Chapter 8 : The Nuclear Factor-κB Transcription Factor Pathway

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The Nuclear Factor-κB Transcription Factor Pathway, Page 1 of 2

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Nuclear factor (NF)-κB activating signals, which are discussed in this chapter, induce phosphorylation of I κB proteins, leading to their ubiquitination and proteasome-mediated degradation. Nuclear translocation of the subunits, however, may not be sufficient for transcriptional activation. NF-κB complexes induce expression of key tumor necrosis factor-α (TNF-α) target genes involved in the inflammatory responses, including leukocyte adhesion molecules and chemokines. Phosphorylation at a single key residue (Ser-276) by protein kinase A enhances RelA interaction with the coactivator CREB-binding protein (CBP), resulting in enhanced transcriptional activation potential. NF-κB is a key mediator of inflammatory cytokineinduced responses. The pathway through which TNF-α induces NF-κB activation is among the most well studied in higher eukaryotes. Absence of RelA results in massive hepatocyte apoptosis during embryogenesis, resulting in embryonic lethality. Studies of mice deficient in the NF-κB RelA subunit provided the first direct evidence of a role for NF-κB in inhibiting apoptosis. The NF-κB transcription factors play key functions in many aspects of the antiviral response. Respiratory syncytial virus (RSV) is a member of the paramyxovirus family that causes acute lower respiratory tract infections, which are characterized by high expression of proinflammatory cytokines and chemokines. Virus induction of the interferon (IFN)-β gene is one of the most studied transcriptional systems in mammals. In the heart, however, NF-κB is important for inducing IFN-β expression and therefore in limiting viral replication. Similarly disparate functions for NF-κB also come into play during induction of virus-induced inflammatory and adaptive immune responses.

Citation: Beg A, Wang X. 2009. The Nuclear Factor-κB Transcription Factor Pathway, p 107-118. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch8

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Lower Respiratory Tract Infections
Herpes simplex virus 1
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Figure 1

Mammalian NF-κB/Rel and IκB family proteins. The mammalian NF-κB family comprises five members: RelA/p65, cRel, RelB, p100/p52, and p105/p50. They have a structurally conserved amino-terminal Rel homology region, which contains functional domains responsible for dimerization and DNA binding. RelA/p65, cRel, and RelB also have nonhomologous carboxy-terminal transactivation domains. p100 and p105 have carboxy-terminal ankyrin repeats that are homologous to IκB family proteins. p50 and p52 proteins are generated by proteolytic processing of p105 and p100, respectively. IκB family proteins, which are featured by ankyrin repeats, contain IκB-α, IκB-β, IκB-γ, IκB-ε, IκB-ζ (also known as MAIL and INAP), Bcl-3, p105, and p100. IκB-α, IκB-β, and IκB-ε are prototypical IκBs that retain NF-κB proteins in the cytoplasm. Unprocessed p100 and p105 also function as inhibitors of NF-κB. IκB-γ is identical to the carboxy-terminal region of p105 and specifically inhibits p50-containing NF-κB dimers. p105, IκB-γ, and prototypical IκBs (IκB-α and IκB-β) use a similar mechanism to bind but a different mechanism to regulate the subcellular localization of NF-κB. In contrast, Bcl-3 interacts specifically with p50 and p52 homodimers and can induce expression of NF-κB-regulated genes. Similar to Bcl-3, IκB-ζ also functions as an activator of gene expression by specific association with p50.

Citation: Beg A, Wang X. 2009. The Nuclear Factor-κB Transcription Factor Pathway, p 107-118. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch8
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Image of Figure 2
Figure 2

NF-κB activation pathways during viral infection. NF-κB can be activated by many stimuli, including bacterial and viral products, inflammatory cytokines, and antigen receptors. NF-κB plays vital roles in mediating intracellular responses to pathogens that are recognized by pattern recognition receptors (PRRs) such as TLRs. Bacterial product LPS or RSV F protein is recognized by the cell surface-expressed TLR4. Viral single-stranded RNA (ssRNA) and viral DNA can be recognized by TLR7 and TLR9, respectively, which are expressed in the endosomal compartment. Active virus replication-generated viral doublestranded RNA (dsRNA) and viral DNA are sensed by intracellular PRRs RIG-I/MDA-5 and DAI (DNA-dependent activator of IFN regulatory factors), respectively, in the cytoplasm. PRR engagement by its ligand results in activation of IKK complex, composed of kinases IKK-α and IKK-β and the regulatory subunit IKK-γ (also known as NEMO). IκB-α and IκB-β proteins are phosphorylated by the activated IKK complex. Phosphorylated IκBs are then ubiquitinated by β-TrCP (transducin repeat-containing protein), which targets it for degradation by the proteasome. This releases NF-κB dimers from cytoplasmic NF-κB/IκB complexes and allows them to translocate to the nucleus and activate target gene expression.

Citation: Beg A, Wang X. 2009. The Nuclear Factor-κB Transcription Factor Pathway, p 107-118. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch8
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1. Akira, S., and, K. Takeda. 2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4:499511.
2. Akira, S.,, S. Uematsu, and, O. Takeuchi. 2006. Pathogen recognition and innate immunity. Cell 124:783801.
3. Alcamo, E.,, J. P. Mizgerd,, B. H. Horwitz,, R. Bronson,, A. A. Beg,, M. Scott,, C. M. Doerschuk,, R. O. Hynes, and, D. Baltimore. 2001. Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-κB in leukocyte recruitment. J. Immunol. 167:15921600.
4. Anest, V.,, J. L. Hanson,, P. C. Cogswell,, K. A. Steinbrecher,, B. D. Strahl, and, A. S. Baldwin. 2003. A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression. Nature 423:659663.
5. Beg, A. A., and, D. Baltimore. 1996. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274:782784.
6. Beg, A. A.,, W. C. Sha,, R. T. Bronson,, S. Ghosh, and, D. Baltimore. 1995. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376:167170.
7. Bonizzi, G.,, M. Bebien,, D. C. Otero,, K. E. Johnson-Vroom,, Y. Cao,, D. Vu,, A. G. Jegga,, B. J. Aronow,, G. Ghosh,, R. C. Rickert, and, M. Karin. 2004. Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. EMBO J. 23:42024210.
8. Bonizzi, G., and, M. Karin. 2004. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25:280288.
9. Bosisio, D.,, I. Marazzi,, A. Agresti,, N. Shimizu,, M. E. Bianchi, and, G. Natoli. 2006. A hyper-dynamic equilibrium between promoter-bound and nucleoplasmic dimers controls NF-kappaB-dependent gene activity. EMBO J. 25:798810.
10. Caamano, J.,, J. Alexander,, L. Craig,, R. Bravo, and, C. A. Hunter. 1999. The NF-κB family member RelB is required for innate and adaptive immunity to Toxoplasma gondii. J. Immunol 163:44534461.
11. Caamano, J. H.,, C. A. Rizzo,, S. K. Durham,, D. S. Barton,, C. Raventos-Suarez,, C. M. Snapper, and, R. Bravo. 1998. Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J. Exp. Med. 187:185196.
12. Chang, L.,, H. Kamata,, G. Solinas,, J. L. Luo,, S. Maeda,, K. Venuprasad,, Y. C. Liu, and, M. Karin. 2006. The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIP(L) turnover. Cell 124:601613.
13. Chen, G., and, D. V. Goeddel. 2002. TNF-R1 signaling: a beautiful pathway. Science 296:16341635.
14. Chen, L. F.,, Y. Mu, and, W. C. Greene. 2002. Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. Embo J. 21:65396548.
15. Chu, W. M.,, D. Ostertag,, Z. W. Li,, L. Chang,, Y. Chen,, Y. Hu,, B. Williams,, J. Perrault, and, M. Karin. 1999. JNK2 and IKKbeta are required for activating the innate response to viral infection. Immunity 11:721731.
16. Connolly, J. L.,, S. E. Rodgers,, P. Clarke,, D. W. Ballard,, L. D. Kerr,, K. L. Tyler, and, T. S. Dermody. 2000. Reovirus-induced apoptosis requires activation of transcription factor NF-kappaB. J. Virol. 74:29812989.
17. Covert, M. W.,, T. H. Leung,, J. E. Gaston, and, D. Baltimore. 2005. Achieving stability of lipopolysac-charide-induced NF-kappaB activation. Science 309:18541857.
18. Dejardin, E.,, N. M. Droin,, M. Delhase,, E. Haas,, Y. Cao,, C. Makris,, Z. W. Li,, M. Karin,, C. F. Ware, and, D. R. Green. 2002. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 17:525535.
19. De Smaele, E.,, F. Zazzeroni,, S. Papa,, D. U. Nguyen,, R. Jin,, J. Jones,, R. Cong, and, G. Franzoso. 2001. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414:308313.
20. Diebold, S. S.,, T. Kaisho,, H. Hemmi,, S. Akira, and, C. Reis e Sousa. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:15291531.
21. Ducut Sigala, J. L.,, V. Bottero,, D. B. Young,, A. Shevchenko,, F. Mercurio, and, I. M. Verma. 2004. Activation of transcription factor NF-kappaB requires ELKS, an IkappaB kinase regulatory subunit. Science 304:19631967.
22. Franzoso, G.,, L. Carlson,, L. Poljak,, E. W. Shores,, S. Epstein,, A. Leonardi,, A. Grinberg,, T. Tran,, T. Scharton-Kersten,, M. Anver,, P. Love,, K. Brown, and, U. Siebenlist. 1998. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J. Exp. Med. 187:147159.
23. Franzoso, G.,, L. Carlson,, L. Xing,, L. Poljak,, E. W. Shores,, K. D. Brown,, A. Leonardi,, T. Tran,, B. F. Boyce, and, U. Siebenlist. 1997. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev. 11:34823496.
24. Gerondakis, S.,, R. Grumont,, R. Gugasyan,, L. Wong,, I. Isomura,, W. Ho, and, A. Banerjee. 2006. Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 25:67816799.
25. Gerondakis, S., and, A. Strasser. 2003. The role of Rel/NF-kappaB transcription factors in B lymphocyte survival. Semin. Immunol. 15:159166.
26. Ghosh, S.,, A. M. Gifford,, L. R. Rivere,, P. Tempest,, G. P. Nolan, and, D. Baltimore. 1990. Cloning of the p50 DNA binding subunit of NF-kB: homology to rel and dorsal. Cell 62:10191029.
27. Goodkin, M. L.,, A. T. Ting, and, J. A. Blaho. 2003. NF-kappaB is required for apoptosis prevention during herpes simplex virus type 1 infection. J. Virol. 77:72617280.
28. Greene, W. C., and, L. F. Chen. 2004. Regulation of NF-kappaB action by reversible acetylation. Novartis Found. Symp. 259:208217; discussion 218–225.
29. Haeberle, H. A.,, A. Casola,, Z. Gatalica,, S. Petronella,, H. J. Dieterich,, P. B. Ernst,, A. R. Brasier, and, R. P. Garofalo. 2004. IkappaB kinase is a critical regulator of chemokine expression and lung inflammation in respiratory syncytial virus infection. J. Virol. 78:22322241.
30. Haeberle, H. A.,, R. Takizawa,, A. Casola,, A. R. Brasier,, H. J. Dieterich,, N. Van Rooijen,, Z. Gatalica, and, R. P. Garofalo. 2002. Respiratory syncytial virus-induced activation of nuclear factor-kappaB in the lung involves alveolar macrophages and Toll-like receptor 4-dependent pathways. J. Infect. Dis. 186:11991206.
31. Hansberger, M. W.,, J. A. Campbell,, P. Danthi,, P. Arrate,, K. N. Pennington,, K. B. Marcu,, D. W. Ballard, and, T. S. Dermody. 2007. IkappaB kinase subunits alpha and gamma are required for activation of NF-kappaB and induction of apoptosis by mammalian reovirus. J. Virol. 81:13601371.
32. Hayden, M. S., and, S. Ghosh. 2004. Signaling to NF-kappaB. Genes Dev. 18:21952224.
33. Hayden, M. S.,, A. P. West, and, S. Ghosh. 2006. NF-kappaB and the immune response. Oncogene 25:67586780.
34. Haynes, L. M.,, D. D. Moore,, E. A. Kurt-Jones,, R. W. Finberg,, L. J. Anderson, and, R. A. Tripp. 2001. Involvement of Toll-like receptor 4 in innate immunity to respiratory syncytial virus. J. Virol. 75:1073010737.
35. Hiscott, J.,, T. L. Nguyen,, M. Arguello,, P. Nakhaei, and, S. Paz. 2006. Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses. Oncogene 25:68446867.
36. Honda, K.,, A. Takaoka, and, T. Taniguchi. 2006. Type I interferon gene induction by the interferon regulatory factor family of transcription factors. Immunity 25:349360.
37. Hoshino, K.,, T. Sugiyama,, M. Matsumoto,, T. Tanaka,, M. Saito,, H. Hemmi,, O. Ohara,, S. Akira, and, T. Kaisho. 2006. IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440:949953.
38. Hu, Y.,, V. Baud,, M. Delhase,, P. Zhang,, T. Deerinck,, M. Ellisman,, R. Johnson, and, M. Karin. 1999. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 284:316320.
39. Hu, Y.,, V. Baud,, T. Oga,, K. I. Kim,, K. Yoshida, and, M. Karin. 2001. IKKalpha controls formation of the epidermis independently of NF-kappaB. Nature 410:710714.
40. Ishimaru, N.,, H. Kishimoto,, Y. Hayashi, and, J. Sprent. 2006. Regulation of naive T cell function by the NF-kappaB2 pathway. Nat. Immunol. 7:763772.
41. Iwasaki, A., and, R. Medzhitov. 2004. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5:987995.
42. Karin, M., and, Y. Ben-Neriah. 2000. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18:621663.
43. Karin, M., and, F. R. Greten. 2005. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5:749759.
44. Kato, H.,, S. Sato,, M. Yoneyama,, M. Yamamoto,, S. Uematsu,, K. Matsui,, T. Tsujimura,, K. Takeda,, T. Fujita,, O. Takeuchi, and, S. Akira. 2005. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:1928.
45. Kontgen, F.,, R. J. Grumont,, A. Strasser,, D. Metcalf,, R. Li,, D. Tarlinton, and, S. Gerondakis. 1995. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 9:19651977.
46. Kuhnel, F.,, L. Zender,, Y. Paul,, M. K. Tietze,, C. Trautwein,, M. Manns, and, S. Kubicka. 2000. NF-kappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis. J. Biol. Chem. 275:64216427.
47. Kumagai, Y.,, O. Takeuchi,, H. Kato,, H. Kumar,, K. Matsui,, E. Morii,, K. Aozasa,, T. Kawai, and, S. Akira. 2007. Alveolar macrophages are the primary interferon-alpha producer in pulmonary infection with RNA viruses. Immunity 27:240252.
48. Kurt-Jones, E. A.,, L. Popova,, L. Kwinn,, L. M. Haynes,, L. P. Jones,, R. A. Tripp,, E. E. Walsh,, M. W. Freeman,, D. T. Golenbock,, L. J. Anderson, and, R. W. Finberg. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol 1:398401.
49. Le Bon, A.,, M. Montoya,, M. J. Edwards,, C. Thompson,, S. A. Burke,, M. Ashton,, D. Lo,, D. F. Tough, and, P. Borrow. 2006. A role for the transcription factor RelB in IFN-alpha production and in IFN-alpha-stimulated cross-priming. Eur. J. Immunol 36:20852093.
50. Lenardo, M. J.,, C. M. Fan,, T. Maniatis, and, D. Baltimore. 1989. The involvement of NF-κB in β-interferon gene regulation reveals its role as widely inducible mediator of signal transduction. Cell 57:287294.
51. Leung, T. H.,, A. Hoffmann, and, D. Baltimore. 2004. One nucleotide in a kappaB site can determine cofactor specificity for NF-kappaB dimers. Cell 118:453464.
52. Li, M.,, W. Shillinglaw,, W. J. Henzel, and, A. A. Beg. 2001. The RelA(p65) subunit of NF-kappa B is essential for inhibiting double-stranded RNA-induced cytotoxicity. J. Biol. Chem. 276:11851194.
53. Li, Q.,, G. Estepa,, S. Memet,, A. Israel, and, I. M. Verma. 2000. Complete lack of NF-kappaB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev. 14:17291733.
54. Li, Q.,, Q. Lu,, J. Y. Hwang,, D. Buscher,, K. F. Lee,, J. C. Izpisua-Belmonte, and, I. M. Verma. 1999. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13:13221328.
55. Li, Q.,, D. Van Antwerp,, F. Mercurio,, K. F. Lee, and, I. M. Verma. 1999. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284:321325.
56. Li, Z. W.,, W. Chu,, Y. Hu,, M. Delhase,, T. Deerinck,, M. Ellisman,, R. Johnson, and, M. Karin. 1999. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J. Exp. Med. 189:18391845.
57. Liu, P.,, M. Jamaluddin,, K. Li,, R. P. Garofalo,, A. Casola, and, A. R. Brasier. 2007. Retinoic acid-inducible gene I mediates early antiviral response and Toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells. J. Virol. 81:14011411.
58. Liu, Y. J. 2005. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23:275306.
59. Lo, D.,, L. Feng,, L. Li,, M. J. Carson,, M. Crowley,, M. Pauza,, A. Nguyen, and, C. R. Reilly. 1999. Integrating innate and adaptive immunity in the whole animal. Immunol. Rev. 169:225239.
60. Lund, J. M.,, L. Alexopoulou,, A. Sato,, M. Karow,, N. C. Adams,, N. W. Gale,, A. Iwasaki, and, R. A. Flavell. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. USA 101:55985603.
61. Marianneau, P.,, A. Cardona,, L. Edelman,, V. Deubel, and, P. Despres. 1997. Dengue virus replication in human hepatoma cells activates NF-kappaB which in turn induces apoptotic cell death. J. Virol. 71:32443249.
62. Martin, E.,, B. O’Sullivan,, P. Low, and, R. Thomas. 2003. Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. Immunity 18:155167.
63. Natoli, G.,, S. Saccani,, D. Bosisio, and, I. Marazzi. 2005. Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time. Nat. Immunol. 6:439445.
64. Neri, A.,, C.-C. Chang,, L. Lombardi,, M. Salina,, P. Corradini,, A. T. Maiolo,, R. S. Chaganti, and, R. Dalla-Favera. 1991. B cell lymphoma-associated chromosomal translocation involves candidate oncogene, lyt-10, homologous to NF-κB p50. Cell 67:10751087.
65. Nolan, G. P.,, S. Ghosh,, H.-C. Liou,, P. Tempst, and, D. Baltimore. 1991. DNA binding and IkB inhibition of the cloned p65 subunit of NF-kB, a rel-related polypeptide. Cell 64:961969.
66. O’Donnell, S. M.,, M. W. Hansberger,, J. L. Connolly,, J. D. Chappell,, M. J. Watson,, J. M. Pierce,, J. D. Wetzel,, W. Han,, E. S. Barton,, J. C. Forrest,, T. Valyi-Nagy,, F. E. Yull,, T. S. Blackwell,, J. N. Rottman,, B. Sherry, and, T. S. Dermody. 2005. Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease. J. Clin. Invest. 115:23412350.
67. Ouaaz, F.,, J. Arron,, Y. Zheng,, Y. Choi, and, A. A. Beg. 2002. Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity 16:257270.
68. Ouaaz, F.,, M. Li, and, A. A. Beg. 1999. A critical role for the RelA subunit of nuclear factor kappaB in regulation of multiple immune-response genes and in Fas-induced cell death. J. Exp. Med. 189:9991004.
69. Panne, D.,, T. Maniatis, and, S. C. Harrison. 2007. An atomic model of the interferon-beta enhanceosome. Cell 129:11111123.
70. Park, J. M.,, F. R. Greten,, A. Wong,, R. J. Westrick,, J. S. Arthur,, K. Otsu,, A. Hoffmann,, M. Montminy, and, M. Karin. 2005. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis—CREB and NF-kappaB as key regulators. Immunity 23:319329.
71. Pasparakis, M.,, G. Courtois,, M. Hafner,, M. Schmidt-Supprian,, A. Nenci,, A. Toksoy,, M. Krampert,, M. Goebeler,, R. Gillitzer,, A. Israel,, T. Krieg,, K. Rajewsky, and, I. Haase. 2002. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417:861866.
72. Pham, C. G.,, C. Bubici,, F. Zazzeroni,, S. Papa,, J. Jones,, K. Alvarez,, S. Jayawardena,, E. De Smaele,, R. Cong,, C. Beaumont,, F. M. Torti,, S. V. Torti, and, G. Franzoso. 2004. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 119:529542.
73. Pohl, T.,, R. Gugasyan,, R. J. Grumont,, A. Strasser,, D. Metcalf,, D. Tarlinton,, W. Sha,, D. Baltimore, and, S. Gerondakis. 2002. The combined absence of NF-kappa B1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells. Proc. Natl. Acad. Sci. USA 99:45144519.
74. Saccani, S.,, S. Pantano, and, G. Natoli. 2003. Modulation of NF-kappaB activity by exchange of dimers. Mol. Cell 11:15631574.
75. Sakurai, H.,, H. Chiba,, H. Miyoshi,, T. Sugita, and, W. Toriumi. 1999. IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J. Biol. Chem. 274:3035330356.
76. Sanjabi, S.,, K. J. Williams,, S. Saccani,, L. Zhou,, A. Hoffmann,, G. Ghosh,, S. Gerondakis,, G. Natoli, and, S. T. Smale. 2005. A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. Genes Dev. 19:21382151.
77. Schulze-Luehrmann, J., and, S. Ghosh. 2006. Antigen-receptor signaling to nuclear factor kappa B. Immunity 25:701715.
78. Schwarz, E. M.,, C. Badorff,, T. S. Hiura,, R. Wessely,, A. Badorff,, I. M. Verma, and, K. U. Knowlton. 1998. NF-kappaB-mediated inhibition of apoptosis is required for encephalomyocarditis virus virulence: a mechanism of resistance in p50 knockout mice. J. Virol. 72:56545660.
79. Sen, R., and, D. Baltimore. 1986. Inducibility of κ immunoglobulin enhancer-binding protein NF-kB by a posttranslational mechanism. Cell 47:921928.
80. Sen, R., and, D. Baltimore. 1986. Multiple nuclear factors interact with the immunoglobulin enhancers. Cell 46:705716.
81. Senftleben, U.,, Y. Cao,, G. Xiao,, F. R. Greten,, G. Krahn,, G. Bonizzi,, Y. Chen,, Y. Hu,, A. Fong,, S. C. Sun, and, M. Karin. 2001. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293:14951499.
82. Sha, W. C.,, H. C. Liou,, E. I. Tuomanen, and, D. Baltimore. 1995. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80:321330.
83. Siebenlist, U.,, K. Brown, and, E. Claudio. 2005. Control of lymphocyte development by nuclear factor-kappaB. Nat. Rev. Immunol. 5:435445.
84. Sil, A. K.,, S. Maeda,, Y. Sano,, D. R. Roop, and, M. Karin. 2004. IkappaB kinase-alpha acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428:660664.
85. Speirs, K.,, L. Lieberman,, J. Caamano,, C. A. Hunter, and, P. Scott. 2004. Cutting edge: NF-kappaB2 is a negative regulator of dendritic cell function. J. Immunol 172:752756.
86. Steinbrecher, K. A.,, W. Wilson, III,, P. C. Cogswell, and, A. S. Baldwin. 2005. Glycogen synthase kinase 3β functions to specify gene-specific, NF-κB-dependent transcription. Mol. Cell. Biol. 25:84448455.
87. Tang, G.,, Y. Minemoto,, B. Dibling,, N. H. Purcell,, Z. Li,, M. Karin, and, A. Lin. 2001. Inhibition of JNK activation through NF-kappaB target genes. Nature 414:313317.
88. Thanos, D., and, T. Maniatis. 1995. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell 83:10911100.
89. Tian, B.,, Y. Zhang,, B. A. Luxon,, R. P. Garofalo,, A. Casola,, M. Sinha, and, A. R. Brasier. 2002. Identification of NF-kappaB-dependent gene networks in respiratory syncytial virus-infected cells. J. Virol. 76:68006814.
90. Wang, J.,, X. Wang,, S. Hussain,, Y. Zheng,, S. Sanjabi,, F. Ouaaz, and, A. A. Beg. 2007. Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells. J. Immunol. 178:67776788.
91. Wang, X.,, S. Hussain,, E. J. Wang,, X. Wang,, M. O. Li,, A. Garcia-Sastre, and, A. A. Beg. 2007. Lack of essential role of NF-kappa B p50, RelA, and cRel subunits in virus-induced type 1 IFN expression. J. Immunol. 178:67706776.
92. Weih, F., and, J. Caamano. 2003. Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol. Rev. 195:91105.
93. Weih, F.,, D. Carrasco,, S. K. Durham,, D. S. Barton,, C. A. Rizzo,, R.-P. Ryseck,, S. A. Lira, and, R. Bravo. 1995. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κB/Rel family. Cell 80:331340.
94. Werner, S. L.,, D. Barken, and, A. Hoffmann. 2005. Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 309:18571861.
95. Yamamoto, M.,, S. Yamazaki,, S. Uematsu,, S. Sato,, H. Hemmi,, K. Hoshino,, T. Kaisho,, H. Kuwata,, O. Takeuchi,, K. Takeshige,, T. Saitoh,, S. Yamaoka,, N. Yamamoto,, S. Yamamoto,, T. Muta,, K. Takeda, and, S. Akira. 2004. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature 430:218222.
96. Yamamoto, Y.,, U. N. Verma,, S. Prajapati,, Y. T. Kwak, and, R. B. Gaynor. 2003. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature 423:655659.
97. Yang, F.,, E. Tang,, K. Guan, and, C. Y. Wang. 2003. IKK beta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. J. Immunol. 170:56305635.
98. Zaragoza, C.,, M. Saura,, E. Y. Padalko,, E. Lopez-Rivera,, T. R. Lizarbe,, S. Lamas, and, C. J. Lowenstein. 2006. Viral protease cleavage of inhibitor of kappaBalpha triggers host cell apoptosis. Proc. Natl. Acad. Sci. USA 103:1905119056.
99. Zhang, X.,, H. Wang,, E. Claudio,, K. Brown, and, U. Siebenlist. 2007. A role for the IkappaB family member Bcl-3 in the control of central immunologic tolerance. Immunity 27:438452.
100. Zhao, T.,, L. Yang,, Q. Sun,, M. Arguello,, D. W. Ballard,, J. Hiscott, and, R. Lin. 2007. The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathways. Nat. Immunol. 8:592600.
101. Zheng, Y.,, M. Vig,, J. Lyons,, L. Van Parijs, and, A. A. Beg. 2003. Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for NF-κB in regulating mature T cell survival and in vivo function. J. Exp. Med. 197:861874.
102. Zhong, H.,, R. E. Voll, and, S. Ghosh. 1998. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol. Cell. 1:661671.
103. Zhu, M.,, R. K. Chin,, P. A. Christiansen,, J. C. Lo,, X. Liu,, C. Ware,, U. Siebenlist, and, Y. X. Fu. 2006. NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J. Clin. Invest. 116:29642971.

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