Advertisement

Journal of Molecular Medicine

, Volume 85, Issue 11, pp 1187–1202 | Cite as

Many faces of NF-κB signaling induced by genotoxic stress

  • Zhao-Hui Wu
  • Shigeki Miyamoto
Review

Abstract

The nuclear factor-κB (NF-κB) family of dimeric transcription factors plays pivotal roles in physiologic and pathologic processes, including immune and inflammatory responses and development and progression of various human cancers. Inactive NF-κB dimers normally exist in the cytoplasm in association with inhibitor proteins belonging to the inhibitor of NF-κB (IκB) family of related proteins. Activation of NF-κB involves its release from IκB and subsequent nuclear translocation to induce expression of target genes. Intense research effort has revealed many distinct signaling pathways and mechanisms of NF-κB activation induced by immune and inflammatory stimuli. These aspects of NF-κB biology have been amply reviewed in the literature. However, those that involve DNA-damaging agents are less well understood, and multiple conflicting pathways and mechanisms have been described in the literature. In this review, we summarize the proposed mechanisms of NF-κB activation by various DNA-damaging agents, discuss the significance of such activation in the context of cancer treatment, and highlight some of the critical questions that remain to be addressed in future studies.

Keywords

Nuclear factor-κB DNA damage Cancer ATM Cancer therapy 

Abbreviations

ATM

ataxia-telangiectasia mutated

ATR

ataxia-telangiectasia and Rad3 related

CK2

casein kinase 2

CPT

Camptothecin

Dox

Doxorubicin

DSB

DNA double-strand break

ELKS

protein enriched with glutamate, leucine, lysine, and serine

HED-ID

hypohydrotic ectodermal dysplasia with severe immunodeficiency

HSP

heat-shock protein

IκB

inhibitor of NF-κB

IKK

IκB kinase

IR

ionizing radiation

MDC1

mediator of DNA damage checkpoint 1

MDR1

multidrug resistance gene 1

NF-κB

nuclear factor-kappa B

NEMO

NF-κB essential modulator

NIK

NF-κB inducing kinase

RIP

receptor-interacting protein kinase

TAK

TGFβ associated kinase

TRAF

TNF receptor-associated factor

IRAK

IL-1 receptor-associated kinase

p53BP1

p53 binding protein 1

PIASy

protein inhibitor of activated STATy

PIDD

p53 induced protein with a death domain

ROS

reactive oxygen species

UV

ultraviolet radiation

XP

xeroderma pigmentosum

Notes

Acknowledgment

We would like to apologize to the many researchers whose contributions were not covered or cited due to limitation of the space or our oversight. Related research in author’s laboratory is supported by NIH (R01CA077474 to S.M.), and a Special Fellowship from the Leukemia and Lymphoma Society to Z.W.

References

  1. 1.
    Karin M (2006) Nuclear factor–kappaB in cancer development and progression. Nature 441:431–436PubMedGoogle Scholar
  2. 2.
    Perkins ND (2007) Integrating cell-signalling pathways with NF–kappaB and IKK function. Nat Rev Mol Cell Biol 8:49–62PubMedGoogle Scholar
  3. 3.
    Ghosh S, Karin M (2002) Missing pieces in the NF–kappaB puzzle. Cell 109(Suppl):S81–S96Google Scholar
  4. 4.
    Ghosh S, May MJ, Kopp EB (1998) NF–kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260PubMedGoogle Scholar
  5. 5.
    Li Q, Verma IM (2002) NF–kappaB regulation in the immune system. Nat Rev Immunol 2:725–734PubMedGoogle Scholar
  6. 6.
    Hayden MS, Ghosh S (2004) Signaling to NF–kappaB. Genes Dev 18:2195–2224PubMedGoogle Scholar
  7. 7.
    Huxford T, Huang DB, Malek S, Ghosh G (1998) The crystal structure of the IkappaBalpha/NF–kappaB complex reveals mechanisms of NF–kappaB inactivation. Cell 95:759–770PubMedGoogle Scholar
  8. 8.
    Huang TT, Miyamoto S (2001) Postrepression activation of NF–kappaB requires the amino-terminal nuclear export signal specific to IkappaBalpha. Mol Cell Biol 21:4737–4747PubMedGoogle Scholar
  9. 9.
    Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (1997) The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF–kappaB activation. Cell 91:243–252PubMedGoogle Scholar
  10. 10.
    Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, Israel A (1998) Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF–kappaB activation. Cell 93:1231–1240PubMedGoogle Scholar
  11. 11.
    Chen G, Cao P, Goeddel DV (2002) TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Mol Cell 9:401–410PubMedGoogle Scholar
  12. 12.
    Sigala JLD, Bottero V, Young DB, Shevchenko A, Mercurio F, Verma IM (2004) Activation of transcription factor NF–kappaB requires ELKS, an IkappaB kinase regulatory subunit. Science 304:1963–1967Google Scholar
  13. 13.
    Chen ZJ, Parent L, Maniatis T (1996) Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 84:853–862PubMedGoogle Scholar
  14. 14.
    Chen ZJ (2005) Ubiquitin signalling in the NF–kappaB pathway. Nat Cell Biol 7:758–765PubMedGoogle Scholar
  15. 15.
    Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF–kappaB. J Clin Invest 107:241–246PubMedGoogle Scholar
  16. 16.
    Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF–[kappa]B activity. Annu Rev Immunol 18:621–663PubMedGoogle Scholar
  17. 17.
    Karin M, Lin A (2002) NF–kappaB at the crossroads of life and death. Nat Immunol 3:221–227PubMedGoogle Scholar
  18. 18.
    Bonizzi G, Karin M (2004) The two NF–kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288PubMedGoogle Scholar
  19. 19.
    Xiao G, Harhaj EW, Sun SC (2001) NF–kappaB-inducing kinase regulates the processing of NF–kappaB2 p100. Mol Cell 7:401–409PubMedGoogle Scholar
  20. 20.
    Shiloh Y (2006) The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31:402–410PubMedGoogle Scholar
  21. 21.
    Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3:155–168PubMedGoogle Scholar
  22. 22.
    Criswell T, Leskov K, Miyamoto S, Luo G, Boothman DA (2003) Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation. Oncogene 22:5813–5827PubMedGoogle Scholar
  23. 23.
    Lisby M, Barlow JH, Burgess RC, Rothstein R (2004) Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118:699–713PubMedGoogle Scholar
  24. 24.
    Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S et al (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749–1753PubMedGoogle Scholar
  25. 25.
    Lavin MF, Shiloh Y (1997) The genetic defect in ataxia–telangiectasia. Annu Rev Immunol 15:177–202PubMedGoogle Scholar
  26. 26.
    Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506PubMedGoogle Scholar
  27. 27.
    Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA–PKcs to sites of DNA damage. Nature 434:605–611PubMedGoogle Scholar
  28. 28.
    Kitagawa R, Kastan MB (2005) The ATM-dependent DNA damage signaling pathway. Cold Spring Harb Symp Quant Biol 70:99–109PubMedGoogle Scholar
  29. 29.
    Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF (2006) Involvement of novel autophosphorylation sites in ATM activation. EMBO J 25:3504–3514PubMedGoogle Scholar
  30. 30.
    Sun Y, Jiang X, Chen S, Fernandes N, Price BD (2005) A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. PNAS 102:13182–13187PubMedGoogle Scholar
  31. 31.
    Pellegrini M, Celeste A, Difilippantonio S, Guo R, Wang W, Feigenbaum L, Nussenzweig A (2006) Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo. Nature 443:222–225PubMedGoogle Scholar
  32. 32.
    Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273:5858–5868PubMedGoogle Scholar
  33. 33.
    Rogakou EP, Boon C, Redon C, Bonner WM (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146:905–916PubMedGoogle Scholar
  34. 34.
    McGowan CH, Russell P (2004) The DNA damage response: sensing and signaling. Curr Opin Cell Biol 16:629–633PubMedGoogle Scholar
  35. 35.
    Jung M, Dritschilo A (1996) Signal transduction and cellular responses to ionizing radiation. Semin Radiat Oncol 6:268–272PubMedGoogle Scholar
  36. 36.
    Jung M, Zhang Y, Lee S, Dritschilo A (1995) Correction of radiation sensitivity in ataxia telangiectasia cells by a truncated I kappa B-alpha. Science 268:1619–1621PubMedGoogle Scholar
  37. 37.
    Lee SJ, Dimtchev A, Lavin MF, Dritschilo A, Jung M (1998) A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF–kappaB. Oncogene 17:1821–1826PubMedGoogle Scholar
  38. 38.
    Li N, Banin S, Ouyang H, Li GC, Courtois G, Shiloh Y, Karin M, Rotman G (2001) ATM is required for Ikappa B kinase (IKK) activation in response to DNA double strand breaks. J Biol Chem 276:8898–8903PubMedGoogle Scholar
  39. 39.
    Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S (2003) Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF–kappaB activation by genotoxic stress. Cell 115:565–576PubMedGoogle Scholar
  40. 40.
    Wu ZH, Shi Y, Tibbetts RS, Miyamoto S (2006) Molecular linkage between the kinase ATM and NF–kappaB signaling in response to genotoxic stimuli. Science 311:1141–1146PubMedGoogle Scholar
  41. 41.
    Basu S, Rosenzweig KR, Youmell M, Price BD (1998) The DNA-dependent protein kinase participates in the activation of NF kappa B following DNA damage. Biochem Biophys Res Commun 247:79–83PubMedGoogle Scholar
  42. 42.
    Chan DW, Gately DP, Urban S, Galloway AM, Lees-Miller SP, Yen T, Allalunis-Turner J (1998) Lack of correlation between ATM protein expression and tumour cell radiosensitivity. Int J Radiat Biol 74:217–224PubMedGoogle Scholar
  43. 43.
    Wang Y, Meng A, Lang H, Brown SA, Konopa JL, Kindy MS, Schmiedt RA, Thompson JS, Zhou D (2004) Activation of nuclear factor kappaB In vivo selectively protects the murine small intestine against ionizing radiation-induced damage. Cancer Res 64:6240–6246PubMedGoogle Scholar
  44. 44.
    Zhou D, Brown SA, Yu T, Chen G, Barve S, Kang BC, Thompson JS (1999) A high dose of ionizing radiation induces tissue-specific activation of nuclear factor–kappaB in vivo. Radiat Res 151:703–709PubMedGoogle Scholar
  45. 45.
    Raju U, Gumin GJ, Tofilon PJ (2000) Radiation-induced transcription factor activation in the rat cerebral cortex. Int J Radiat Biol 76:1045–1053PubMedGoogle Scholar
  46. 46.
    Wang CY, Cusack JC Jr, Liu R, Baldwin AS Jr (1999) Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF–kappaB. Nat Med 5:412–417PubMedGoogle Scholar
  47. 47.
    Huang TT, Wuerzberger-Davis SM, Seufzer BJ, Shumway SD, Kurama T, Boothman DA, Miyamoto S (2000) NF–kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events. J Biol Chem 275:9501–9509PubMedGoogle Scholar
  48. 48.
    Piret B, Piette J (1996) Topoisomerase poisons activate the transcription factor NF–kappaB in ACH-2 and CEM cells. Nucleic Acids Res 24:4242–4248PubMedGoogle Scholar
  49. 49.
    Piret B, Schoonbroodt S, Piette J (1999) The ATM protein is required for sustained activation of NF–kappaB following DNA damage. Oncogene 18:2261–2271PubMedGoogle Scholar
  50. 50.
    Panta GR, Kaur S, Cavin LG, Cortes ML, Mercurio F, Lothstein L, Sweatman TW, Israel M, Arsura M (2004) ATM and the catalytic subunit of DNA-dependent protein kinase activate NF–{kappa}B through a common MEK/extracellular signal-regulated kinase/p90rsk signaling pathway in response to distinct forms of DNA damage. Mol Cell Biol 24:1823–1835PubMedGoogle Scholar
  51. 51.
    Wu S, Tan M, Hu Y, Wang JL, Scheuner D, Kaufman RJ (2004) Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis. J Biol Chem 279:34898–34902PubMedGoogle Scholar
  52. 52.
    Brach MA, Hass R, Sherman ML, Gunji H, Weichselbaum R, Kufe D (1991) Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest 88:691–695PubMedCrossRefGoogle Scholar
  53. 53.
    Uckun FM, Schieven GL, Tuel-Ahlgren LM, Dibirdik I, Myers DE, Ledbetter JA, Song CW (1993) Tyrosine phosphorylation is a mandatory proximal step in radiation-induced activation of the protein kinase C signaling pathway in human B-lymphocyte precursors. Proc Natl Acad Sci USA 90:252–256PubMedGoogle Scholar
  54. 54.
    Mohan N, Meltz ML (1994) Induction of nuclear factor kappa B after low-dose ionizing radiation involves a reactive oxygen intermediate signaling pathway. Radiat Res 140:97–104PubMedGoogle Scholar
  55. 55.
    Bian X, McAllister-Lucas LM, Shao F, Schumacher KR, Feng Z, Porter AG, Castle VP, Opipari AW Jr (2001) NF–kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. J Biol Chem 276:48921–48929PubMedGoogle Scholar
  56. 56.
    Boland MP, Foster SJ, O’Neill LA (1997) Daunorubicin activates NFkappaB and induces kappaB-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells. J Biol Chem 272:12952–12960PubMedGoogle Scholar
  57. 57.
    Russell JS, Raju U, Gumin GJ, Lang FF, Wilson DR, Huet T, Tofilon PJ (2002) Inhibition of radiation-induced nuclear factor–kappaB activation by an anti-Ras single-chain antibody fragment: lack of involvement in radiosensitization. Cancer Res 62:2318–2326PubMedGoogle Scholar
  58. 58.
    Jung M, Kondratyev A, Lee SA, Dimtchev A, Dritschilo A (1997) ATM gene product phosphorylates I kappa B-alpha. Cancer Res 57:24–27PubMedGoogle Scholar
  59. 59.
    Li N, Karin M (1998) Ionizing radiation and short wavelength UV activate NF–kappaB through two distinct mechanisms. Proc Natl Acad Sci USA 95:13012–13017PubMedGoogle Scholar
  60. 60.
    Bottero V, Busuttil V, Loubat A, Magne N, Fischel JL, Milano G, Peyron JF (2001) Activation of nuclear factor kappaB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to apoptosis in HeLa human carcinoma cells. Cancer Res 61:7785–7791PubMedGoogle Scholar
  61. 61.
    Huang TT, Feinberg SL, Suryanarayanan S, Miyamoto S (2002) The zinc finger domain of NEMO is selectively required for NF–kappa B activation by UV radiation and topoisomerase inhibitors. Mol Cell Biol 22:5813–5825PubMedGoogle Scholar
  62. 62.
    Mabb AM, Wuerzberger-Davis SM, Miyamoto S (2006) PIASy mediates NEMO sumoylation and NF–kappaB activation in response to genotoxic stress. Nat Cell Biol 8:986–993PubMedGoogle Scholar
  63. 63.
    Janssens S, Tinel A, Lippens S, Tschopp J (2005) PIDD mediates NF–kappaB activation in response to DNA damage. Cell 123:1079–1092PubMedGoogle Scholar
  64. 64.
    Hur GM, Lewis J, Yang Q, Lin Y, Nakano H, Nedospasov S, Liu ZG (2003) The death domain kinase RIP has an essential role in DNA damage-induced NF–kappa B activation. Genes Dev 17:873–882PubMedGoogle Scholar
  65. 65.
    Wuerzberger-Davis SM, Nakamura Y, Seufzer BJ, Miyamoto S (2006) NF–kappaB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage. OncogeneGoogle Scholar
  66. 66.
    Cadet J, Sage E, Douki T (2005) Ultraviolet radiation-mediated damage to cellular DNA. Mutat Res 571:3–17PubMedGoogle Scholar
  67. 67.
    Stein B, Rahmsdorf HJ, Steffen A, Litfin M, Herrlich P (1989) UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein. Mol Cell Biol 9:5169–5181PubMedGoogle Scholar
  68. 68.
    Taher MM, Baumgardner T, Dent P, Valerie K (1999) Genetic evidence that stress-activated p38 MAP kinase is necessary but not sufficient for UV activation of HIV gene expression. Biochemistry 38:13055–13062PubMedGoogle Scholar
  69. 69.
    Devary Y, Rosette C, DiDonato JA, Karin M (1993) NF–kappa B activation by ultraviolet light not dependent on a nuclear signal. Science 261:1442–1445PubMedGoogle Scholar
  70. 70.
    Bender K, Gottlicher M, Whiteside S, Rahmsdorf HJ, Herrlich P (1998) Sequential DNA damage-independent and -dependent activation of NF–kappaB by UV. EMBO J 17:5170–5181PubMedGoogle Scholar
  71. 71.
    Muotri AR, Bottero V, Tergaonkar V, Correa RG (2006) UV-mediated NF–kappaB activation is abolished in deficient XPC/D primary fibroblasts. Cell Cycle 5:1085–1089PubMedGoogle Scholar
  72. 72.
    Kato J, Tomohisa, Delhase M, Hoffmann A, Karin M (2003) CK2 Is a C-Terminal I[kappa]B Kinase Responsible for NF-[kappa]B Activation during the UV Response. Mol Cell 12:829–839PubMedGoogle Scholar
  73. 73.
    Krappmann D, Wulczyn FG, Scheidereit C (1996) Different mechanisms control signal-induced degradation and basal turnover of the NF-kappaB inhibitor IkappaB alpha in vivo. EMBO J 15:6716–6726PubMedGoogle Scholar
  74. 74.
    Halliday GM (2005) Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res 571:107–120PubMedGoogle Scholar
  75. 75.
    Terui T, Okuyama R, Tagami H (2001) Molecular events occurring behind ultraviolet-induced skin inflammation. Curr Opin Allergy Clin Immunol 1:461–467PubMedGoogle Scholar
  76. 76.
    Simon MM, Aragane Y, Schwarz A, Luger TA, Schwarz T (1994) UVB light induces nuclear factor kappa B (NF kappa B) activity independently from chromosomal DNA damage in cell-free cytosolic extracts. J Invest Dermatol 102:422–427PubMedGoogle Scholar
  77. 77.
    Tobin D, van Hogerlinden M, Toftgard R (1998) UVB-induced association of tumor necrosis factor (TNF) receptor 1/TNF receptor-associated factor-2 mediates activation of Rel proteins. Proc Natl Acad Sci USA 95:565–569PubMedGoogle Scholar
  78. 78.
    Reelfs O, Tyrrell RM, Pourzand C (2004) Ultraviolet a radiation-induced immediate iron release is a key modulator of the activation of NF–kappaB in human skin fibroblasts. J Invest Dermatol 122:1440–1447PubMedGoogle Scholar
  79. 79.
    Wang CY, Mayo MW, Baldwin AS Jr (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF–kappaB. Science 274:784–787PubMedGoogle Scholar
  80. 80.
    Russo SM, Tepper JE, Baldwin AS Jr, Liu R, Adams J, Elliott P, Cusack JC Jr (2001) Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF–kappaB. Int J Radiat Oncol Biol Phys 50:183–193PubMedGoogle Scholar
  81. 81.
    Chang PY, Miyamoto S (2006) Nuclear factor-kappaB dimer exchange promotes a p21(waf1/cip1) superinduction response in human T leukemic cells. Mol Cancer Res 4:101–112PubMedGoogle Scholar
  82. 82.
    Wuerzberger-Davis SM, Chang PY, Berchtold C, Miyamoto S (2005) Enhanced G2-M arrest by nuclear factor-{kappa}B-dependent p21waf1/cip1 induction. Mol Cancer Res 3:345–353PubMedGoogle Scholar
  83. 83.
    Dutta J, Fan Y, Gupta N, Fan G, Gelinas C (2006) Current insights into the regulation of programmed cell death by NF–kappaB. Oncogene 25:6800–6816PubMedGoogle Scholar
  84. 84.
    Rashi-Elkeles S, Elkon R, Weizman N, Linhart C, Amariglio N, Sternberg G, Rechavi G, Barzilai A, Shamir R, Shiloh Y (2006) Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine lymphoid tissue. Oncogene 25:1584–1592PubMedGoogle Scholar
  85. 85.
    Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR (1998) DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF–kappa B and AP-1. Mol Cell 1:543–551PubMedGoogle Scholar
  86. 86.
    Kim HJ, Hawke N, Baldwin AS (2006) NF–kappaB and IKK as therapeutic targets in cancer. Cell Death Differ 13:738–747PubMedGoogle Scholar
  87. 87.
    Rocha S, Garrett MD, Campbell KJ, Schumm K, Perkins ND (2005) Regulation of NF–kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor. EMBO J 24:1157–1169PubMedGoogle Scholar
  88. 88.
    Campbell KJ, Rocha S, Perkins ND (2004) Active repression of antiapoptotic gene expression by RelA(p65) NF–kappa B. Mol Cell 13:853–865PubMedGoogle Scholar
  89. 89.
    Campbell KJ, Witty JM, Rocha S, Perkins ND (2006) Cisplatin mimics ARF tumor suppressor regulation of RelA (p65) nuclear factor–{kappa}B transactivation. Cancer Res 66:929–935PubMedGoogle Scholar
  90. 90.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedGoogle Scholar
  91. 91.
    Aggarwal BB (2004) Nuclear factor–kappaB: the enemy within. Cancer Cell 6:203–208PubMedGoogle Scholar
  92. 92.
    Karin M, Cao Y, Greten FR, Li ZW (2002) NF–kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–310PubMedGoogle Scholar
  93. 93.
    Karin M, Lawrence T, Nizet V (2006) Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124:823–835PubMedGoogle Scholar
  94. 94.
    Nakanishi C, Toi M (2005) Nuclear factor–kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 5:297–309PubMedGoogle Scholar
  95. 95.
    Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, Jacobs N, Gielen J, Merville MP, Bours V (2003) NF–kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22:90–97PubMedGoogle Scholar
  96. 96.
    Richardson PG, Mitsiades C, Hideshima T, Anderson KC (2006) Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med 57:33–47PubMedGoogle Scholar
  97. 97.
    Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor–kappaB inhibition. Cancer Res 61:3535–3540PubMedGoogle Scholar
  98. 98.
    Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA, Elliott PJ, Adams J, Callery MP (2001) 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 82:110–122PubMedGoogle Scholar
  99. 99.
    Karin M, Yamamoto Y, Wang QM (2004) The IKK NF–kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3:17–26PubMedGoogle Scholar
  100. 100.
    Gilmore TD, Herscovitch M (2006) Inhibitors of NF–[kappa]B signaling: 785 and counting. Oncogene 25:6887–6899PubMedGoogle Scholar
  101. 101.
    Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15:2177–2196PubMedGoogle Scholar
  102. 102.
    Stiff T, Walker SA, Cerosaletti K, Goodarzi AA, Petermann E, Concannon P, O’Driscoll M, Jeggo PA (2006) ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO JGoogle Scholar
  103. 103.
    Luo JL, Kamata H, Karin M (2005) The anti-death machinery in IKK/NF–kappaB signaling. J Clin Immunol 25:541–550PubMedGoogle Scholar
  104. 104.
    Albor A, El-Hizawi S, Horn EJ, Laederich M, Frosk P, Wrogemann K, Kulesz-Martin M (2006) The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB. J Biol Chem 281:25850–25866PubMedGoogle Scholar
  105. 105.
    Luan B, Zhang Z, Wu Y, Kang J, Pei G (2005) Beta-arrestin2 functions as a phosphorylation-regulated suppressor of UV-induced NF–kappaB activation. EMBO J 24:4237–4246PubMedGoogle Scholar
  106. 106.
    Yokoyama S, Nakano H, Yamazaki T, Tamai K, Hanada K, Takahashi G (2005) Enhancement of ultraviolet-induced apoptosis by NF–kappaB decoy oligonucleotides. Br J Dermatol 153(Suppl 2):47–51PubMedGoogle Scholar
  107. 107.
    Stark LA, Dunlop MG (2005) Nucleolar sequestration of RelA (p65) regulates NF–kappaB-driven transcription and apoptosis. Mol Cell Biol 25:5985–6004PubMedGoogle Scholar
  108. 108.
    Soldatenkov VA, Dritschilo A, Ronai Z, Fuchs SY (1999) Inhibition of homologue of Slimb (HOS) function sensitizes human melanoma cells for apoptosis. Cancer Res 59:5085–5088PubMedGoogle Scholar
  109. 109.
    van Hogerlinden M, Rozell BL, Ahrlund-Richter L, Toftgard R (1999) Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor–kappaB signaling. Cancer Res 59:3299–3303PubMedGoogle Scholar
  110. 110.
    Qin JZ, Chaturvedi V, Denning MF, Choubey D, Diaz MO, Nickoloff BJ (1999) Role of NF–kappaB in the apoptotic-resistant phenotype of keratinocytes. J Biol Chem 274:37957–37964PubMedGoogle Scholar
  111. 111.
    Liu J, Yang D, Minemoto Y, Leitges M, Rosner MR, Lin A (2006) NF–[kappa]B is required for UV-Induced JNK activation via induction of PKC[delta]. Mol Cell 21:467–480PubMedGoogle Scholar
  112. 112.
    Poppelmann B, Klimmek K, Strozyk E, Voss R, Schwarz T, Kulms D (2005) NF{kappa}B-dependent down-regulation of tumor necrosis factor receptor-associated proteins contributes to interleukin-1-mediated enhancement of ultraviolet B-induced apoptosis. J Biol Chem 280:15635–15643PubMedGoogle Scholar
  113. 113.
    Thyss R, Virolle V, Imbert V, Peyron JF, Aberdam D, Virolle T (2005) NF–kappaB/Egr-1/Gadd45 are sequentially activated upon UVB irradiation to mediate epidermal cell death. EMBO J 24:128–137PubMedGoogle Scholar
  114. 114.
    Fan C, Yang J, Engelhardt JF (2002) Temporal pattern of NFkappaB activation influences apoptotic cell fate in a stimuli-dependent fashion. J Cell Sci 115:4843–4853PubMedGoogle Scholar
  115. 115.
    Ivanov VN, Ronai Z (2000) p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF–kappaB activity and Fas expression. Oncogene 19:3003–3012PubMedGoogle Scholar
  116. 116.
    Strozyk E, Poppelmann B, Schwarz T, Kulms D (2006) Differential effects of NF–kappaB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome. Oncogene 25:6239–6251PubMedGoogle Scholar
  117. 117.
    Kim BY, Kim KA, Kwon O, Kim SO, Kim MS, Kim BS, Oh WK, Kim GD, Jung M, Ahn JS (2005) NF–kappaB inhibition radiosensitizes Ki–Ras-transformed cells to ionizing radiation. Carcinogenesis 26:1395–1403PubMedGoogle Scholar
  118. 118.
    Wang T, Hu YC, Dong S, Fan M, Tamae D, Ozeki M, Gao Q, Gius D, Li JJ (2005) Co-activation of ERK, NF–kappaB, and GADD45beta in response to ionizing radiation. J Biol Chem 280:12593–12601PubMedGoogle Scholar
  119. 119.
    Weston VJ, Austen B, Wei W, Marston E, Alvi A, Lawson S, Darbyshire PJ, Griffiths M, Hill F, Mann JR, Moss PA, Taylor AM, Stankovic T (2004) Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF–kappaB survival pathway signaling. Blood 104:1465–1473PubMedGoogle Scholar
  120. 120.
    Guo G, Wang T, Gao Q, Tamae D, Wong P, Chen T, Chen WC, Shively JE, Wong JY, Li JJ (2004) Expression of ErbB2 enhances radiation-induced NF–kappaB activation. Oncogene 23:535–545PubMedGoogle Scholar
  121. 121.
    Starenki D, Namba H, Saenko V, Ohtsuru A, Yamashita S (2004) Inhibition of nuclear factor–kappaB cascade potentiates the effect of a combination treatment of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 89:410–418PubMedGoogle Scholar
  122. 122.
    Tamatani T, Azuma M, Ashida Y, Motegi K, Takashima R, Harada K, Kawaguchi S, Sato M (2004) Enhanced radiosensitization and chemosensitization in NF–kappaB-suppressed human oral cancer cells via the inhibition of gamma-irradiation- and 5-FU-induced production of IL-6 and IL-8. Int J Cancer 108:912–921PubMedGoogle Scholar
  123. 123.
    Chen X, Shen B, Xia L, Khaletzkiy A, Chu D, Wong JY, Li JJ (2002) Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes. Cancer Res 62:1213–1221PubMedGoogle Scholar
  124. 124.
    Yang CR, Wilson-Van Patten C, Planchon SM, Wuerzberger-Davis SM, Davis TW, Cuthill S, Miyamoto S, Boothman DA (2000) Coordinate modulation of Sp1, NF–kappa B, and p53 in confluent human malignant melanoma cells after ionizing radiation. FASEB J 14:379–390PubMedGoogle Scholar
  125. 125.
    Eliseev RA, Zuscik MJ, Schwarz EM, O’Keefe RJ, Drissi H, Rosier RN (2005) Increased radiation-induced apoptosis of Saos2 cells via inhibition of NFkappaB: a role for c-Jun N-terminal kinase. J Cell Biochem 96:1262–1273PubMedGoogle Scholar
  126. 126.
    Shao R, Karunagaran D, Zhou BP, Li K, Lo SS, Deng J, Chiao P, Hung MC (1997) Inhibition of nuclear factor–kappaB activity is involved in E1A-mediated sensitization of radiation-induced apoptosis. J Biol Chem 272:32739–32742PubMedGoogle Scholar
  127. 127.
    Campbell KJ, Witty JM, Rocha S, Perkins ND (2006) Cisplatin mimics ARF tumor suppressor regulation of RelA (p65) nuclear factor–kappaB transactivation. Cancer Res 66:929–935PubMedGoogle Scholar
  128. 128.
    Aleyasin H, Cregan SP, Iyirhiaro G, O’Hare MJ, Callaghan SM, Slack RS, Park DS (2004) Nuclear factor–(kappa)B modulates the p53 response in neurons exposed to DNA damage. J Neurosci 24:2963–2973PubMedGoogle Scholar
  129. 129.
    de Leseleuc L, Denis F (2006) Inhibition of apoptosis by Nur77 through NF–kappaB activity modulation. Cell Death Differ 13:293–300PubMedGoogle Scholar
  130. 130.
    Russo P, Catassi A, Malacarne D, Margaritora S, Cesario A, Festi L, Mule A, Ferri L, Granone P (2005) Tumor necrosis factor enhances SN38-mediated apoptosis in mesothelioma cells. Cancer 103:1503–1518PubMedGoogle Scholar
  131. 131.
    Li Z, Niu J, Uwagawa T, Peng B, Chiao PJ (2005) Function of polo-like kinase 3 in NF–kappaB-mediated proapoptotic response. J Biol Chem 280:16843–16850PubMedGoogle Scholar
  132. 132.
    Song JY, Lim JW, Kim H, Kim KH (2003) Role of NF–kappaB and DNA repair protein Ku on apoptosis in pancreatic acinar cells. Ann N Y Acad Sci 1010:259–263PubMedGoogle Scholar
  133. 133.
    Culmsee C, Siewe J, Junker V, Retiounskaia M, Schwarz S, Camandola S, El-Metainy S, Behnke H, Mattson MP, Krieglstein J (2003) Reciprocal inhibition of p53 and nuclear factor–kappaB transcriptional activities determines cell survival or death in neurons. J Neurosci 23:8586–8595PubMedGoogle Scholar
  134. 134.
    Sreenivasan Y, Sarkar A, Manna SK (2003) Mechanism of cytosine arabinoside-mediated apoptosis: role of Rel A (p65) dephosphorylation. Oncogene 22:4356–4369PubMedGoogle Scholar
  135. 135.
    Weaver KD, Yeyeodu S, Cusack JC Jr, Baldwin AS Jr, Ewend MG (2003) Potentiation of chemotherapeutic agents following antagonism of nuclear factor kappa B in human gliomas. J Neuro-oncol 61:187–196Google Scholar
  136. 136.
    Lavon I, Pikarsky E, Gutkovich E, Goldberg I, Bar J, Oren M, Ben-Neriah Y (2003) Nuclear factor–kappaB protects the liver against genotoxic stress and functions independently of p53. Cancer Res 63:25–30PubMedGoogle Scholar
  137. 137.
    Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380PubMedGoogle Scholar
  138. 138.
    Yin KJ, Chen SD, Lee JM, Xu J, Hsu CY (2002) ATM gene regulates oxygen–glucose deprivation-induced nuclear factor–kappaB DNA-binding activity and downstream apoptotic cascade in mouse cerebrovascular endothelial cells. Stroke 33:2471–2477PubMedGoogle Scholar
  139. 139.
    Arlt A, Vorndamm J, Muerkoster S, Yu H, Schmidt WE, Folsch UR, Schafer H (2002) Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. Cancer Res 62:910–916PubMedGoogle Scholar
  140. 140.
    Jones DR, Broad RM, Comeau LD, Parsons SJ, Mayo MW (2002) Inhibition of nuclear factor kappaB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation. J Thorac Cardiovasc Surg 123:310–317PubMedGoogle Scholar
  141. 141.
    Bottero V, Busuttil V, Loubat A, Magne N, Fischel J-L, Milano G, Peyron J-F (2001) Activation of nuclear factor {kappa}B through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to apoptosis in HeLa human carcinoma cells. Cancer Res 61:7785–7791PubMedGoogle Scholar
  142. 142.
    Tabata M, Tabata R, Grabowski DR, Bukowski RM, Ganapathi MK, Ganapathi R (2001) Roles of NF-kappa B and 26 S proteasome in apoptotic cell death induced by topoisomerase I and II poisons in human nonsmall cell lung carcinoma. J Biol Chem 276:8029–8036PubMedGoogle Scholar
  143. 143.
    Hellin AC, Bentires-Alj M, Verlaet M, Benoit V, Gielen J, Bours V, Merville MP (2000) Roles of nuclear factor–kappaB, p53, and p21/WAF1 in daunomycin-induced cell cycle arrest and apoptosis. J Pharmacol Exp Ther 295:870–878PubMedGoogle Scholar
  144. 144.
    Marinovich M, Viviani B, Corsini E, Ghilardi F, Galli CL (1996) NF–[kappa]B activation by triphenyltin triggers apoptosis in HL-60 cells. Exp Cell Res 226:98–104PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of Wisconsin–MadisonMadisonUSA

Personalised recommendations