treasure trove for drug development. Nat Rev Drug Discov 2004; 3(1):17–26.PubMedCrossRefGoogle Scholar
  136. 136.
    Ohazama A, Hu Y, Schmidt-Ullrich R et al. A dual role for Ikk alpha in tooth development. Dev Cell 2004; 6(2):219–227.PubMedCrossRefGoogle Scholar
  137. 137.
    Senftleben U, Cao Y, Xiao G et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001; 293(5534):1495–1499.PubMedCrossRefGoogle Scholar
  138. 138.
    Burke JR. Targeting I kappa B kinase for the treatment of inflammatory and other disorders. Curr Opin Drug Discov Devel 2003; 6(5):720–728.PubMedGoogle Scholar
  139. 139.
    Penolazzi L, Lambertini E, Borgatti M et al. Decoy oligodeoxynudeotides targeting NF-kappaB transcription factors: Induction of apoptosis in human primary osteoclasts. Biochem Pharmacol 2003; 66(7):1189–1198.PubMedCrossRefGoogle Scholar
  140. 140.
    Giannoukakis N, Bonham CA, Qian S et al. Prolongation of cardiac allograft survival using dendritic cells treated with NF-κB decoy oligodeoxyribonudeotides. Mol Ther 2000; 1(5 Pt 1):430–437.PubMedCrossRefGoogle Scholar
  141. 141.
    Hess DC, Howard E, Cheng C et al. Hypertonic mannitol loading of NF-kappaB transcription factor decoys in human brain microvascular endothelial cells blocks upregulation of ICAM-1. Stroke 2000; 31(5):1179–1186.PubMedGoogle Scholar
  142. 142.
    Lee IK, Ahn JD, Kim HS et al. Advantages of the circular dumbbell decoy in gene therapy and studies of gene regulation. Curr Drug Targets 2003; 4(8):619–623.PubMedCrossRefGoogle Scholar
  143. 143.
    Crooke ST. Antisense strategies. Curr Mol Med 2004; 4(5):465–487.PubMedCrossRefGoogle Scholar
  144. 144.
    Tiscornia G, Singer O, Ikawa M et al. A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA 2003; 100(4):1844–1848.PubMedCrossRefGoogle Scholar
  145. 145.
    Takaesu G, Surabhi RM, Park KJ et al. TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J Mol Biol 2003; 326(1):105–115.PubMedCrossRefGoogle Scholar
  146. 146.
    Pinkenburg O, Platz J, Beisswenger C et al. Inhibition of NF-kappaB mediated inflammation by siRNA expressed by recombinant adeno-associated virus. J Virol Methods 2004; 120(1):119–122.PubMedCrossRefGoogle Scholar
  147. 147.
    Guo J, Verma UN, Gaynor RB et al. Enhanced chemosensitivity to irinotecan by RNA interference-mediated down-regulation of the nuclear factor-kappaB p65 subunit. Clin Cancer Res 2004; 10(10):3333–3341.PubMedCrossRefGoogle Scholar
  148. 148.
    Sledz CA, Holko M, de Veer MJ et al. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 2003; 5(9):834–839.PubMedCrossRefGoogle Scholar
  149. 149.
    Yamamoto Y, Gaynor RB. IkappaB kinases: Key regulators of the NF-kappaB pathway. Trends Biochem Sci 2004; 29(2):72–79.PubMedCrossRefGoogle Scholar
  150. 150.
    Sizemore N, Leung S, Stark GR. Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol 1999; 19(7):4798–4805.PubMedGoogle Scholar
  151. 151.
    Mitsiades CS, Mitsiades N, Koutsilieris M. The Akt pathway: Molecular targets for anti-cancer drug development. Curr Cancer Drug Targets 2004; 4(3):235–256.PubMedCrossRefGoogle Scholar
  152. 152.
    Hoeflich KP, Luo J, Rubie EA et al. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 2000; 406(6791):86–90.PubMedCrossRefGoogle Scholar
  153. 153.
    Vermeulen L, De Wilde G, Van Damme P et al. Transcriptional activation of the NF-kappaB p65 subunit by mitogen-and stress-activated protein kinase-1 (MSK1). EMBO J 2003; 22(6):1313–1324.PubMedCrossRefGoogle Scholar
  154. 154.
    Cavin LG, Romieu-Mourez R, Panta GR et al. Inhibition of CK2 activity by TGF-betal promotes IkappaB-alpha protein stabilization and apoptosis of immortalized hepatocytes. Hepatology 2003;38(6):1540–1551.PubMedGoogle Scholar
  155. 155.
    Maloney A, Workman P. HSP90 as a new therapeutic target for cancer therapy: The story unfolds. Expert Opin Biol Ther 2002; 2(1):3–24.PubMedCrossRefGoogle Scholar
  156. 156.
    Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 2001; 107(2):135–142.PubMedGoogle Scholar
  157. 157.
    Tak PP, Firestein GS. NF-kappaB: A key role in inflammatory diseases. J Clin Invest 2001;107(1):7–11.PubMedGoogle Scholar
  158. 158.
    St Johnston D. The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet 2002; 3(3):176–188.PubMedCrossRefGoogle Scholar
  159. 159.
    Silverman N, Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev 2001; 15(18):2321–2342.PubMedCrossRefGoogle Scholar
  160. 160.
    Correa RG, Tergaonkar V, Ng JK et al. Characterization of NF-kappa B/I kappa B proteins in zebra fish and their involvement in notochord development. Mol Cell Biol 2004; 24(12):5257–5268.PubMedCrossRefGoogle Scholar
  161. 161.
    Chan J, Bayliss PE, Wood JM et al. Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. Cancer Cell 2002; 1(3):257–267.PubMedCrossRefGoogle Scholar
  162. 162.
    Pichler FB, Laurenson S, Williams LC et al. Chemical discovery and global gene expression analysis in zebrafish. Nat Biotechnol 2003; 21(8):879–883.PubMedCrossRefGoogle Scholar
  163. 163.
    Trede NS, Langenau DM, Traver D et al. The use of zebrafish to understand immunity. Immunity 2004; 20(4):367–379.PubMedCrossRefGoogle Scholar
  164. 164.
    Peterson RT, Shaw SY, Peterson TA et al. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol 2004; 22(5):595–599.PubMedCrossRefGoogle Scholar
  165. 165.
    MacRae CA, Peterson RT. Zebraflsh-based small molecule discovery. Chem Biol 2003;10(10):901–908.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  1. 1.Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUSA

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