It takes two to tango: IκBs, the multifunctional partners of NF-κB

Immunological Reviews

Volumn 246, Issue 1, 2012, Pages 59-76

  Hinz, Michael ^a   Arslan, Seda Çöl ^a   Scheidereit, Claus ^a  

^a MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE   (Germany)

Author keywords

Atypical I Bs; NF B; Precursor proteins; Typical I Bs

Indexed keywords

CYCLIN D1; DEOXYCHOLIC ACID; I KAPPA B; I KAPPA B ALPHA; I KAPPA B BETA; I KAPPA B ETA; I KAPPA B KINASE EPSILON; I KAPPA B NS; I KAPPA B ZETA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; NUCLEIC ACID BINDING PROTEIN; PROTEIN BCL 3; PROTEIN P100; PROTEIN P105; PROTEIN P50; PROTEIN P52; SYNAPTOTAGMIN I; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ARTICLE; CYTOPLASM; DNA BINDING; FEEDBACK SYSTEM; GENE EXPRESSION; HUMAN; INNATE IMMUNITY; LYMPHOID TISSUE; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION; UBIQUITINATION;

ANIMALS; GENE EXPRESSION REGULATION; HUMANS; I-KAPPA B PROTEINS; NF-KAPPA B; PROTEIN BINDING; SIGNAL TRANSDUCTION;

EID: 84858744393     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2012.01102.x     Document Type: Article

References (231)

1. Kawakami K, Scheidereit C, Roeder RG. Identification and purification of a human immunoglobulin-enhancer-binding protein (NF-kappa B) that activates transcription from a human immunodeficiency virus type 1 promoter in vitro. Proc Natl Acad Sci USA 1988;85:4700-4704.
2. Meyer R, et al. Cloning of the DNA-binding subunit of human nuclear factor kappa B: the level of its mRNA is strongly regulated by phorbol ester or tumor necrosis factor alpha. Proc Natl Acad Sci USA 1991;88:966-970.
3. Courtois G, Gilmore TD. Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene 2006;25:6831-6843.
4. Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell 2008;132:344-362.
5. Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 2009;27:693-733.
6. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986;46:705-716.
7. Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 1986;47:921-928.
8. Lenardo MJ, Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 1989;58:227-229.
9. Baeuerle PA, Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 1988;242:540-546.
10. Baeuerle PA, Baltimore D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell 1988;53:211-217.
11. Baeuerle PA, Baltimore D. A 65-kappaD subunit of active NF-kappaB is required for inhibition of NF-kappaB by I kappaB. Genes Dev 1989;3:1689-1698.
12. Ghosh S, Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature 1990;344:678-682.
13. Naumann M, Scheidereit C. Activation of NF-kappa B in vivo is regulated by multiple phosphorylations. EMBO J 1994;13:4597-4607.
14. Alkalay I, et al. In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B. Mol Cell Biol 1995;15:1294-1301.
15. DiDonato JA, Mercurio F, Karin M. Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B. Mol Cell Biol 1995;15:1302-1311.
16. Finco TS, Beg AA, Baldwin AS Jr. Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors. Proc Natl Acad Sci U S A 1994;91:11884-11888.
17. Lin R, Beauparlant P, Makris C, Meloche S, Hiscott J. Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. Mol Cell Biol 1996;16:1401-1409.
18. Miyamoto S, Maki M, Schmitt MJ, Hatanaka M, Verma IM. Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B. Proc Natl Acad Sci U S A 1994;91:12740-12744.
19. Brockman JA, et al. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol 1995;15:2809-2818.
20. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 1995;267:1485-1488.
21. Mercurio F, et al. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 1997;278:860-866.
22. Rothwarf DM, Zandi E, Natoli G, Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 1998;395:297-300.
23. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 1997;278:866-869.
24. Yamaoka S, et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 1998;93:1231-1240.
25. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 1997;91:243-252.
26. Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr. Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol Cell Biol 1993;13:3301-3310.
27. Brown K, Park S, Kanno T, Franzoso G, Siebenlist U. Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci U S A 1993;90:2532-2536.
28. Mellits KH, Hay RT, Goodbourn S. Proteolytic degradation of MAD3 (I kappa B alpha) and enhanced processing of the NF-kappa B precursor p105 are obligatory steps in the activation of NF-kappa B. Nucleic Acids Res 1993;21:5059-5066.
29. Sun SC, Ganchi PA, Ballard DW, Greene WC. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science 1993;259:1912-1915.
30. Lin YC, Brown K, Siebenlist U. Activation of NF-kappa B requires proteolysis of the inhibitor I kappa B-alpha: signal-induced phosphorylation of I kappa B-alpha alone does not release active NF-kappa B. Proc Natl Acad Sci U S A 1995;92:552-556.
31. Henkel T, Machleidt T, Alkalay I, Kronke M, Ben-Neriah Y, Baeuerle PA. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature 1993;365:182-185.
32. Chen Z, et al. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 1995;9:1586-1597.
33. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 1994;78:773-785.
34. Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y. Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 1995;92:10599-10603.
35. Spencer E, Jiang J, Chen ZJ. Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. Genes Dev 1999;13:284-294.
36. Tan P, et al. Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha. Mol Cell 1999;3:527-533.
37. Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev 1999;13:270-283.
38. Yaron A, et al. Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature 1998;396:590-594.
39. Kanarek N, London N, Schueler-Furman O, Ben-Neriah Y. Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol 2010;2:a000166.
40. Hohmann HP, Remy R, Scheidereit C, van Loon AP. Maintenance of NF-kappa B activity is dependent on protein synthesis and the continuous presence of external stimuli. Mol Cell Biol 1991;11:259-266.
41. Cordle SR, Donald R, Read MA, Hawiger J. Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-kappa B proteins in human monocytic THP-1 cells. J Biol Chem 1993;268:11803-11810.
42. de Martin R, et al. Cytokine-inducible expression in endothelial cells of an I kappa B alpha-like gene is regulated by NF kappa B. EMBO J 1993;12:2773-2779.
43. Le Bail O, Schmidt-Ullrich R, Israel A. Promoter analysis of the gene encoding the I kappa B-alpha/MAD3 inhibitor of NF-kappa B: positive regulation by members of the rel/NF-kappa B family. EMBO J 1993;12:5043-5049.
44. Zabel U, Henkel T, Silva MS, Baeuerle PA. Nuclear uptake control of NF-kappa B by MAD-3, an I kappa B protein present in the nucleus. EMBO J 1993;12:201-211.
45. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996;274:782-784.
46. Klement JF, et al. IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice. Mol Cell Biol 1996;16:2341-2349.
47. Haskill S, et al. Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell 1991;65:1281-1289.
48. Thompson JE, Phillips RJ, Erdjument-Bromage H, Tempst P, Ghosh S. I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell 1995;80:573-582.
49. Zabel U, Baeuerle PA. Purified human I kappa B can rapidly dissociate the complex of the NF-kappa B transcription factor with its cognate DNA. Cell 1990;61:255-265.
50. Li Z, Nabel GJ. A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription. Mol Cell Biol 1997;17:6184-6190.
51. Simeonidis S, Liang S, Chen G, Thanos D. Cloning and functional characterization of mouse IkappaBepsilon. Proc Natl Acad Sci U S A 1997;94:14372-14377.
52. Whiteside ST, Epinat JC, Rice NR, Israel A. I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity. EMBO J 1997;16:1413-1426.
53. Ohno H, Takimoto G, McKeithan TW. The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell 1990;60:991-997.
54. Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K, Siebenlist U. The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition. Nature 1992;359:339-342.
55. Hatada EN, et al. The ankyrin repeat domains of the NF-kappa B precursor p105 and the protooncogene bcl-3 act as specific inhibitors of NF-kappa B DNA binding. Proc Natl Acad Sci U S A 1992;89:2489-2493.
56. Wulczyn FG, Naumann M, Scheidereit C. Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B. Nature 1992;358:597-599.
57. Bours V, et al. The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers. Cell 1993;72:729-739.
58. Fujita T, Nolan GP, Liou HC, Scott ML, Baltimore D. The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-kappa B p50 homodimers. Genes Dev 1993;7:1354-1363.
59. Haruta H, Kato A, Todokoro K. Isolation of a novel interleukin-1-inducible nuclear protein bearing ankyrin-repeat motifs. J Biol Chem 2001;276:12485-12488.
60. Kitamura H, Kanehira K, Okita K, Morimatsu M, Saito M. MAIL, a novel nuclear I kappa B protein that potentiates LPS-induced IL-6 production. FEBS Lett 2000;485:53-56.
61. Yamazaki S, Muta T, Takeshige K. A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei. J Biol Chem 2001;276:27657-27662.
62. Fiorini E, et al. Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor. Mol Cell 2002;9:637-648.
63. Yamauchi S, Ito H, Miyajima A. IkappaBeta, a nuclear IkappaB protein, positively regulates the NF-kappaB-mediated expression of proinflammatory cytokines. Proc Natl Acad Sci U S A 2010;107:11924-11929.
64. Bours V, et al. A novel mitogen-inducible gene product related to p50/p105-NF-kappa B participates in transactivation through a kappa B site. Mol Cell Biol 1992;12:685-695.
65. Bours V, Villalobos J, Burd PR, Kelly K, Siebenlist U. Cloning of a mitogen-inducible gene encoding a kappa B DNA-binding protein with homology to the rel oncogene and to cell-cycle motifs. Nature 1990;348:76-80.
66. Ghosh S, Gifford AM, Riviere LR, Tempst P, Nolan GP, Baltimore D. Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell 1990;62:1019-1029.
67. Kieran M, et al. The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell 1990;62:1007-1018.
68. Neri A, et al. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell 1991;67:1075-1087.
69. Schmid RM, Perkins ND, Duckett CS, Andrews PC, Nabel GJ. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature 1991;352:733-736.
70. Beinke S, Ley SC. Functions of NF-kappaB1 and NF-kappaB2 in immune cell biology. Biochem J 2004;382:393-409.
71. Sun SC. The noncanonical NF-κB pathway. Immunol Rev 2012;246:125-140.
72. Degnan BM, Vervoort M, Larroux C, Richards GS. Early evolution of metazoan transcription factors. Curr Opin Genet Dev 2009;19:591-599.
73. Gilmore TD, Wolenski FS. NF-κB: where did it come from and why? Immunol Rev 2012;246:14-35.
74. Hetru C, Hoffmann JA. NF-kappaB in the immune response of Drosophila. Cold Spring Harb Perspect Biol 2009;1:a000232.
75. Sullivan JC, Kalaitzidis D, Gilmore TD, Finnerty JR. Rel homology domain-containing transcription factors in the cnidarian Nematostella vectensis. Dev Genes Evol 2007;217:63-72.
76. Wang XW, Tan NS, Ho B, Ding JL. Evidence for the ancient origin of the NF-kappaB/IkappaB cascade: its archaic role in pathogen infection and immunity. Proc Natl Acad Sci U S A 2006;103:4204-4209.
77. Wolenski FS, et al. Characterization of the core elements of the NF-kappaB signaling pathway of the sea anemone Nematostella vectensis. Mol Cell Biol 2011;31:1076-1087.
78. Huxford T, Ghosh G. A structural guide to proteins of the NF-kappaB signaling module. Cold Spring Harb Perspect Biol 2009;1:a000075.
79. Li J, Mahajan A, Tsai MD. Ankyrin repeat: a unique motif mediating protein-protein interactions. Biochemistry 2006;45:15168-15178.
80. Zheng C, Yin Q, Wu H. Structural studies of NF-kappaB signaling. Cell Res 2011;21:183-195.
81. Lernbecher T, Kistler B, Wirth T. Two distinct mechanisms contribute to the constitutive activation of RelB in lymphoid cells. EMBO J 1994;13:4060-4069.
82. Tergaonkar V, Correa RG, Ikawa M, Verma IM. Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity. Nat Cell Biol 2005;7:921-923.
83. Hoffmann A, Levchenko A, Scott ML, Baltimore D. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 2002;298:1241-1245.
84. Memet S, et al. IkappaBepsilon-deficient mice: reduction of one T cell precursor subspecies and enhanced Ig isotype switching and cytokine synthesis. J Immunol 1999;163:5994-6005.
85. Rao P, et al. IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response. Nature 2010;466:1115-1119.
86. Scheibel M, et al. IkappaBbeta is an essential co-activator for LPS-induced IL-1beta transcription in vivo. J Exp Med 2010;207:2621-2630.
87. Cheng JD, Ryseck RP, Attar RM, Dambach D, Bravo R. Functional redundancy of the nuclear factor kappa B inhibitors I kappa B alpha and I kappa B beta. J Exp Med 1998;188:1055-1062.
88. Goudeau B, et al. IkappaBalpha/IkappaBepsilon deficiency reveals that a critical NF-kappaB dosage is required for lymphocyte survival. Proc Natl Acad Sci U S A 2003;100:15800-15805.
89. Samson SI, et al. Combined deficiency in IkappaBalpha and IkappaBepsilon reveals a critical window of NF-kappaB activity in natural killer cell differentiation. Blood 2004;103:4573-4580.
90. Beg AA, Ruben SM, Scheinman RI, Haskill S, Rosen CA, Baldwin AS Jr. I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention. Genes Dev 1992;6:1899-1913.
91. Nolan GP, Ghosh S, Liou HC, Tempst P, Baltimore D. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell 1991;64:961-969.
92. Malek S, Chen Y, Huxford T, Ghosh G. IkappaBbeta, but not IkappaBalpha, functions as a classical cytoplasmic inhibitor of NF-kappaB dimers by masking both NF-kappaB nuclear localization sequences in resting cells. J Biol Chem 2001;276:45225-45235.
93. Tran K, Merika M, Thanos D. Distinct functional properties of IkappaB alpha and IkappaB beta. Mol Cell Biol 1997;17:5386-5399.
94. Hirano F, et al. Alternative splicing variants of IkappaB beta establish differential NF-kappaB signal responsiveness in human cells. Mol Cell Biol 1998;18:2596-2607.
95. Dobrzanski P, Ryseck RP, Bravo R. Differential interactions of Rel-NF-kappa B complexes with I kappa B alpha determine pools of constitutive and inducible NF-kappa B activity. EMBO J 1994;13:4608-4616.
96. Huang TT, Kudo N, Yoshida M, Miyamoto S. A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes. Proc Natl Acad Sci U S A 2000;97:1014-1019.
97. Johnson C, Van Antwerp D, Hope TJ. An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. EMBO J 1999;18:6682-6693.
98. Tam WF, Lee LH, Davis L, Sen R. Cytoplasmic sequestration of rel proteins by IkappaBalpha requires CRM1-dependent nuclear export. Mol Cell Biol 2000;20:2269-2284.
99. Jacobs MD, Harrison SC. Structure of an IkappaBalpha/NF-kappaB complex. Cell 1998;95:749-758.
100. Arenzana-Seisdedos F, Thompson J, Rodriguez MS, Bachelerie F, Thomas D, Hay RT. Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B. Mol Cell Biol 1995;15:2689-2696.
101. Chen L, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 2001;293:1653-1657.
102. Sachdev S, Hoffmann A, Hannink M. Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences. Mol Cell Biol 1998;18:2524-2534.
103. Turpin P, Hay RT, Dargemont C. Characterization of IkappaBalpha nuclear import pathway. J Biol Chem 1999;274:6804-6812.
104. Huang TT, Miyamoto S. Postrepression activation of NF-kappaB requires the amino-terminal nuclear export signal specific to IkappaBalpha. Mol Cell Biol 2001;21:4737-4747.
105. Wuerzberger-Davis SM, et al. Nuclear export of the NF-kappaB inhibitor IkappaBalpha is required for proper B cell and secondary lymphoid tissue formation. Immunity 2011;34:188-200.
106. Bosisio D, Marazzi I, Agresti A, Shimizu N, Bianchi ME, Natoli G. A hyper-dynamic equilibrium between promoter-bound and nucleoplasmic dimers controls NF-kappaB-dependent gene activity. EMBO J 2006;25:798-810.
107. Bergqvist S, Alverdi V, Mengel B, Hoffmann A, Ghosh G, Komives EA. Kinetic enhancement of NF-kappaBxDNA dissociation by IkappaBalpha. Proc Natl Acad Sci U S A 2009;106:19328-19333.
108. Sue SC, Alverdi V, Komives EA, Dyson HJ. Detection of a ternary complex of NF-kappaB and IkappaBalpha with DNA provides insights into how IkappaBalpha removes NF-kappaB from transcription sites. Proc Natl Acad Sci U S A 2011;108:1367-1372.
109. Link E, Kerr LD, Schreck R, Zabel U, Verma I, Baeuerle PA. Purified I kappa B-beta is inactivated upon dephosphorylation. J Biol Chem 1992;267:239-246.
110. DiDonato J, et al. Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol Cell Biol 1996;16:1295-1304.
111. Wu C, Ghosh S. beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta. J Biol Chem 1999;274:29591-29594.
112. Budde LM, Wu C, Tilman C, Douglas I, Ghosh S. Regulation of IkappaBbeta expression in testis. Mol Biol Cell 2002;13:4179-4194.
113. Hertlein E, Wang J, Ladner KJ, Bakkar N, Guttridge DC. RelA/p65 regulation of IkappaBbeta. Mol Cell Biol 2005;25:4956-4968.
114. Phillips RJ, Ghosh S. Regulation of IkappaB beta in WEHI 231 mature B cells. Mol Cell Biol 1997;17:4390-4396.
115. Suyang H, Phillips R, Douglas I, Ghosh S. Role of unphosphorylated, newly synthesized I kappa B beta in persistent activation of NF-kappa B. Mol Cell Biol 1996;16:5444-5449.
116. Malek S, Huang DB, Huxford T, Ghosh S, Ghosh G. X-ray crystal structure of an IkappaBbeta x NF-kappaB p65 homodimer complex. J Biol Chem 2003;278:23094-23100.
117. DeLuca C, Kwon H, Pelletier N, Wainberg MA, Hiscott J. NF-kappaB protects HIV-1-infected myeloid cells from apoptosis. Virology 1998;244:27-38.
118. Shirane M, Hatakeyama S, Hattori K, Nakayama K. Common pathway for the ubiquitination of IkappaBalpha, IkappaBbeta, and IkappaBepsilon mediated by the F-box protein FWD1. J Biol Chem 1999;274:28169-28174.
119. Lee SH, Hannink M. Characterization of the nuclear import and export functions of Ikappa B(epsilon). J Biol Chem 2002;277:23358-23366.
120. Kearns JD, Basak S, Werner SL, Huang CS, Hoffmann A. IkappaBepsilon provides negative feedback to control NF-kappaB oscillations, signaling dynamics, and inflammatory gene expression. J Cell Biol 2006;173:659-664.
121. Mercurio F, DiDonato JA, Rosette C, Karin M. p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. Genes Dev 1993;7:705-718.
122. Naumann M, Nieters A, Hatada EN, Scheidereit C. NF-kappa B precursor p100 inhibits nuclear translocation and DNA binding of NF-kappa B/rel-factors. Oncogene 1993;8:2275-2281.
123. Naumann M, Wulczyn FG, Scheidereit C. The NF-kappa B precursor p105 and the proto-oncogene product Bcl-3 are I kappa B molecules and control nuclear translocation of NF-kappa B. EMBO J 1993;12:213-222.
124. Rice NR, MacKichan ML, Israel A. The precursor of NF-kappa B p50 has I kappa B-like functions. Cell 1992;71:243-253.
125. Scheinman RI, Beg AA, Baldwin AS Jr. NF-kappa B p100 (Lyt-10) is a component of H2TF1 and can function as an I kappa B-like molecule. Mol Cell Biol 1993;13:6089-6101.
126. Gerondakis S, et al. Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 2006;25:6781-6799.
127. Lombardi L, et al. Structural and functional characterization of the promoter regions of the NFKB2 gene. Nucleic Acids Res 1995;23:2328-2336.
128. Ten RM, et al. The characterization of the promoter of the gene encoding the p50 subunit of NF-kappa B indicates that it participates in its own regulation. EMBO J 1992;11:195-203.
129. Belich MP, Salmeron A, Johnston LH, Ley SC. TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. Nature 1999;397:363-368.
130. Harhaj EW, Maggirwar SB, Sun SC. Inhibition of p105 processing by NF-kappaB proteins in transiently transfected cells. Oncogene 1996;12:2385-2392.
131. 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 1999;18:4766-4778.
132. Cohen S, Achbert-Weiner H, Ciechanover A. Dual effects of IkappaB kinase beta-mediated phosphorylation on p105 Fate: SCF(beta-TrCP)-dependent degradation and SCF(beta-TrCP)-independent processing. Mol Cell Biol 2004;24:475-486.
133. Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C. Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha. Mol Cell Biol 2001;21:1024-1035.
134. Lang V, et al. betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932. Mol Cell Biol 2003;23:402-413.
135. Sriskantharajah S, et al. Proteolysis of NF-kappaB1 p105 is essential for T cell antigen receptor-induced proliferation. Nat Immunol 2009;10:38-47.
136. Ishimaru N, Kishimoto H, Hayashi Y, Sprent J. Regulation of naive T cell function by the NF-kappaB2 pathway. Nat Immunol 2006;7:763-772.
137. Basak S, et al. A fourth IkappaB protein within the NF-kappaB signaling module. Cell 2007;128:369-381.
138. Savinova OV, Hoffmann A, Ghosh G. The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol Cell 2009;34:591-602.
139. Solan NJ, Miyoshi H, Carmona EM, Bren GD, Paya CV. RelB cellular regulation and transcriptional activity are regulated by p100. J Biol Chem 2002;277:1405-1418.
140. Derudder E, Dejardin E, Pritchard LL, Green DR, Korner M, Baud V. RelB/p50 dimers are differentially regulated by tumor necrosis factor-alpha and lymphotoxin-beta receptor activation: critical roles for p100. J Biol Chem 2003;278:23278-23284.
141. Lessard L, et al. NF-kappaB2 processing and p52 nuclear accumulation after androgenic stimulation of LNCaP prostate cancer cells. Cell Signal 2007;19:1093-1100.
142. Madge LA, May MJ. Classical NF-kappaB activation negatively regulates noncanonical NF-kappaB-dependent CXCL12 expression. J Biol Chem 2010;285:38069-38077.
143. Saccani S, Pantano S, Natoli G. Modulation of NF-kappaB activity by exchange of dimers. Mol Cell 2003;11:1563-1574.
144. Ghosh S, Hayden MS. New regulators of NF-kappaB in inflammation. Nat Rev Immunol 2008;8:837-848.
145. Yamamoto M, et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature 2004;430:218-222.
146. Nolan GP, et al. The bcl-3 proto-oncogene encodes a nuclear I kappa B-like molecule that preferentially interacts with NF-kappa B p50 and p52 in a phosphorylation-dependent manner. Mol Cell Biol 1993;13:3557-3566.
147. Franzoso G, et al. The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites. EMBO J 1993;12:3893-3901.
148. Watanabe N, Iwamura T, Shinoda T, Fujita T. Regulation of NFKB1 proteins by the candidate oncoprotein BCL-3: generation of NF-kappaB homodimers from the cytoplasmic pool of p50-p105 and nuclear translocation. EMBO J 1997;16:3609-3620.
149. Zhang Q, Didonato JA, Karin M, McKeithan TW. BCL3 encodes a nuclear protein which can alter the subcellular location of NF-kappa B proteins. Mol Cell Biol 1994;14:3915-3926.
150. Bundy DL, McKeithan TW. Diverse effects of BCL3 phosphorylation on its modulation of NF-kappaB p52 homodimer binding to DNA. J Biol Chem 1997;272:33132-33139.
151. Wu CL, Kandarian SC, Jackman RW. Identification of genes that elicit disuse muscle atrophy via the transcription factors p50 and Bcl-3. PLoS ONE 2011;6:e16171.
152. Yang J, Williams RS, Kelly DP. Bcl3 interacts cooperatively with peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha to coactivate nuclear receptors estrogen-related receptor alpha and PPARalpha. Mol Cell Biol 2009;29:4091-4102.
153. Mathas S, et al. Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas. Blood 2005;106:4287-4293.
154. Kashatus D, Cogswell P, Baldwin AS. Expression of the Bcl-3 proto-oncogene suppresses p53 activation. Genes Dev 2006;20:225-235.
155. Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 2006;125:665-677.
156. Westerheide SD, Mayo MW, Anest V, Hanson JL, Baldwin AS Jr. The putative oncoprotein Bcl-3 induces cyclin D1 to stimulate G(1) transition. Mol Cell Biol 2001;21:8428-8436.
157. Massoumi R, et al. Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma. J Exp Med 2009;206:221-232.
158. Harhaj EW, Dixit VM. Regulation of NF-κB by deubiquitinases. Immunol Rev 2012;246:107-124.
159. Dechend R, et al. The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators. Oncogene 1999;18:3316-3323.
160. Keutgens A, et al. The repressing function of the oncoprotein BCL-3 requires CtBP, while its polyubiquitination and degradation involve the E3 ligase TBLR1. Mol Cell Biol 2010;30:4006-4021.
161. Miyazaki I, Simizu S, Okumura H, Takagi S, Osada H. A small-molecule inhibitor shows that pirin regulates migration of melanoma cells. Nat Chem Biol 2010;6:667-673.
162. Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Cell 2002;110:55-67.
163. Dong JT, et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 1995;268:884-886.
164. Kim JH, et al. Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes. Nature 2005;434:921-926.
165. Carmody RJ, Ruan Q, Palmer S, Hilliard B, Chen YH. Negative regulation of toll-like receptor signaling by NF-kappaB p50 ubiquitination blockade. Science 2007;317:675-678.
166. Franzoso G, et al. Critical roles for the Bcl-3 oncoprotein in T cell-mediated immunity, splenic microarchitecture, and germinal center reactions. Immunity 1997;6:479-490.
167. Franzoso G, et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 1997;11:3482-3496.
168. Pene F, et al. The IkappaB family member Bcl-3 coordinates the pulmonary defense against Klebsiella pneumoniae infection. J Immunol 2011;186:2412-2421.
169. Schwarz EM, Krimpenfort P, Berns A, Verma IM. Immunological defects in mice with a targeted disruption in Bcl-3. Genes Dev 1997;11:187-197.
170. Kreisel D, et al. Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis. J Clin Invest 2011;121:265-276.
171. Zhang X, Wang H, Claudio E, Brown K, Siebenlist U. A role for the IkappaB family member Bcl-3 in the control of central immunologic tolerance. Immunity 2007;27:438-452.
172. Motoyama M, Yamazaki S, Eto-Kimura A, Takeshige K, Muta T. Positive and negative regulation of nuclear factor-kappaB-mediated transcription by IkappaB-zeta, an inducible nuclear protein. J Biol Chem 2005;280:7444-7451.
173. Shiina T, et al. Targeted disruption of MAIL, a nuclear IkappaB protein, leads to severe atopic dermatitis-like disease. J Biol Chem 2004;279:55493-55498.
174. Yamazaki S, Matsuo S, Muta T, Yamamoto M, Akira S, Takeshige K. Gene-specific requirement of a nuclear protein, IkappaB-zeta, for promoter association of inflammatory transcription regulators. J Biol Chem 2008;283:32404-32411.
175. Kannan Y, et al. IkappaBzeta augments IL-12- and IL-18-mediated IFN-gamma production in human NK cells. Blood 2011;117:2855-2863.
176. Miyake T, et al. IkappaBzeta is essential for natural killer cell activation in response to IL-12 and IL-18. Proc Natl Acad Sci U S A 2010;107:17680-17685.
177. Raices RM, et al. A novel role for IkappaBzeta in the regulation of IFNgamma production. PLoS ONE 2009;4:e6776.
178. Okamoto K, et al. IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors. Nature 2010;464:1381-1385.
179. Kuwata H, et al. IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation. Immunity 2006;24:41-51.
180. Touma M, et al. Functional role for I kappa BNS in T cell cytokine regulation as revealed by targeted gene disruption. J Immunol 2007;179:1681-1692.
181. Hirotani T, et al. The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. J Immunol 2005;174:3650-3657.
182. Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY. The ankyrin repeat as molecular architecture for protein recognition. Protein Sci 2004;13:1435-1448.
183. Ferreiro DU, Komives EA. Molecular mechanisms of system control of NF-kappaB signaling by IkappaBalpha. Biochemistry 2010;49:1560-1567.
184. Croy CH, Bergqvist S, Huxford T, Ghosh G, Komives EA. Biophysical characterization of the free IkappaBalpha ankyrin repeat domain in solution. Protein Sci 2004;13:1767-1777.
185. Lamboy JA, Kim H, Lee KS, Ha T, Komives EA. Visualization of the nanospring dynamics of the IkappaBalpha ankyrin repeat domain in real time. Proc Natl Acad Sci U S A 2011;108:10178-10183.
186. Sue SC, Cervantes C, Komives EA, Dyson HJ. Transfer of flexibility between ankyrin repeats in IkappaB* upon formation of the NF-kappaB complex. J Mol Biol 2008;380:917-931.
187. Truhlar SM, Torpey JW, Komives EA. Regions of IkappaBalpha that are critical for its inhibition of NF-kappaB. DNA interaction fold upon binding to NF-kappaB. Proc Natl Acad Sci U S A 2006;103:18951-18956.
188. Hatada EN, Naumann M, Scheidereit C. Common structural constituents confer I kappa B activity to NF-kappa B p105 and I kappa B/MAD-3. EMBO J 1993;12:2781-2788.
189. Ghosh G, Wang WY-F, Huang D-B, Fusco A. NF-κB regulation: lessons from structures. Immunol Rev 2012;246:36-58.
190. Huxford T, Huang DB, Malek S, Ghosh G. The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation. Cell 1998;95:759-770.
191. Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-kappaB signaling module. Oncogene 2006;25:6706-6716.
192. Basak S, Behar M, Hoffman A. Lessons from mathematical modeling the NF-κB pathway. Immunol Rev 2012;246:221-238.
193. Kanarek N, Ben-Neriah Y. Regulation of NF-κB by ubiquitination and degradation of the IκBs. Immunol Rev 2012;246:77-94.
194. Usui S, et al. Endogenous Muscle Atrophy F-Box Mediates Pressure Overload-Induced Cardiac Hypertrophy Through Regulation of Nuclear Factor-{kappa}B. Circ Res 2011;109:161-171.
195. Heilker R, et al. The kinetics of association and phosphorylation of IkappaB isoforms by IkappaB kinase 2 correlate with their cellular regulation in human endothelial cells. Biochemistry 1999;38:6231-6238.
196. Kato T Jr, Delhase M, Hoffmann A, Karin M. CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response. Mol Cell 2003;12:829-839.
197. McElhinny JA, Trushin SA, Bren GD, Chester N, Paya CV. Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, and T-291 and is required for its degradation. Mol Cell Biol 1996;16:899-906.
198. Schwarz EM, Van Antwerp D, Verma IM. Constitutive phosphorylation of IkappaBalpha by casein kinase II occurs preferentially at serine 293: requirement for degradation of free IkappaBalpha. Mol Cell Biol 1996;16:3554-3559.
199. Perkins ND. Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene 2006;25:6717-6730.
200. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998;16:225-260.
201. Krappmann D, Wulczyn FG, Scheidereit C. Different mechanisms control signal-induced degradation and basal turnover of the NF-kappaB inhibitor IkappaB alpha in vivo. EMBO J 1996;15:6716-6726.
202. Mathes E, O'Dea EL, Hoffmann A, Ghosh G. NF-kappaB dictates the degradation pathway of IkappaBalpha. EMBO J 2008;27:1357-1367.
203. Alvarez-Castelao B, Castano JG. Mechanism of direct degradation of IkappaBalpha by 20S proteasome. FEBS Lett 2005;579:4797-4802.
204. Pando MP, Verma IM. Signal-dependent and -independent degradation of free and NF-kappa B-bound IkappaBalpha. J Biol Chem 2000;275:21278-21286.
205. Guan Y, Yao H, Zheng Z, Qiu G, Sun K. MiR-125b targets BCL3 and suppresses ovarian cancer proliferation. Int J Cancer 2011;128:2274-2283.
206. Lindenblatt C, Schulze-Osthoff K, Totzke G. IkappaBzeta expression is regulated by miR-124a. Cell Cycle 2009;8:2019-2023.
207. Lei X, et al. Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol 2010;12:193-199.
208. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 1995;376:167-170.
209. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 1996;274:787-789.
210. Wang CY, Mayo MW, Baldwin AS Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 1996;274:784-787.
211. Hinz M, Loser P, Mathas S, Krappmann D, Dorken B, Scheidereit C. Constitutive NF-kappaB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells. Blood 2001;97:2798-2807.
212. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998;281:1680-1683.
213. Zong WX, Edelstein LC, Chen C, Bash J, Gelinas C. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. Genes Dev 1999;13:382-387.
214. Chen C, Edelstein LC, Gelinas C. The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol 2000;20:2687-2695.
215. Grumont RJ, Rourke IJ, Gerondakis S. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev 1999;13:400-411.
216. Bargou RC, et al. High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood 1996;87:4340-4347.
217. Bargou RC, et al. Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest 1997;100:2961-2969.
218. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS Jr. NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 1999;19:5785-5799.
219. Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C, Strauss M. NF-kappaB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999;19:2690-2698.
220. Hinz M, et al. Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med 2002;196:605-617.
221. Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001;194:1861-1874.
222. Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS Jr. A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev 1998;12:968-981.
223. Pikarsky E, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461-466.
224. Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 2011;12:715-723.
225. Chaturvedi MM, Sung B, Yadav VR, Kannappan R, Aggarwal BB. NF-kappaB addiction and its role in cancer: 'one size does not fit all'. Oncogene 2011;30:1615-1630.
226. Lim K-H, Yang Y, Staudt L. Pathogenic importance and therapheutic implications of NF-κB in lymphoid malignancies. Immunol Rev 2012;246:359-378.
227. DiDonato JA, Mercurio F, Karin M. NF-κB and the link between inflammation and cancer. Immunol Rev 2012;246:379-400.
228. Schmidt-Ullrich R, Aebischer T, Hulsken J, Birchmeier W, Klemm U, Scheidereit C. Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. Development 2001;128:3843-3853.
229. Freund C, et al. Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo. Circulation 2005;111:2319-2325.
230. Kaltschmidt B, Kaltschmidt C. NF-kappaB in the nervous system. Cold Spring Harb Perspect Biol 2009;1:a001271.
231. Kasowski M, et al. Variation in transcription factor binding among humans. Science 2010;328:232-235.