Cancer and Metastasis Reviews

, Volume 22, Issue 4, pp 405–422 | Cite as

Deregulation of NF-κB and its upstream kinases in cancer

Article

Abstract

The transcription factor NF-κB is known for its function in regulating immune and inflammatory responses. However, recent evidence suggests that NF-κB also plays a pivotal role in controlling cell proliferation, apoptosis, and cell migration. Deregulated activation of NF-κB has been observed in various cancers. Over the past few years, significant progress has been made to elucidate the mechanisms of NF-κB activation in both normal and cancer cells. Notably, a large number of protein kinases have been shown to stimulate NF-κB activity under different conditions, and some of these kinases are aberrantly activated in cancer cells. In this review, we discuss our current knowledge of NF-κB activation, with a focus on the NF-κB-activating kinases and their roles in cancer formation.

NF-κB NF-κB activating kinases cancer cell signaling IKK 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Karin M, Delhase M: The I kappa B kinase (IKK) and NF-kappa B: Key elements of proinflammatory signaling. Semin Immunol 12: 85–98, 2000Google Scholar
  2. 2.
    Silverman N, Maniatis T: NF-κB signaling pathways in mammalian and insect innate immunity. Genes & Dev 15: 2321–2342, 2001Google Scholar
  3. 3.
    Fan CM, Maniatis T: Generation of p50 subnit of NF-κB by processing of p105 through an ATP-dependent pathway. Nature 354: 395–398, 1991Google Scholar
  4. 4.
    Baldwin AS Jr: The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14: 649–683, 1996Google Scholar
  5. 5.
    Rice NR, MacKichanML, Israel A: The precursor of NFκB p50 has IκB-like functions. Cell 71: 243–253, 1992Google Scholar
  6. 6.
    Mercurio F, DiDonato JA, Rosette C, Karin M: p105 and p98 precursor proteins play an active role in NF-κB-mediated signal transduction. Genes Dev 7: 705–718, 1993Google Scholar
  7. 7.
    Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K, Siebenlist U: The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-κB-mediated inhibition. Nature 359: 339–342, 1992Google Scholar
  8. 8.
    Wulczyn FG, Naumann M, Scheidereit C: Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-κB. Nature 358: 597–599, 1992Google Scholar
  9. 9.
    Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U: The oncoprotein Bcl-3 directly transactivates through κB motifs via association with DNA-binding p50B homodimers. Cell 72: 729–739, 1993Google Scholar
  10. 10.
    Fujita T, Nolan GP, Liou HC, Scott ML, Baltimore D: The candidate proto-oncogene bcl-3 encodes a transcriptional coactivatorthat activates through NF-kappa B p50 homodimers. Genes & Dev 7: 1354–1363, 1993Google Scholar
  11. 11.
    Whiteside ST, Epinat JC, Rice NR, Israël A: I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity. EMBO J 16: 1413–1426, 1997Google Scholar
  12. 12.
    Solan NJ, Miyoshi H, Carmona EM, Bren GD, Paya CV: RelB cellular regulation and transcriptional activity are regulated by p100. J Biol Chem 277: 1405–1418, 2002Google Scholar
  13. 13.
    Pahl HL: Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18: 6853–6866, 1999Google Scholar
  14. 14.
    Rayet B, Gelinas C: Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18: 6938–6947, 1999Google Scholar
  15. 15.
    Baldwin AS: Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Invest 107: 241–246, 2001Google Scholar
  16. 16.
    Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K, Royer HD, Scheidereit C, Dorken B: High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood 87: 4340–4347, 1996Google Scholar
  17. 17.
    Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C: Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14: 399–402, 2000Google Scholar
  18. 18.
    Sovak MA, B∈llas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM, Sonenshein GE: Aberrant nuclear factor-kappaB/ Rel expression and the pathogenesis of breast cancer. J Clin Invest 100: 2952–2960, 1997Google Scholar
  19. 19.
    Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJJ, Sledge GWJ: Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17: 3629–3639, 1997Google Scholar
  20. 20.
    Lind DS, Hochwald SN, Malaty J, Rekkas S, Hebig P, Mishra G, Moldawer LL, Copeland EMr, Mackay S: Nuclear factor-kappa B is upregulated in colorectal cancer. Surgery 130: 363–369, 2001Google Scholar
  21. 21.
    Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ: Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60: 5334–5339, 2000Google Scholar
  22. 22.
    Palayoor ST, Youmell MY, Calderwood SK, Coleman CN, Price BD: Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18: 7389–7394, 1999Google Scholar
  23. 23.
    Tai DI, Tsai SL, Chang YH, Huang SN, Chen TC, Chang KS, Liaw YF: Constitutive activation of nuclear factor kappaB in hepatocellular car cinoma. Cancer 89: 2274–2281, 2000Google Scholar
  24. 24.
    Meyskens FLJ, Buckmeier JA, McNulty SE, Tohidian NB: Activation of nuclear factor-kappa B in human metastatic melanomacells and the effect of oxidative stress. Clin Cancer Res 5: 1197–1202, 1999Google Scholar
  25. 25.
    Yang J, Richmond A: Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. Cancer Res 61: 4901–4909, 2001Google Scholar
  26. 26.
    Wang C-Y, Mayo MW, Baldwin AS Jr: TNF-and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-κB. Science 274: 784–787, 1996Google Scholar
  27. 27.
    Iwanaga M, Mori K, Iida T, Urata Y, Matsuo T, Yasunaga A, Shibata S, Kondo T: Nuclear factor kappa B dependent induction of gamma glutamylcysteine synthetase by ionizing radiation in T98G human glioblastoma cells. Free Radic Biol Med 24: 1256–1268, 1998Google Scholar
  28. 28.
    Barinaga M: Life-death balance within the cell. Science 274: 724, 1996Google Scholar
  29. 29.
    Kontgen F, Grumont RJ, Strasser A, Metcalf D, Li R, Tarlinton D, Gerondakis S: Mice lacking the c-rel protooncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev 15: 1965–1977, 1995Google Scholar
  30. 30.
    Caamano JH, Rizzo CA, Durham SK, Barton DS, Raventos-Suarez C, Snapper CM, Bravo R: Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med 187: 185–196, 1998Google Scholar
  31. 31.
    Franzoso G, Carlson L, Poljak L, Shores EW, Epstein S, Leonardi A, Grinberg A, Tran T, Scharton-Kersten T, Anver M, Love P, Brown K, Siebenlist U: Mice deficient in nuclear factor(NF)-kapp a B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J Exp Med 187: 147–159, 1998Google Scholar
  32. 32.
    Karin M, B∈n-Neriah Y: Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annu Rev Immunol 18: 621–663, 2000Google Scholar
  33. 33.
    Sun S-C, Ganchi PA, Ballard DW, Greene WC: NF-κB controls expression of inhibitor IκBa: evidence for an inducible autoregulatory pathway. Science 259: 1912–1915, 1993Google Scholar
  34. 34.
    Ling L, Cao Z, Goeddel DV: NF-κB-inducing kinase activates IKK-a by phosphorylation of Ser-176. Proc Natl Acad Sci USA 95: 3792–3797, 1998Google Scholar
  35. 35.
    Delhase M, Hayakawa M, Chen Y, Karin M: Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 284: 309–313, 1999Google Scholar
  36. 36.
    Ghosh S, Karin M: Missing pieces in the NF-κB puzzle. Cell 109: S81-S96, 2002Google Scholar
  37. 37.
    Xiao G, Harhaj EW, Sun SC: NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 7: 401–409, 2001Google Scholar
  38. 38.
    Senftleben U, Cao Y, Xiao G, Kraehn G, Greten F, Chen Y, Hu Y, Fong A, Sun S-C, Karin M: Activation of IKKa of a second, evolutionary conserved, NF-κB signaling pathway. Science 293: 1495–1499, 2001Google Scholar
  39. 39.
    Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M, Sun SC: Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: Evidence forthe involvement of IKKa. EMBO J 20: 6805–6815, 2001Google Scholar
  40. 40.
    Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR: Distinct roles of the IκB kinase a and ß subunits in liberating nuclear factor kappa B (NF-κB) from IκB and in phosphorylating the p65 subunit of NF-κB. J Biol Chem 277: 3863–3869, 2002Google Scholar
  41. 41.
    Davis M, Hatzubai A, Andersen JS, Bβn-Shushan E, Fisher GZ, Yaron A, Bauskin A, Mercurio F, Mann M, Bβ-Neriah Y: Pseudosubstrate regulation of the SCF(ß-TrCP) ubiquitin ligase by hnRNP-U. Genes Dev 16: 439–451, 2002Google Scholar
  42. 42.
    Johnson C, Van Antwerp D, Hope TJ: An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBa. EMBO J 18: 6682–6693, 1999Google Scholar
  43. 43.
    Rodriguez MS, Thompson J, Hay RT, Dargemont C: Nuclear retention of IκBa protects it from signal-induced degradation and inhibits nuclear factor κB transcriptional activation. J Biol Chem 274: 9108–9115, 1999Google Scholar
  44. 44.
    Huang TT, Kudo N, Yoshida M, Miyamoto S: A nuclear export signal in the N-terminal regulatory domain of IκBa controls cytoplasmic localization of inactive NF-κB/IκBa complexes. Proc Natl Acad Sci USA 97: 1014–1019, 2000Google Scholar
  45. 45.
    Tam WF, Lee LH, Davis L, Sen R: Cytoplasmic sequestration of rel proteins by IκBa requires CRM1-dependent nuclear expor t. Mol Cell Biol 20: 2269–2284, 2000Google Scholar
  46. 46.
    Thompson JE, Phillips RJ, Erdjument-Bromage H, Tempst P, Ghosh S: IκB-ß regulates the persistent response in a biphasic activation of NF-κB. Cell 80: 573–582, 1995Google Scholar
  47. 47.
    Harhaj EW, Maggirwar SB, Good L, Sun S-C: CD28 mediates a potent costimulatory signal for rapid degradation of IκBß which is associated with accelerated activation of various NF-κB/Rel heterodimers. Mol Cell Biol 16: 6736–6743, 1996Google Scholar
  48. 48.
    Harhaj EW, Maggirwar SB, Sun S-C: Inhibition of p105 processing by NF-κB proteins in transiently transfected cells. Oncogene 12: 2385–2392, 1996Google Scholar
  49. 49.
    Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C: NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes. EMBO J 18: 4766–4778, 1999Google Scholar
  50. 50.
    Harhaj EW, Sun S-C: IκB kinases serve as a target of CD28 signaling. J Biol Chem 273: 25185–25190, 1998Google Scholar
  51. 51.
    Orian A, Gonen H, BErcovich B, Fajerman I, Eytan E, Israel A, Mercurio F, Iwai K, Schwartz AL, Ciechanover A: SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its Cterminus by IkappaB kinase. EMBO J 19: 2580–2591, 2000Google Scholar
  52. 52.
    Dejardin E, Droin NM, Delhase M, Haas E, Cao Y, Makris C, Li ZW, Karin M, Ware CF, Green DR: The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 17: 525–535, 2002Google Scholar
  53. 53.
    Claudio E, Brown K, Park S, Wang H, Siebenlist U: BAFF-induced NEMO-independent processing of NFkappaB2 in maturing B cells. Nat Immunol 3: 958–965, 2002Google Scholar
  54. 54.
    Kayagaki N, Yan M, Seshasayee D, Wang H, Lee W, French DM, Grewal IS, Cochran AG, Gordon NC, Yin J, StarovasnikMA, Dixit VM: BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. Immunity 17: 515–524, 2002Google Scholar
  55. 55.
    Coope HJ, Atkinson PG, Huhse B, B∈lich M, Janzen J, Holman MJ, Klaus GG, Johnston LH, Ley SC: CD40 regulates the processing of NF-kappaB2 p100 to p52. EMBO J 15: 5375–5385, 2002Google Scholar
  56. 56.
    Naumann M, Scheidereit C: Activation of NF-κB in vivo is regulated by multiple phosphorylations. EMBO J 13: 4597–4607, 1994Google Scholar
  57. 57.
    Zhong H, Voll RE, Ghosh S: Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell 1: 661–671, 1998Google Scholar
  58. 58.
    Wang D, Baldwin ASJ: Activation of nuclear factor-kappaB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. J Biol Chem 273: 29411–29416, 1998Google Scholar
  59. 59.
    Martin AG, Fresno M: Tumor necrosis factor-a activation of NF-κB requires the phosphorylation of Ser-471 in the transactivation domain of c-Rel. J Biol Chem 275: 24383–24391, 2000Google Scholar
  60. 60.
    Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S: The transcriptional activity of NF-κB is regulated by the IκB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 89: 413–424, 1997Google Scholar
  61. 61.
    Norris JL, Baldwin AJ: Oncogenic Ras enhances NF-kappaB transcriptional activity through Raf-dependent and Raf-independent mitogen-activated protein kinase signaling pathways. J Biol Chem 274: 13841–13846, 1999Google Scholar
  62. 62.
    Wang D, Westerheide SD, Hanson JL, Baldwin AS Jr: Tumor necrosis factor a-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem 275: 32592–32597, 2000Google Scholar
  63. 63.
    Anrather J, Csizmadia V, Soares MP, Winkler H: Regulation of NF-kappaB RelA phosphorylation and transcriptional activity by p21(ras) and protein kinase Czeta in primary endothelial cells. J Biol Chem 274: 13594–13603, 1999Google Scholar
  64. 64.
    Leitges M, Sanz L, Martin P, Duran A, Braun U, Garcia JF, Camaccho F, Diaz-Meco MT, Rennert PD, Moscat J: Targeted disruption of the ?PKC gene results in the impairment of the NF-κB pathway. Mol Cell 8: 771–780, 2001Google Scholar
  65. 65.
    Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W: IκB kinases phosphorylate NF-κB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 274: 30353–30356, 1999Google Scholar
  66. 66.
    Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR: Requirement for glycogen synthase kinase-3beta in cell survival and NF-κB activation. Nature 406: 86–90, 2000Google Scholar
  67. 67.
    Bonnard M, Mirtsos C, Suzuki S, Graham K, Juang J, Ng M, Itie A, Wakeham A, Shahinian A, Henzel WJ: Deficiency of T2K leads to apoptotic liverdegener ation and impaired NF-κB-dependent gene transcription. EMBO J 19: 4976–4985, 2000Google Scholar
  68. 68.
    Yin L, Wu L, Wesche H, Arthur CD, White JM, Goeddel DV, Schreiber RD: Defective lymphotoxin-beta receptorinduced NF-kappaB transcriptional activity in NIK-deficient mice. Science 291: 2162–2165, 2001Google Scholar
  69. 69.
    Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS Jr: Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-κB. Mol Cell Biol 20: 1626–1638, 2000Google Scholar
  70. 70.
    Sizemore N, Leung S, Stark GR: Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit. Mol Cell Biol 19: 4798–4805, 1999Google Scholar
  71. 71.
    Madrid LV, Mayo MW, Reuther JY, Baldwin AS Jr: Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 276: 18934–18940, 2001Google Scholar
  72. 72.
    Lee FS, HaglerJ, Chen ZJ, Maniatis T: Activation of the IκBa kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88: 213–222, 1997Google Scholar
  73. 73.
    Malinin NL, Boldin MP, Kovalenko AV, Wallach D: MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature 385: 540–544, 1997Google Scholar
  74. 74.
    B∈lich MP, Salmeron A, Johnston LH, Ley SC: TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. Nature 397: 363–368, 1999Google Scholar
  75. 75.
    Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC: The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-κB acting through the NF-κB-inducing kinase and IκB kinases. Immunity 10: 271–280, 1999Google Scholar
  76. 76.
    Yang J, Lin Y, Guo Z, Cheng J, Huang J, Deng L, Liao W, Chen Z, Liu Z, Su B: The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat Immunol 2: 620–624, 2001Google Scholar
  77. 77.
    Lallena M-J, Diaz-Meco MT, Bren G, Paya CV, Moscat J: Activation of IκB kinase b by protein kinase C isoforms. Mol Cell Biol 19: 2180–2188, 1999Google Scholar
  78. 78.
    Coudronniere N, Villalba M, Englund N, Altman A: NFkappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta. Proc Natl Acad Sci USA 97: 3394–3399, 2000Google Scholar
  79. 79.
    Lin X, O'Mahony A, Mu Y, Geleziunas R, Greene WC: Protein kinase C-theta participates in NF-kappaB activation induced by CD3-CD28 costimulation through selective activation of IkappaB kinase beta. Mol Cell Biol 20: 933–2940, 2000Google Scholar
  80. 80.
    Khoshnan A, Bae D, Tindell CA, Nel AE: The physical association of protein kinase C with a lipid raft-associated inhibitor of kappa B factor kinase (IKK) complex plays a role in the activation of the NF-kappa B cascade by TCR and CD28. J Immunol 165: 6933–6940, 2000Google Scholar
  81. 81.
    Saijo K, Mecklenbrauker I, Santana A, Leitger M, Schmedt C, Tarakhovsky A: Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha. J Exp Med 195: 1647–1652, 2002Google Scholar
  82. 82.
    Krappmann D, Patke A, Heissmeyer V, Scheidereit C: Bcell receptor-and phorbol ester-induced NF-kappaB and c-Jun N-terminal kinase activation in B cells requires novel protein kinase C's. Mol Cell Biol 21: 6640–6650, 2001Google Scholar
  83. 83.
    Castrillo A, Pennington DJ, Otto F, Parker PJ, Owen MJ, Bosca L: Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection. J Exp Med 194: 1231–1242, 2001Google Scholar
  84. 84.
    Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, Annes J, Petrzilka D, Kupfer A, Schwartzberg PL, Littman DR: PKC-? is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404: 402–407, 2000Google Scholar
  85. 85.
    Su TT, Guo B, Kawakami Y, SommerK, Chae K, Humphries LA, Kato RM, Kang S, Patrone L, Wall R, Teitell M, Leitges M, Kawakami T, Rawlings DJ: PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol 3: 780–786, 2002Google Scholar
  86. 86.
    Ruland J, Duncan GS, Elia A, del Barco Barrantes I, Nguyen L, Plyte S, Millar DG, Bouchard D, Wakeham A, Ohashi PS, Mak TW: Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. Cell 104: 33–42, 2001Google Scholar
  87. 87.
    Gaide O, Martinon F, Micheau O, Bonnet D, Thome M, Tschopp J: Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation. FEBS Lett 496: 121–127, 2001Google Scholar
  88. 88.
    McAllister-Lucas LM, Inohara N, Lucas PC, Ruland J, B∈nito A, Li Q, Chen S, Chen FF, Yamaoka S, Verma IM, Mak TW, Nunez G: Bimp1, a MAGUK family memberlinking protein kinase C activation to Bcl10-mediated NF-kappaB induction. J Biol Chem 276: 30589–30597, 2001Google Scholar
  89. 89.
    Gaide O, Favier B, Legler DF, Bonnet D, Brissoni B, Valitutti S, Bron C, Tschopp J, Thome M: CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation. Nat Immunol 3: 836–843, 2002Google Scholar
  90. 90.
    Wang D, You Y, Case SM, McAllister-Lucas LM, Wang L, DiStefano PS, Nunez G, BErtin J, Lin X: A requirement for CARMA1 in TCR-induced NF-kappa B activation. Nat Immunol 3: 830–835, 2002Google Scholar
  91. 91.
    B∈rtin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, Merriam S, Du MQ, Dyer MJ, Robison KE, DiStefano PS, Alnemri ES: CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B. J Biol Chem 275: 41082–41086, 2000Google Scholar
  92. 92.
    B∈rtin J, Wang L, Guo Y, Jacobson MD, Poyet JL, Srinivasula SM, Merriam S, DiStefano PS, Alnemri ES: CARD11 and CARD14 are novel caspase recruitment domain (CARD)/ membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B. J Biol Chem 276: 11877–11882, 2001Google Scholar
  93. 93.
    Arch RH, Gedrich RW, Thompson CB: Tumor necrosis factor receptor-associated factors (TRAFs)-a family of adaptor proteins that regulates life and death. Genes & Dev 12: 2821–2830, 1998Google Scholar
  94. 94.
    Wajant H, Henkler F, Scheurich P: The TNF-receptor-associated factor-family: Scaffold molecules for cytokine receptors, kinases and their regulators. Cell Signal 13: 389–400, 2002Google Scholar
  95. 95.
    Baud V, Liu ZG, B?nnett B, Suzuki N, Xia Y, Karin M: Signaling by proinflammatory cytokines: Oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an aminoterminal effector domain. Genes & Dev 13: 1297–1308, 1999Google Scholar
  96. 96.
    Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW: TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40 and LPS signaling. Genes & Dev 13: 1015–1024, 1999Google Scholar
  97. 97.
    Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J: Severe osteopetrosis, defective interleukin-1 signaling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4: 353–362, 1999Google Scholar
  98. 98.
    Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ: Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiqutitinconjugating enzyme complex and a unique polyubiquitin chain. Cell 103: 351–361, 2000Google Scholar
  99. 99.
    Wang C, Deng L, Hong M, Akkaraju GR, Inoue J-I, Chen ZJ: TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412: 346–351, 2001Google Scholar
  100. 100.
    Horie R, Watanabe T, Ito K, Morisita Y, Watanabe M, Ishida T, Higashihara M, Kadin M, Watanabe T: Cytoplasmic aggregation of TRAF2 and TRAF5 proteins in the Hodgkin-Reed-Sternberg cells. Am J Pathol 160: 1647–1654, 2002Google Scholar
  101. 101.
    Cahir McFarland ED, Izumi KM, Mosialos G: Epsteinbarr virus transformation: Involvement of latent membrane protein 1-mediated activation of NF-kappaB. Oncogene 18: 6959–6964, 1999Google Scholar
  102. 102.
    Gilmore TD: Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel. Oncogene 18: 6925–6937, 1999Google Scholar
  103. 103.
    Carrasco D, Rizzo CA, Dorfman D, Brave R: The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice. EMBO J 15: 3640–3650, 1996Google Scholar
  104. 104.
    Gilmore TD, Cormier C, Jean-Jacques J, Gapuzan ME: Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel. Oncogene 20: 7098–7103, 2001Google Scholar
  105. 105.
    Staudt LM: The molecular and cellular or igins of Hodgkin's disease. J Exp Med 191: 207–212, 2000Google Scholar
  106. 106.
    Wood KM, Roff M, Hay RT: Defective IkappaBalpha in Hodgkin cell lines with constitutively active NF-kappaB. Oncogene 16: 2131–2139, 1998Google Scholar
  107. 107.
    Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT: Mutations in the IκBa gene in Hodgkin's disease suggest a tumor suppressor role for IkappaBalpha. Oncogene 18: 3063–3070, 1999Google Scholar
  108. 108.
    Emmerich F, Meiser M, Hummel M, Demel G, Foss HD, Jundt F, Mathas S, Krappmann D, Scheidereit C, Stein H, Dorken B: Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells. Blood 94: 3129–3134, 1999Google Scholar
  109. 109.
    Jungnickel B, Staratschek-Jox A, Brauninger A, Spieker T, Wolf J, Diehl V, HansmannML, Rajewsky K, Kuppers R: Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med 191: 395–402, 1999Google Scholar
  110. 110.
    Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C, Dorken B: Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest 100: 2961–2969, 1997Google Scholar
  111. 111.
    Ishikawa H, Claudio E, Dambach D, Raventos-Suarez C, Ryan C, Bravo R: Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor (NF-κB1) but expressing p50. J Exp Med 187: 985–996, 1998Google Scholar
  112. 112.
    Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin JAS: Selective activation of NF-kappa B subunits in human breast cancer: Potential roles for NF-kappa B2/ p52 and forBcl-3. Oncogene 19: 1123–1131, 2000Google Scholar
  113. 113.
    Wang Y, Cui H, Schroering A, Ding JL, Lane WS, McGill G, FisherDE, Ding H-F: NF-κB2 p100 is a pro-apoptotic protein with anti-oncogenic function. Nature Cell Biol in press:, 2002Google Scholar
  114. 114.
    McKeithan TW, Takimoto GS, Ohno H, Bjorling VS, Morgan R, Hecht BK, Dube I, Sandberg AA, Rowley JD: BCL3 rearrangements and t(14:19) in chronic lymphocytic leukemia and otherB-cell malignancies: A molecular and cytogenetic study. Genes Chromosomes Cancer 20: 64–72, 1997Google Scholar
  115. 115.
    Ong ST, Hackbarth ML, Degenstein LC, Baunoch DA, Anastasi J, McKeithan TW: Lymphadenopathy, splenomegaly, and altered immunoglobulin production in BCL3 transgenic mice. Oncogene 16: 2333–2343, 1998Google Scholar
  116. 116.
    Shet AS, Jahagirdar BN, Verfaillie CM: Chronic myelogenous leukemia: Mechanisms underlying disease progression. Leukemia 16: 1402–1411, 2002Google Scholar
  117. 117.
    Kurzrock R, Gutterman JU, Talpaz M: The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med 319: 990–998, 1988Google Scholar
  118. 118.
    Hamdane M, David-Cordonnier MH, D'Halluin JC: Activation of p65 NF-kappaB protein by p210BCR-ABL in a myeloid cell line (P210BCR-ABL activates p65 NF-kappaB). Oncogene 15: 2267–2275, 1997Google Scholar
  119. 119.
    Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin ASJ: A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev 12: 968–981, 1998Google Scholar
  120. 120.
    Korus M, Mahon GM, Cheng L, Whitehead IP: p38 MAPK-mediated activation of NF-kappaB by the Rho-GEF domain of Bcr. Oncogene 21: 4601–4612, 2002Google Scholar
  121. 121.
    Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M, Price H, Karran L, Majekodunmi O, Wlodarska I, Pan L, Crook T, Hamoudi R, Isaacson PG, DyerMJ: Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumortypes. Cell 96: 35–45, 1999Google Scholar
  122. 122.
    Zhang Q, Siebert R, Yan M, Hinzmann B, Cui X, Xue L, Rakestraw KM, Naeve CW, B∈ckmann G, Weisenburger DD, Sanger WG, Nowotny H, Vesely M, Callet-Bauchu E, Salles G, Dixit VM, Rosenthal A, Schlegelberger B, Morris SW: Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 22: 63–68, 1999Google Scholar
  123. 123.
    Costanzo A, Guiet C, Vito P: c-E10 is a caspase-recruiting domain-containing protein that interacts with components of death receptors signaling pathway and activates nuclear factor-kappaB. J Biol Chem 274: 20127–20132, 1999Google Scholar
  124. 124.
    Koseki T, Inohara N, Chen S, Carrio R, Merino J, Hottiger MO, Nabel GJ, Nunez G: CIPER, a novel NF kappaB-activating protein containing a caspase recruitment domain with homology to Herpesvirus-2 protein E10. J Biol Chem 274: 9955–9961, 1999Google Scholar
  125. 125.
    Srinivasula SM, Ahmad M, Lin JH, Poyet JL, Fernandes-Alnemri T, Tsichlis PN, Alnemri ES: CLAP, a novel caspase recruitment domain-containing protein in the tumor necrosis factor receptor pathway, regulates NFkappaB activation and apoptosis. J Biol Chem 274: 17946–17954, 1999Google Scholar
  126. 126.
    Thome M, Martinon F, Hofmann K, Rubio V, Steiner V, SchneiderP, Mattmann C, Tschopp J: Equine herpesvirus-2 E10 gene product, but not its cellular homologue, activates NF-kappaB transcription factor and c-Jun N-terminal kinase. J Biol Chem 274: 9962–9968, 1999Google Scholar
  127. 127.
    Yan M, Lee J, Schilbach S, Goddard A, Dixit V: mE10, a novel caspase recruitment domain-containing proapoptotic molecule. J Biol Chem 274: 10287–10292, 1999Google Scholar
  128. 128.
    Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H, Ota H, Nakamura S, Morishima Y, Taniwaki M, Seto M: A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 18: 5785–5794, 1999Google Scholar
  129. 129.
    Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, HagemeijerA, Van den B∈rghe H, Marynen P: The apoptosis inhibitorgene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21)p6ssociated with mucosa-associated lymphoid tissue lymphomas. Blood 93: 3601–3609, 1999Google Scholar
  130. 130.
    Morgan JA, Yin Y, Borowsky AD, Kuo F, Nourmand N, Koontz JI, Reynolds C, Soreng L, Griffin CA, Graeme-Cook F, Harris NL, Weisenburger D, Pinkus GS, Fletcher JA, Sklar J: Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res 59: 6205–6213, 1999Google Scholar
  131. 131.
    Uren AG, O'Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV, Dixit VM: Identification of paracaspases and metacaspases: Two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol Cell 6: 961–967, 2000Google Scholar
  132. 132.
    Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed ME, Chen FF, Yamaoka S, Seto M, Nunez G: Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem 276: 19012–19019, 2001Google Scholar
  133. 133.
    Bos JL: ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689, 1989Google Scholar
  134. 134.
    Ellis CA, Clark G: The importance of being K-Ras. Cell Signal 12: 425–434, 2000Google Scholar
  135. 135.
    Finco TS, Westwick JK, Norris JL, Bβg AA, Der CJ, Baldwin AJ: Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J Biol Chem 272: 24113–24116, 1997Google Scholar
  136. 136.
    Arsura M, Mercurio F, Oliver AL, Thorgeirsson SS, Sonenshein GE: Role of the IkappaB kinase complex in oncogenic Ras-and Raf-mediated transformation of rat liverepithelial cells. Mol Cell Biol 20: 5381–5391, 2000Google Scholar
  137. 137.
    Wang D, Richmond A: Nuclearfactor-kappa B activation by the CXC chemokine melanoma growth-stimulatory activity/growth-regulated protein involves the MEKK1/ p38 mitogen-activated protein kinase pathway. J Biol Chem 276: 3650–3659, 2001Google Scholar
  138. 138.
    Kim BY, Gaynor RB, Song K, Dritschilo A, Jung M: Constitutive activation of NF-kappaB in Ki-ras-transformed prostate epithelial cells. Oncogene 21: 4490–4497, 2002Google Scholar
  139. 139.
    Mayo MW, Wang C-Y, Cogswell PC, Rogers-Graham KS, Lowe SW, Der CJ, Bαldwin Jr. AS: Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278: 1812–1815, 1997Google Scholar
  140. 140.
    Sun S-C, Ballard DW: Persistent activation of NF-κB by the Tax transforming protein of HTLV-1: hijacking cellular IκB kinases. Oncogene 18: 6948–6958, 1999Google Scholar
  141. 141.
    Hiscott J, Kwon H, Genin P: Hostile takeovers: Viral appropriation of the NF-kappaB pathway. J Clin Invest 107: 143–151, 2001Google Scholar
  142. 142.
    Poiesz BF, Ruscetti FW, GazdarAF, Bunn PA, Minna JD, Gallo RC: Detection and isolation of a type C retrovirus particles from fresh cultured lymphocytes of a pateint with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 77: 7415–7419, 1980Google Scholar
  143. 143.
    Yoshida M, Miyoshi I, Hinuma Y: Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci USA 79: 2031–2035, 1982Google Scholar
  144. 144.
    Geleziunas R, Ferrell S, Lin X, Mu Y, Cunningham ET Jr, Grant M, Connelly MA, Hambor JE, Marcu KB, Greene WC: Human T-cell leukemia virus type 1 Tax induction of NF-κB involves activation of the IκB kinase a (IKKa) and IKKß cellularkinases. Mol Cell Biol 18: 5157–5165, 1998Google Scholar
  145. 145.
    Uhlik M, Good L, Xiao G, Harhaj EW, Zandi E, Karin M, Sun S-C: NF-kappaB-inducing kinase and IkappaB kinase participate in human T-cell leukemia virus I Taxmediated NF-kappaB activation. J Biol Chem 273: 21132–21136, 1998Google Scholar
  146. 146.
    Yin M-J, Christerson LB, Yamamoto Y, Kwak Y-T, Xu S, Mercurio F, Barbose M, Cobb MH, Gaynor RB: HTLV-I Tax protein binds to MEKK1 to stimulate IκB kinase activity and NF-κB activation. Cell 93: 875–884, 1998Google Scholar
  147. 147.
    Yamaoka S, Courtois G, Bβssia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, Israel A: Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93: 1231–1240, 1998Google Scholar
  148. 148.
    Harhaj EW, Good L, Xiao G-T, Uhlik M, Cvijic ME, Rivera I, Sun S-C: Somatic mutagenesis studies of NF-kappa B signaling in human T cells: Evidence for an essential role of IKK gamma in NF-kappa B activation by T-cell costimulatory signals and HTLV-I Tax protein. Oncogene 19: 1386–1391, 2000Google Scholar
  149. 149.
    Chu Z-L, Shin Y-A, Yang J-M, DiDonato JA, Ballard DW: IKK? mediates the interaction of cellular IκB kinases with the Tax transforming protein of human T cell leukemia virus type 1. J Biol Chem 274: 15297–15300, 1999Google Scholar
  150. 150.
    Harhaj EW, Sun S-C: IKK? serves as a docking subunit of the IκB kinase and mediates interaction of IKK with the human T-cell leukemia virus Tax protein. J Biol Chem 274: 22911–22914, 1999Google Scholar
  151. 151.
    Jin D-Y, Giordano V, Kibler KV, Nakano H, Jeang K-T: Role of adaptorfunction in oncoprotein-mediated activation of NF-κB: HTLV-I Tax interacts directly with IκB kinase ?. J Biol Chem 274: 17402–17405, 1999Google Scholar
  152. 152.
    Xiao G, Harhaj EW, Sun S-C: Domain-specific interaction with IKK? is an essential step in Tax-mediated activation of IKK. J Biol Chem 275: 34060–34067, 2000Google Scholar
  153. 153.
    Xiao G, Sun SC: Activation of IKKalpha and IKKbeta through their fusion with HTLV-I tax protein. Oncogene 19: 5198–5203, 2000Google Scholar
  154. 154.
    Jin DY, Jeang KT: HTLV-I Tax self-association in optimal trans-activation function. Nucl Acids Res 25: 379–387, 1997Google Scholar
  155. 155.
    Kieff E: Epstein-Barr virus—increasing evidence of a link to carcinoma. N Engl J Med 333: 724–726, 1995Google Scholar
  156. 156.
    Rickinson AB, Kieff E Epstein-Barr Virus. In: KDHP Fields BN, eds. Virology, pp. 2397–2446. New York: Raven Press, 1996.Google Scholar
  157. 157.
    Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E, Rickinson A: Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programe cell death. Cell 65: 1107–1115, 1991Google Scholar
  158. 158.
    Laherty CD, Hu HM, Opipari AW, Wang F, Dixit VM: The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. J Biol Chem 267: 24157–24160, 1992Google Scholar
  159. 159.
    Wang S, Rowe M, Lundgren E: Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. CancerRes 56: 4610–4613, 1996Google Scholar
  160. 160.
    D'souza B, Rowe M, Walls D: The bfl-1 gene is transcriptionally upregulated by the Epstein-Barr virus LMP1, and its expression promotes the survival of a Burkitt's lymphoma cell line. J Virol 74: 6652–6658, 2000Google Scholar
  161. 161.
    Devergne O, Hatzivassiliou E, Izumi KM, Kaye KM, Kleijnen MF, Kieff E, Mosialos G: Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: Role in NF-kappaB activation. Mol Cell Biol 16: 7098–7108, 1996Google Scholar
  162. 162.
    Mosialos G, Birkenbach M, Yalamanchili R, Van Arsdale T, Ware C, Kieff E: The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80: 389–399, 1995Google Scholar
  163. 163.
    Devergne O, Cahir McFarland ED, Mosialos G, Izumi KM, Ware CF, Kieff E: Role of the TRAF binding site and NF-kappaB activation in Epstein-Barr virus latent membrane protein 1-induced cell gene expression. J Virol 72: 7900–7908, 1998Google Scholar
  164. 164.
    Schultheiss U, Puschner S, Kremmer E, Mak TW, Engelmann H, Hammerschmidt W, Kieser A: TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1. EMBO J 20: 5678–5691, 2001Google Scholar
  165. 165.
    He Z, Xin B, Yang X, Chan C, Cao L: Nuclearfactor-κB activation is involved in LMP1-mediated transformation and tumorigenesis of rat-1 fibroblasts. Cancer Res 60: 1845–1848, 2000Google Scholar
  166. 166.
    Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J, Kieff E: NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci USA 97: 6055–6060, 2000Google Scholar
  167. 167.
    Feuillard J, Schuhmacher M, Kohanna S, Asso-Bonnet M, Ledeur F, Joubert-Caron R, Bissieres P, Polack A, Bornkamm GW, Raphael M: Inducible loss of NF-κB activity is associated with apoptosis and Bcl-2 downregulation in Epstein-Barr virus-transformed B lymphocytes. Blood 95: 2068–2075, 2000Google Scholar
  168. 168.
    B∈asley RP, Lin CC, Hwang LY, Chien CS: Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan. Lancet 2: 1129–1133, 1981Google Scholar
  169. 169.
    Diao J, Garces R, Richardson CD: X protein of heptitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 12: 189–205, 2001Google Scholar
  170. 170.
    Kekulé AS, Lauer U, Weiss L, Luber B, Hofschneider PH: Hepatitis B virus transactivator HBx uses a tumor promoter signaling pathway. Nature 361: 742–745, 1993Google Scholar
  171. 171.
    Wei R, Sirma H, Giannini C, Kremsdoft D, B∈ssia C, Dargemont C, Brechot C, Israel A: Direct association and nuclear import of the hepatitis B virus X protein with the NF-κB inhibitorI κBa. Mol Cell Biol 19: 6345–6354, 1999Google Scholar
  172. 172.
    Meyer M, Caselmann WH, Schluter V, Schreck R, Hofschneider PH, Baeuerle PA: Hepatitis B virus transactivator MHBst: Activation of NF-κB, selective inhibition by antioxidants and integral membrane localization. EMBO J 11: 2991–3001, 1992Google Scholar
  173. 173.
    Kekule AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R: The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 343: 457–461, 1990Google Scholar
  174. 174.
    Hildt E, Saher G, Bruss V, Hofschneider PH: The hepatitis B virus large surface protein (LHBs) is a transcriptional activator. Virology 225: 235–239, 1996Google Scholar
  175. 175.
    Hildt E, Munz B, Saher G, Reifenberg K, Hofschneider PH: The PreS2 activator MHBs(t) of hepatitis B virus activates c-raf-1/Erk2 signaling in transgenic mice. EMBO J 21: 525–535, 2002Google Scholar
  176. 176.
    Dhawan P, Richmond A: A novel NF-κB-inducing kinase-MAPK signaling pathway up-regulates NF-κB activity in melanoma cells. J Biol Chem 277: 7920–7928, 2002Google Scholar
  177. 177.
    Sourvinos G, Tsatsanis C, Spandidos DA: Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Oncogene 18: 4968–4973, 1999Google Scholar
  178. 178.
    Miyoshi J, Higashi T, Mukai H, Ohuchi T, Kakunaga T: Structure and transforming potential of the human cot oncogene encoding a putative protein kinase. Mol Cell Biol 11: 4088–4096, 1991Google Scholar
  179. 179.
    Patriotis C, Makris A, Bβar SE, Tsichlis PN: Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progress of rodent T-cell lymphomas and in T-cell activation. Proc Natl Acad Sci USA 90: 2251–2255, 1993Google Scholar
  180. 180.
    Makris A, Patriotis C, Bβar SE, Tsichlis PN: Genomic organization and expression of Tpl-2 in normal cells and Moloney murine leukemia virus-induced rat T-cell lymphomas: Activation by provirus insertion. J Virol 67: 4283–4289, 1993Google Scholar
  181. 181.
    Ceci JD, Patriotis CP, Tsatsanis C, Makris AM, Kovatch R, Swing DA, Jenkins NA, Tsichlis PN, Copeland NG: Tpl-2 is an oncogenic kinase that is activated by carboxyterminal trunction. Genes Dev 11: 688–700, 1997Google Scholar
  182. 182.
    Pianetti S, Arsura M, Romieu-Mourez R, Coffey RJ, Sonenshein GE: Her-2/neu overexpression induces NFkappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumorsuppr essorPTEN. Oncogene 20: 1287–1299, 2001Google Scholar
  183. 183.
    Vale T, Ngo TT, White MA, Lipsky PE: Raf-induced transformation requires an interleukin 1 autocrine loop. Cancer Res 61: 602–607, 2001Google Scholar
  184. 184.
    Arlt A, Vorndamm J, Muerkoster S, Yu H, Schmidt WE, Folsch UR, Schafer H: Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. Cancer Res 62: 910–916, 2002Google Scholar
  185. 185.
    Skinnider BF, Kapp U, Mak TW: Interleukin 13: a growth factor in hodgkin lymphoma. Int Arch Allergy Immunol 126: 267–276, 2001Google Scholar
  186. 186.
    Skinnider BF, Kapp U, Mak TW: The role of interleukin 13 in classical Hodgkin lymphoma. Leuk Lymphoma 43: 1203–1210, 2002Google Scholar
  187. 187.
    Hagemann C, Blank JL: The ups and downs of MEK kinase interactions. Cell Signal 13: 863–875, 2001Google Scholar
  188. 188.
    Pomerantz JL, Baltimore D: NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J 18: 6694–6704, 1999Google Scholar
  189. 189.
    Hehner SP, Hofmann TG, Ushmorov A, Dienz O, Wing-Lan Leung I, Lassam N, Scheidereit C, Droge W, Schmitz ML: Mixed-lineage kinase 3 delivers CD3/CD28-derived signals into the IkappaB kinase complex. Mol Cell Biol 20: 2556–2568, 2000Google Scholar
  190. 190.
    Baumann B, Weber CK, Troppmair J, Whiteside S, Israel A, Rapp UR, Wirth T: Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proc Natl Acad Sci USA 97: 4615–4620, 2000Google Scholar
  191. 191.
    Hsu H, Shu HB, Pan MG, Goeddel DV: TRADDTRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84: 299–308, 1996Google Scholar
  192. 192.
    Hu WH, Johnson H, Shu HB: Activation of NF-kappaB by FADD, Casper, and caspase-8. J Biol Chem 275: 10838–10844, 2000Google Scholar
  193. 193.
    Hsu H, Huang J, Shu HB, Bαichwal V, Goeddel DV: TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4: 387–396, 1996Google Scholar
  194. 194.
    McCarthy JV, Ni J, Dixit VM: RIP2 is a novel NFkappaB-activating and cell death-inducing kinase. J Biol Chem 273: 16968–16975, 1998Google Scholar
  195. 195.
    Yu PW, Huang BC, Shen M, Quast J, Chan E, Xu X, Nolan GP, Payan DG, Luo Y: Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB. Curr Biol 9: 539–542, 1999Google Scholar
  196. 196.
    Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L: Activation of the NF-kappaB pathway by caspase 8 and its homologs. Oncogene 19: 4451–4460, 2000Google Scholar
  197. 197.
    Muzio M, Ni J, Feng P, Dixit VM: IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1signaling. Science 278: 1612–1615, 1997Google Scholar
  198. 198.
    Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer JL, Di Marco F, French L, Tschopp J: MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 273: 12203–12209, 1998Google Scholar
  199. 199.
    Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA: Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413: 78–83, 2001Google Scholar
  200. 200.
    Horng T, Barton GM, Medzhitov R: TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2: 835–841, 2001Google Scholar
  201. 201.
    Cao Z, Henzel WJ, Gao X: IRAK: a kinase associated with the interleukin-1 receptor. Science 271: 1128–1131, 1996Google Scholar
  202. 202.
    Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z: IRAK-M is a novel memberof the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem 274: 19403–19410, 1999Google Scholar
  203. 203.
    Li S, Strelow A, Fontana EJ, Wesche H: IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA 99: 5567–5572, 2002Google Scholar
  204. 204.
    Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, Carrio R, Merino J, Liu D, Ni J, Nunez G: Nod1, an Apaf-1-like activatorof caspase-9 and nuclear factorkappaB. J Biol Chem 274: 14560–14567, 1999Google Scholar
  205. 205.
    Ogura Y, Inohara N, Bβnito A, Chen FF, Yamaoka S, Nunez G: Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276: 4812–4818, 2001Google Scholar
  206. 206.
    Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, DonnerDB: NF-kappaB activation by tumor necrosis factor requires the Akt serine-threonine kinase. Nature 401: 82–85, 1999Google Scholar
  207. 207.
    Romashkova JA, Makarov SS: NF-kappaB is a target of AKT in anti-apoptotic PDGF signaling. Nature 401: 86–90, 1999Google Scholar
  208. 208.
    Perona R, Montaner S, Saniger L, Sanchez-Perez I, Bravo R, Lacal JC: Activation of the nuclearfactor-kappaB by Rho, CDC42, and Rac-1 proteins. Genes Dev 11: 463–475, 1997Google Scholar
  209. 209.
    D'Acquisto F, Ghosh S: PACT and PKR: turning on NFkappa B in the absence of virus. Sci STKE 89: RE1, 2001Google Scholar
  210. 210.
    Li X, Commane M, Nie H, Hua X, Chatterjee-Kishore M, Wald D, Haag M, Stark GR: Act1, an NF-kappa B-activating protein. Proc Natl Acad Sci USA 97: 10489–10493, 2000Google Scholar
  211. 211.
    Leonardi A, Chariot A, Claudio E, Cunningham K, Siebenlist U: CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Proc Natl Acad Sci USA 97: 10494–10499, 2000Google Scholar
  212. 212.
    Foryst-Ludwig A, Naumann M: p21-activated kinase 1 activates the nuclearfactorkappa B (NF-kappa B)-inducing kinase-Ikappa B kinases NF-kappa B pathway and proinflammatory cytokines in Helicobacter pylori infection. J Biol Chem 275: 39779–39785, 2000Google Scholar
  213. 213.
    Frost JA, Swantek JL, Stippec S, Yin MJ, Gaynor R, Cobb MH: Stimulation of NFkappa B activity by multiple signaling pathways requires PAK1. J Biol Chem 275: 19693–19699, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyPennsylvania State University College of MedicineHersheyUSA

Personalised recommendations