Noncanonical NF-κB Signaling in Health and Disease

Trends in Molecular Medicine

Volumn 22, Issue 5, 2016, Pages 414-429

  Cildir, Gökhan ^a,b   Low, Kee Chung ^a   Tergaonkar, Vinay ^a,b,c  

^a INSTITUTE OF MOLECULAR AND CELL BIOLOGY   (Singapore)

^b NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^c UNIVERSITY OF SOUTH AUSTRALIA   (Australia)

Author keywords

NIK; Non canonical NF B signaling; P52 RelB

Indexed keywords

4 (2 AMINOETHYLAMINO) 1,8 DIMETHYLIMIDAZO[1,2 A]QUINOXALINE; ATACICEPT; B CELL ACTIVATING FACTOR; B CELL ACTIVATING FACTOR RECEPTOR; BELIMUMAB; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; BETA INTERFERON; BORTEZOMIB; CARFILZOMIB; CD40 ANTIGEN; CD40 LIGAND; CELL ADHESION MOLECULE; CELL SURFACE RECEPTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDOLEAMINE 2,3 DIOXYGENASE; LATENT MEMBRANE PROTEIN 1; LYMPHOTOXIN BETA RECEPTOR; MONOCLONAL ANTIBODY; NOTCH RECEPTOR; ONCOPROTEIN; OSTEOCLAST DIFFERENTIATION FACTOR; PROTEASOME INHIBITOR; SALINOSPORAMIDE A; STAT3 PROTEIN; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR EZH2; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 2; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 3; UNINDEXED DRUG; PROTEIN BINDING;

ALBERS SCHOENBERG DISEASE; APOPTOSIS; AUTOIMMUNE DISEASE; B LYMPHOCYTE; BONE DISEASE; CANONICAL NF KAPPA B SIGNALING; CELL DIFFERENTIATION; CELL MATURATION; ENZYME PHOSPHORYLATION; HEMATOLOGIC MALIGNANCY; HEMATOPOIESIS; HODGKIN DISEASE; HUMAN; IMMUNITY; IMMUNOPATHOLOGY; INNATE IMMUNITY; LARGE CELL LYMPHOMA; LYMPHOID CELL; METABOLIC DISORDER; MULTIPLE MYELOMA; NASOPHARYNX CARCINOMA; NONCANONICAL NF KAPPA B SIGNALING; NONHUMAN; ORGANOGENESIS; OSTEOCLAST; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; T LYMPHOCYTE SUBPOPULATION; ANIMAL; CELL LINE; CYTOLOGY; DISEASE MODEL; GENETICS; IMMUNE SYSTEM; IMMUNOLOGY; METABOLISM; MOUSE; NEOPLASMS;

ANIMALS; CELL LINE; DISEASE MODELS, ANIMAL; HUMANS; IMMUNE SYSTEM; IMMUNE SYSTEM DISEASES; MICE; NEOPLASMS; NF-KAPPA B; PROTEIN BINDING; SIGNAL TRANSDUCTION;

EID: 84962628953     PISSN: 14714914     EISSN: 1471499X     Source Type: Journal    
DOI: 10.1016/j.molmed.2016.03.002     Document Type: Review

References (141)

1. Tong L., Tergaonkar V. Rho protein GTPases and their interactions with NFkappaB: crossroads of inflammation and matrix biology. Biosci. Rep. 2014, 34:e00115.
2. Perkins N.D. The diverse and complex roles of NF-kappaB subunits in cancer. Nat. Rev. Cancer 2012, 12:121-132.
3. Irelan J.T., et al. A role for IkappaB kinase 2 in bipolar spindle assembly. Proc. Natl. Acad. Sci. U.S.A. 2007, 104:16940-16945.
4. Liao G., et al. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J. Biol. Chem. 2004, 279:26243-26250.
5. Vallabhapurapu S., et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat. Immunol. 2008, 9:1364-1370.
6. Vince J.E., et al. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 2007, 131:682-693.
7. Varfolomeev E., et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 2007, 131:669-681.
8. Zarnegar B.J., et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat. Immunol. 2008, 9:1371-1378.
9. Gardam S., et al. Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response. Blood 2011, 117:4041-4051.
10. Dejardin E., et al. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 2002, 17:525-535.
11. Senftleben U., et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001, 293:1495-1499.
12. Tao Z., et al. p100/IkappaBdelta sequesters and inhibits NF-kappaB through kappaBsome formation. Proc. Natl. Acad. Sci. U.S.A. 2014, 111:15946-15951.
13. Razani B., et al. Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci. Signal. 2010, 3:ra41.
14. Gray C.M., et al. Noncanonical NF-kappaB signaling is limited by classical NF-kappaB activity. Sci. Signal. 2014, 7:ra13.
15. Jin J., et al. The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-kappaB signaling. Nat. Immunol. 2012, 13:1101-1109.
16. Hu H., et al. OTUD7B controls non-canonical NF-kappaB activation through deubiquitination of TRAF3. Nature 2013, 494:371-374.
17. Claudio E., et al. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat. Immunol. 2002, 3:958-965.
18. Allen I.C., et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity 2012, 36:742-754.
19. Miyawaki S., et al. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur. J. Immunol. 1994, 24:429-434.
20. Koike R., et al. The splenic marginal zone is absent in alymphoplastic aly mutant mice. Eur. J. Immunol. 1996, 26:669-675.
21. Shinkura R., et al. Defects of somatic hypermutation and class switching in alymphoplasia (aly) mutant mice. Int. Immunol. 1996, 8:1067-1075.
22. Shinkura R., et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat. Genet. 1999, 22:74-77.
23. Futterer A., et al. The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 1998, 9:59-70.
24. Rooney I.A., et al. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J. Biol. Chem. 2000, 275:14307-14315.
25. Franzoso G., et al. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J. Exp. Med. 1998, 187:147-159.
26. Caamano J.H., et al. Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J. Exp. Med. 1998, 187:185-196.
27. Freyschmidt E.J., et al. Skin inflammation in RelB(-/-) mice leads to defective immunity and impaired clearance of vaccinia virus. J. Allergy Clin. Immunol. 2007, 119:671-679.
28. Weih F., et al. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 1995, 80:331-340.
29. Burkly L., et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 1995, 373:531-536.
30. Shih V.F., et al. Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-kappaB pathways. Nat. Immunol. 2012, 13:1162-1170.
31. Dougall W.C., et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999, 13:2412-2424.
32. Kong Y.Y., et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999, 397:315-323.
33. Franzoso G., et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev. 1997, 11:3482-3496.
34. Batten M., et al. BAFF mediates survival of peripheral immature B lymphocytes. J. Exp. Med. 2000, 192:1453-1466.
35. Schiemann B., et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001, 293:2111-2114.
36. Shulga-Morskaya S., et al. B cell-activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation. J. Immunol. 2004, 173:2331-2341.
37. Yan M., et al. Activation and accumulation of B cells in TACI-deficient mice. Nat. Immunol. 2001, 2:638-643.
38. O'Connor B.P., et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 2004, 199:91-98.
39. Kawabe T., et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994, 1:167-178.
40. Xu J., et al. Mice deficient for the CD40 ligand. Immunity 1994, 1:423-431.
41. Coope H.J., et al. CD40 regulates the processing of NF-kappaB2 p100 to p52. EMBO J. 2002, 21:5375-5385.
42. Saitoh T., et al. TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation. J. Biol. Chem. 2003, 278:36005-36012.
43. Maecker H., et al. TWEAK attenuates the transition from innate to adaptive immunity. Cell 2005, 123:931-944.
44. Wang Z., et al. Constitutive production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression. J. Biol. Chem. 2008, 283:10698-10706.
45. Jellusova J., et al. Context-specific BAFF-R signaling by the NF-kappaB and PI3K pathways. Cell Rep. 2013, 5:1022-1035.
46. Almaden J.V., et al. B-cell survival and development controlled by the coordination of NF-kappaB family members RelB and cRel. Blood 2016, 127:1276-1286.
47. Hahn M., et al. NF-kappaB-inducing kinase is essential for B-cell maintenance in mice. Eur. J. Immunol. 2016, 46:732-741.
48. 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.
49. Lo J.C., et al. Coordination between NF-kappaB family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues. Blood 2006, 107:1048-1055.
50. Lin W.W., et al. The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development. Sci. Signal. 2015, 8:ra88.
51. Mambetsariev N., et al. Nuclear TRAF3 is a negative regulator of CREB in B cells. Proc. Natl. Acad. Sci. U.S.A. 2016, 113:1032-1037.
52. Hu H., et al. Noncanonical NF-kappaB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:12827-12832.
53. Chang J.H., et al. TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. J. Exp. Med. 2014, 211:137-151.
54. Mair F., et al. The NFkappaB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing gammadelta T cells. Elife 2015, 4:e10087.
55. Yu J., et al. T cell-intrinsic function of the noncanonical NF-kappaB pathway in the regulation of GM-CSF expression and experimental autoimmune encephalomyelitis pathogenesis. J. Immunol. 2014, 193:422-430.
56. Tas S.W., et al. Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 2007, 110:1540-1549.
57. Speirs K., et al. Cutting edge: NF-kappa B2 is a negative regulator of dendritic cell function. J. Immunol. 2004, 172:752-756.
58. Katakam A.K., et al. Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells. Proc. Natl. Acad. Sci. U.S.A. 2015, 112:14664-14669.
59. Onder L., et al. Endothelial cell-specific lymphotoxin-beta receptor signaling is critical for lymph node and high endothelial venule formation. J. Exp. Med. 2013, 210:465-473.
60. Jin J., et al. Noncanonical NF-kappaB pathway controls the production of type I interferons in antiviral innate immunity. Immunity 2014, 40:342-354.
61. Jin J., et al. Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages. Nat. Commun. 2015, 6:5930.
62. Lalani A.I., et al. Myeloid cell TRAF3 regulates immune responses and inhibits inflammation and tumor development in mice. J. Immunol. 2015, 194:334-348.
63. Gonzalez-Murillo A., et al. The NFKB inducing kinase modulates hematopoiesis during stress. Stem Cells 2015, 33:2825-2837.
64. Zhao C., et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells 2012, 30:709-718.
65. Wang H.Y., et al. Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:5127-5132.
66. Chen K., et al. Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am. J. Hum. Genet. 2013, 93:812-824.
67. Liu Y., et al. Novel NFKB2 mutation in early-onset CVID. J. Clin. Immunol. 2014, 34:686-690.
68. Warnatz K., et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:13945-13950.
69. Lee C.E., et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood 2014, 124:2964-2972.
70. Yang L., et al. Loss of negative feedback control of nuclear factor-kappaB2 activity in lymphocytes leads to fatal lung inflammation. Am. J. Pathol. 2010, 176:2646-2657.
71. Murray S.E., et al. NF-kappaB-inducing kinase plays an essential T cell-intrinsic role in graft-versus-host disease and lethal autoimmunity in mice. J. Clin. Invest. 2011, 121:4775-4786.
72. Zhang H., et al. NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-kappaB. J. Clin. Invest. 2014, 124:3200-3214.
73. Nakazawa M., et al. NFkappaB2 (p52) promoter activation via Notch signaling pathway in rheumatoid synoviocytes. Int. J. Mol. Med. 2001, 7:31-35.
74. Zhang H., et al. NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-kappaB. J. Clin. Investig. 2014, 124:3200-3214.
75. Miyamoto S. Nuclear initiated NF-kappaB signaling: NEMO and ATM take center stage. Cell Res. 2011, 21:116-130.
76. Keats J.J., et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007, 12:131-144.
77. de Jong S.J., et al. Noncanonical NF-kappaB activation by the oncoprotein Tio occurs through a nonconserved TRAF3-binding motif. Sci. Signal. 2013, 6:ra27.
78. Zhang B., et al. An oncogenic role for alternative NF-kappaB signaling in DLBCL revealed upon deregulated BCL6 expression. Cell Rep. 2015, 11:715-726.
79. Matta H., Chaudhary P.M. Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc. Natl. Acad. Sci. U.S.A. 2004, 101:9399-9404.
80. Eliopoulos A.G., et al. Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-kappaB2 to p52 via an IKKgamma/NEMO-independent signalling pathway. Oncogene 2003, 22:7557-7569.
81. Proust A., et al. p52 Activation in monomorphic B-cell posttransplant lymphoproliferative disorder/diffuse large B-cell lymphoma without BAFF-R expression. Am. J. Pathol. 2011, 179:1630-1637.
82. Park S.G., et al. Up-regulation of cyclin D1 by HBx is mediated by NF-kappaB2/BCL3 complex through kappaB site of cyclin D1 promoter. J. Biol. Chem. 2006, 281:31770-31777.
83. Demchenko Y.N., Kuehl W.M. A critical role for the NFkB pathway in multiple myeloma. Oncotarget 2010, 1:59-68.
84. Fracchiolla N.S., et al. Structural alterations of the NF-kappa B transcription factor lyt-10 in lymphoid malignancies. Oncogene 1993, 8:2839-2845.
85. Chang C.C., et al. Rearranged NFKB-2 genes in lymphoid neoplasms code for constitutively active nuclear transactivators. Mol. Cell. Biol. 1995, 15:5180-5187.
86. Thakur S., et al. Rearrangement and altered expression of the NFKB-2 gene in human cutaneous T-lymphoma cells. Oncogene 1994, 9:2335-2344.
87. Pham L.V., et al. Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-kappaB-inducing kinase while activating both canonical and alternative nuclear factor-kappaB pathways. Blood 2011, 117:200-210.
88. Ranuncolo S.M., et al. Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival. Blood 2012, 120:3756-3763.
89. Rossi D., et al. Alteration of BIRC3 and multiple other NF-kappaB pathway genes in splenic marginal zone lymphoma. Blood 2011, 118:4930-4934.
90. Saitoh Y., et al. Overexpression of NF-kappaB inducing kinase underlies constitutive NF-kappaB activation in lung cancer cells. Lung Cancer 2010, 70:263-270.
91. Uno M., et al. NF-kappaB inducing kinase, a central signaling component of the non-canonical pathway of NF-kappaB, contributes to ovarian cancer progression. PLoS ONE 2014, 9:e88347.
92. Demchenko Y.N., et al. Classical and/or alternative NF-kappaB pathway activation in multiple myeloma. Blood 2010, 115:3541-3552.
93. Rosebeck S., et al. Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 2011, 331:468-472.
94. Nadiminty N., et al. Stat3 activation of NF-(kappa)B p100 processing involves CBP/p300-mediated acetylation. Proc. Natl. Acad. Sci. U.S.A. 2006, 103:7264-7269.
95. De Donatis G.M., et al. NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2. Oncogene 2015, Published online September 14, 2015. 10.1038/onc.2015.331.
96. Iannetti A., et al. Regulation of p53 and Rb links the alternative NF-kappaB pathway to EZH2 expression and cell senescence. PLoS Genet. 2014, 10:e1004642.
97. Vallabhapurapu S.D., et al. Transcriptional repression by the HDAC4-RelB-p52 complex regulates multiple myeloma survival and growth. Nat. Commun. 2015, 6:8428.
98. Li Y., et al. Non-canonical NF-kappaB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nat. Cell. Biol. 2015, 17:1327-1338.
99. Iotsova V., et al. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat. Med. 1997, 3:1285-1289.
100. Xing L., et al. NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis. J. Bone Miner. Res. 2002, 17:1200-1210.
101. Yamashita T., et al. NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J. Biol. Chem. 2007, 282:18245-18253.
102. Whyte M.P., et al. Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 2014, 68:153-161.
103. Moreau P., et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012, 120:947-959.
104. Mortier J., et al. NF-kappaB inducing kinase (NIK) inhibitors: identification of new scaffolds using virtual screening. Bioorg. Med. Chem. Lett. 2010, 20:4515-4520.
105. Demchenko Y.N., et al. Novel inhibitors are cytotoxic for myeloma cells with NFkB inducing kinase-dependent activation of NFkB. Oncotarget 2014, 5:4554-4566.
106. Garcia-Rodriguez J., et al. Inhibition of IkappaB kinase-beta and IkappaB kinase-alpha by heterocyclic adamantyl arotinoids. Bioorg. Med. Chem. 2014, 22:1285-1302.
107. Sanda T., et al. Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor. Clin. Cancer Res. 2005, 11:1974-1982.
108. Gasparian A.V., et al. Selenium compounds inhibit I kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappa B) in prostate cancer cells. Mol. Cancer Ther. 2002, 1:1079-1087.
109. Burke J.R., et al. BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J. Biol. Chem. 2003, 278:1450-1456.
110. Xu Y., et al. SN52, a novel nuclear factor-kappaB inhibitor, blocks nuclear import of RelB:p52 dimer and sensitizes prostate cancer cells to ionizing radiation. Mol. Cancer Ther. 2008, 7:2367-2376.
111. Bekker P.J., et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J. Bone Miner. Res. 2004, 19:1059-1066.
112. Michou L., Brown J.P. Emerging strategies and therapies for treatment of Paget's disease of bone. Drug Des. Devel. Ther. 2011, 5:225-239.
113. Liu Z., Davidson A. BAFF inhibition: a new class of drugs for the treatment of autoimmunity. Exp. Cell Res. 2011, 317:1270-1277.
114. Gilmore T.D., Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 2006, 25:6887-6899.
115. Tergaonkar V., et al. IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy. Mol. Cell Biol. 2003, 23:8070-8083.
116. Tergaonkar V., et al. p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell 2002, 1:493-503.
117. Tergaonkar V., et al. Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity. Nat. Cell Biol. 2005, 7:921-923.
118. Basak S., et al. A fourth IkappaB protein within the NF-kappaB signaling module. Cell 2007, 128:369-381.
119. Liu F., et al. IKK biology. Immunol. Rev. 2012, 246:239-253.
120. Wang V.Y., et al. The transcriptional specificity of NF-kappaB dimers is coded within the kappaB DNA response elements. Cell Rep. 2012, 2:824-839.
121. Siggers T., et al. Principles of dimer-specific gene regulation revealed by a comprehensive characterization of NF-kappaB family DNA binding. Nat. Immunol. 2012, 13:95-102.
122. Zhao B., et al. The NF-kappaB genomic landscape in lymphoblastoid B cells. Cell Rep. 2014, 8:1595-1606.
123. Sun S.C. The noncanonical NF-kappaB pathway. Immunol. Rev. 2012, 246:125-140.
124. Yin L., et al. Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice. Science 2001, 291:2162-2165.
125. Takeda K., et al. Limb and skin abnormalities in mice lacking IKKalpha. Science 1999, 284:313-316.
126. Hu Y., et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 1999, 284:316-320.
127. Matsushima A., et al. Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J. Exp. Med. 2001, 193:631-636.
128. Weih F., et al. p50-NF-kappaB complexes partially compensate for the absence of RelB: severely increased pathology in p50(-/-)relB(-/-) double-knockout mice. J. Exp. Med. 1997, 185:1359-1370.
129. Xu Y., et al. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 1996, 5:407-415.
130. Yeh W.C., et al. Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 1997, 7:715-725.
131. Etemadi N., et al. TRAF2 regulates TNF and NF-kappaB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife 2015, 4:e10592.
132. Conze D.B., et al. Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo. Mol. Cell Biol. 2005, 25:3348-3356.
133. Conte D., et al. Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol. Cell Biol. 2006, 26:699-708.
134. Koni P.A., et al. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 1997, 6:491-500.
135. Girgenrath M., et al. TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. EMBO J. 2006, 25:5826-5839.
136. Zhao Z., et al. TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. J. Immunol. 2007, 179:7949-7958.
137. Zhang X., et al. TWEAK-Fn14 pathway inhibition protects the integrity of the neurovascular unit during cerebral ischemia. J. Cereb. Blood Flow Metab. 2007, 27:534-544.
138. Xia Y., et al. Deficiency of fibroblast growth factor-inducible 14 (Fn14) preserves the filtration barrier and ameliorates lupus nephritis. J. Am. Soc. Nephrol. 2014, 26:1053-1070.
139. Karaca G., et al. TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice. PLoS ONE 2014, 9:e83987.
140. Malle E.K., et al. Nuclear factor kappaB-inducing kinase activation as a mechanism of pancreatic beta cell failure in obesity. J. Exp. Med. 2015, 212:1239-1254.
141. Sheng L., et al. NF-kappaB-inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nat. Med. 2012, 18:943-949.