IκB kinase β (IKKβ/IKK2/IKBKB)-A key molecule in signaling to the transcription factor NF-κB

Cytokine and Growth Factor Reviews

Volumn 19, Issue 2, 2008, Pages 157-165

  Schmid, Johannes A ^a,b   Birbach, Andreas ^b  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

^b MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

Kinase inhibitors; NF B; Signaling cascades; Ubiquitination

Indexed keywords

1 [5 HYDROXY 2 (2 THIENYL) 4 QUINAZOLINYLAMINO] 3 METHYL 2,5 PYRROLEDIONE; 4 (2 AMINOETHYLAMINO) 1,8 DIMETHYLIMIDAZO[1,2 A]QUINOXALINE; 6 CHLORO 7 METHOXY 8 (2 METHYLNICOTINAMIDO) BETA CARBOLINE; 6 CHLORO 8 NICOTINAMIDO BETA CARBOLINE; ACETYLSALICYLIC ACID; ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; ARSENIC TRIOXIDE; BETA CARBOLINE DERIVATIVE; DOUBLE STRANDED RNA; I KAPPA B; I KAPPA B BETA; I KAPPA B KINASE INHIBITOR; IMD 0354; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1; LIPOPOLYSACCHARIDE; N [6 (4 CHLOROPHENOXY)HEXYL] N' CYANO N'' (4 PYRIDYL)GUANIDINE; OXAZINE DERIVATIVE; PROTEASOME; PYRIDOOXAZIN DERIVATIVE; QUINAZOLINE DERIVATIVE; SALICYLATE SODIUM; SC 514; SERINE; SULINDAC; THALIDOMIDE; THIOPHENE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; UNINDEXED DRUG; UREIDOCARBOXAMIDE THIOPHENE DERIVATIVE; I KAPPA B KINASE; UBIQUITIN;

ARTHRITIS; CELL DIFFERENTIATION; CELL LEVEL; CELL PROLIFERATION; CELL SURVIVAL; CHRONIC INFLAMMATION; CHRONIC MYELOID LEUKEMIA; CLINICAL FEATURE; CLINICAL TRIAL; DRUG INHIBITION; ENZYME ACTIVITY; HUMAN; IC 50; IMMUNE SYSTEM; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; SHORT SURVEY; SIGNAL TRANSDUCTION; UBIQUITINATION; ULTRAVIOLET IRRADIATION; VIRUS INFECTION; AMINO ACID SEQUENCE; ANIMAL; APOPTOSIS; BIOLOGICAL MODEL; ENZYME SPECIFICITY; METABOLISM; MOLECULAR GENETICS; MOUSE; PHOSPHORYLATION; PHYSIOLOGY; REVIEW; SEQUENCE HOMOLOGY; TRANSGENIC MOUSE;

AMINO ACID SEQUENCE; ANIMALS; APOPTOSIS; HUMANS; I-KAPPA B KINASE; MICE; MICE, TRANSGENIC; MODELS, BIOLOGICAL; MOLECULAR SEQUENCE DATA; NF-KAPPA B; PHOSPHORYLATION; SEQUENCE HOMOLOGY, AMINO ACID; SIGNAL TRANSDUCTION; SUBSTRATE SPECIFICITY; UBIQUITIN;

EID: 40749090052     PISSN: 13596101     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.cytogfr.2008.01.006     Document Type: Short Survey

References (93)

1. Hacker H., and Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE 2006 (2006) re13
2. Perkins N.D. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8 (2007) 49-62
3. Scheidereit C. IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene 25 (2006) 6685-6705
4. Hayden M.S., and Ghosh S. Signaling to NF-{kappa}B. Genes Develop 18 (2004) 2195-2224
5. Perkins N.D., and Gilmore T.D. Good cop, bad cop: the different faces of NF-kappaB. Cell Death Differ 13 (2006) 759-772
6. Karin M. NF-kappaB and cancer: mechanisms and targets. Mol Carcinog 45 (2006) 355-361
7. Karin M., and Greten F.R. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5 (2005) 749-759
8. Basseres D.S., and Baldwin A. Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene 25 (2006) 6817-6830
9. Courtois G., and Gilmore T.D. Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene 25 (2006) 6831-6843
10. Hayden M.S., West A.P., and Ghosh S. NF-kappaB and the immune response. Oncogene 25 (2006) 6758-6780
11. Kim H.J., Hawke N., and Baldwin A.S. NF-kappaB and IKK as therapeutic targets in cancer. Cell Death Differ 13 (2006) 738-747
12. Yamamoto Y., and Gaynor R.B. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 107 (2001) 135-142
13. Nolan G.P., Ghosh S., Liou H.C., Tempst P., and Baltimore D. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell 64 (1991) 961-969
14. Huxford T., Huang D.B., Malek S., and Ghosh G. The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation. Cell 95 (1998) 759-770
15. Jacobs M.D., and Harrison S.C. Structure of an IkappaBalpha/NF-kappaB complex. Cell 95 (1998) 749-758
16. Birbach A., Gold P., Binder B.R., Hofer E., de Martin R., and Schmid J.A. Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus. J Biol Chem 277 (2002) 10842-10851
17. Huang T.T., Kudo N., Yoshida M., and 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 USA 97 (2000) 1014-1019
18. Johnson C., Van Antwerp D., and Hope T.J. An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. Embo J 18 (1999) 6682-6693
19. Fuchs S.Y., Spiegelman V.S., and Kumar K.G. The many faces of beta-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer. Oncogene 23 (2004) 2028-2036
20. Tan P., Fuchs S.Y., Chen A., Wu K., Gomez C., Ronai Z., et al. Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha. Mol Cell 3 (1999) 527-533
21. Yaron A., Hatzubai A., Davis M., Lavon I., Amit S., Manning A.M., et al. Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature 396 (1998) 590-594
22. DiDonato J.A., Hayakawa M., Rothwarf D.M., Zandi E., and Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388 (1997) 548-554
23. Mercurio F., Zhu H., Murray B.W., Shevchenko A., Bennett B.L., Li J., et al. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 278 (1997) 860-866
24. Woronicz J.D., Gao X., Cao Z., Rothe M., and Goeddel D.V. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 278 (1997) 866-869
25. Zandi E., Rothwarf D.M., Delhase M., Hayakawa M., and Karin M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91 (1997) 243-252
26. Rothwarf D.M., Zandi E., Natoli G., and Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395 (1998) 297-300
27. Yamaoka S., Courtois G., Bessia C., Whiteside S.T., Weil R., Agou F., et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93 (1998) 1231-1240
28. Solt L.A., Madge L.A., Orange J.S., and May M.J. Interleukin-1-induced NF-kappaB activation is NEMO-dependent but does not require IKKbeta. J Biol Chem 282 (2007) 8724-8733
29. Sato S., Sanjo H., Takeda K., Ninomiya-Tsuji J., Yamamoto M., Kawai T., et al. Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 6 (2005) 1087-1095
30. Yang J., Lin Y., Guo Z., Cheng J., Huang J., Deng L., et al. The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat Immunol 2 (2001) 620-624
31. Inohara N., Koseki T., Lin J., del Peso L., Lucas P.C., Chen F.F., et al. An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem 275 (2000) 27823-27831
32. Tegethoff S., Behlke J., and Scheidereit C. Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation. Mol Cell Biol 23 (2003) 2029-2041
33. Chen Z.J. Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7 (2005) 758-765
34. Chen Z.J., Parent L., and Maniatis T. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 84 (1996) 853-862
35. Deng L., Wang C., Spencer E., Yang L., Braun A., You J., et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103 (2000) 351-361
36. Wang C., Deng L., Hong M., Akkaraju G.R., Inoue J., and Chen Z.J. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412 (2001) 346-351
37. Chen Z.J., Bhoj V., and Seth R.B. Ubiquitin, TAK1 and IKK: is there a connection?. Cell Death Differ (2006)
38. May M.J., Larsen S.E., Shim J.H., Madge L.A., and Ghosh S. A novel ubiquitin-like domain in IkappaB kinase beta is required for functional activity of the kinase. J Biol Chem 279 (2004) 45528-45539
39. Boone D.L., Turer E.E., Lee E.G., Ahmad R.C., Wheeler M.T., Tsui C., et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5 (2004) 1052-1060
40. Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S., et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430 (2004) 694-699
41. Brummelkamp T.R., Nijman S.M., Dirac A.M., and Bernards R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424 (2003) 797-801
42. Kovalenko A., Chable-Bessia C., Cantarella G., Israel A., Wallach D., and Courtois G. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424 (2003) 801-805
43. Karin M. How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene 18 (1999) 6867-6874
44. Prajapati S., Verma U., Yamamoto Y., Kwak Y.T., and Gaynor R.B. Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity. J Biol Chem 279 (2004) 1739-1746
45. Chen L.F., and Greene W.C. Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 5 (2004) 392-401
46. Yang F., Tang E., Guan K., and Wang C.Y. IKK beta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. J Immunol 170 (2003) 5630-5635
47. Beinke S., Robinson M.J., Hugunin M., and Ley S.C. Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105. Mol Cell Biol 24 (2004) 9658-9667
48. Waterfield M., Jin W., Reiley W., Zhang M., and Sun S.C. IkappaB kinase is an essential component of the Tpl2 signaling pathway. Mol Cell Biol 24 (2004) 6040-6048
49. Wegener E., Oeckinghaus A., Papadopoulou N., Lavitas L., Schmidt-Supprian M., Ferch U., et al. Essential role for IkappaB kinase beta in remodeling Carma1-Bcl10-Malt1 complexes upon T cell activation. Mol Cell 23 (2006) 13-23
50. Wu Z.H., Shi Y., Tibbetts R.S., and Miyamoto S. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science 311 (2006) 1141-1146
51. Hu M.C., Lee D.F., Xia W., Golfman L.S., Ou-Yang F., Yang J.Y., et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117 (2004) 225-237
52. Gringhuis S.I., Garcia-Vallejo J.J., van Het Hof B., and van Dijk W. Convergent actions of I kappa B kinase beta and protein kinase C delta modulate mRNA stability through phosphorylation of 14-3-3 beta complexed with tristetraprolin. Mol Cell Biol 25 (2005) 6454-6463
53. Gao Z., Hwang D., Bataille F., Lefevre M., York D., Quon M.J., et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277 (2002) 48115-48121
54. Lee S., Andrieu C., Saltel F., Destaing O., Auclair J., Pouchkine V., et al. IkappaB kinase beta phosphorylates Dok1 serines in response to TNF, IL-1, or gamma radiation. Proc Natl Acad Sci USA 101 (2004) 17416-17421
55. Gerondakis S., Grumont R., Gugasyan R., Wong L., Isomura I., Ho W., et al. Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 25 (2006) 6781-6799
56. Li Q., Van Antwerp D., Mercurio F., Lee K.F., and Verma I.M. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284 (1999) 321-325
57. Beg A.A., Sha W.C., Bronson R.T., Ghosh S., and Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376 (1995) 167-170
58. Park J.M., Greten F.R., Wong A., Westrick R.J., Arthur J.S., Otsu K., et al. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis-CREB and NF-kappaB as key regulators. Immunity 23 (2005) 319-329
59. Ruocco M.G., Maeda S., Park J.M., Lawrence T., Hsu L.C., Cao Y., et al. I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J Exp Med 201 (2005) 1677-1687
60. Chen L.W., Egan L., Li Z.W., Greten F.R., Kagnoff M.F., and Karin M. The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med 9 (2003) 575-581
61. Herrmann O., Baumann B., de Lorenzi R., Muhammad S., Zhang W., Kleesiek J., et al. IKK mediates ischemia-induced neuronal death. Nat Med 11 (2005) 1322-1329
62. Pasparakis M., Courtois G., Hafner M., Schmidt-Supprian M., Nenci A., Toksoy A., et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417 (2002) 861-866
63. Maeda S., Chang L., Li Z.W., Luo J.L., Leffert H., and Karin M. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 19 (2003) 725-737
64. Maeda S., Kamata H., Luo J.L., Leffert H., and Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121 (2005) 977-990
65. Lawrence T., Bebien M., Liu G.Y., Nizet V., and Karin M. IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 434 (2005) 1138-1143
66. Arkan M.C., Hevener A.L., Greten F.R., Maeda S., Li Z.W., Long J.M., et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11 (2005) 191-198
67. Pasparakis M., Schmidt-Supprian M., and Rajewsky K. IkappaB kinase signaling is essential for maintenance of mature B cells. J Exp Med 196 (2002) 743-752
68. Schmidt-Supprian M., Tian J., Grant E.P., Pasparakis M., Maehr R., Ovaa H., et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc Natl Acad Sci USA 101 (2004) 4566-4571
69. Cai D., Frantz J.D., Tawa Jr. N.E., Melendez P.A., Oh B.C., Lidov H.G., et al. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119 (2004) 285-298
70. Voll R.E., Jimi E., Phillips R.J., Barber D.F., Rincon M., Hayday A.C., et al. NF-kappa B activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13 (2000) 677-689
71. Yin M.J., Yamamoto Y., and Gaynor R.B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396 (1998) 77-80
72. Yamamoto Y., Yin M.J., Lin K.M., and Gaynor R.B. Sulindac inhibits activation of the NF-kappaB pathway. J Biol Chem 274 (1999) 27307-27314
73. Keifer J.A., Guttridge D.C., Ashburner B.P., and Baldwin Jr. A.S. Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 276 (2001) 22382-22387
74. Rossi A., Kapahi P., Natoli G., Takahashi T., Chen Y., Karin M., et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 403 (2000) 103-108
75. Waxman S., and Anderson K.C. History of the development of arsenic derivatives in cancer therapy. Oncologist 6 Suppl. 2 (2001) 3-10
76. Kapahi P., Takahashi T., Natoli G., Adams S.R., Chen Y., Tsien R.Y., et al. Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J Biol Chem 275 (2000) 36062-36066
77. Reynaert N.L., van der Vliet A., Guala A.S., McGovern T., Hristova M., Pantano C., et al. Dynamic redox control of NF-kappaB through glutaredoxin-regulated S-glutathionylation of inhibitory kappaB kinase beta. Proc Natl Acad Sci USA 103 (2006) 13086-13091
78. Hammaker D., Sweeney S., and Firestein G.S. Signal transduction networks in rheumatoid arthritis. Ann Rheum Dis 62 Suppl. 2 (2003) ii86-ii89
79. Karin M., Yamamoto Y., and Wang Q.M. The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3 (2004) 17-26
80. Castro A.C., Dang L.C., Soucy F., Grenier L., Mazdiyasni H., Hottelet M., et al. Novel IKK inhibitors: beta-carbolines. Bioorg Med Chem Lett 13 (2003) 2419-2422
81. Kishore N., Sommers C., Mathialagan S., Guzova J., Yao M., Hauser S., et al. A selective IKK-2 inhibitor blocks NF-kappa B-dependent gene expression in interleukin-1 beta-stimulated synovial fibroblasts. J Biol Chem 278 (2003) 32861-32871
82. Nagashima K., Sasseville V.G., Wen D., Bielecki A., Yang H., Simpson C., et al. Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKbeta. Blood 107 (2006) 4266-4273
83. Schopf L., Savinainen A., Anderson K., Kujawa J., DuPont M., Silva M., et al. IKKbeta inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. Arthritis Rheum 54 (2006) 3163-3173
84. Burke J.R., Pattoli M.A., Gregor K.R., Brassil P.J., MacMaster J.F., McIntyre K.W., 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 278 (2003) 1450-1456
85. McIntyre K.W., Shuster D.J., Gillooly K.M., Dambach D.M., Pattoli M.A., Lu P., et al. A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum 48 (2003) 2652-2659
86. MacMaster J.F., Dambach D.M., Lee D.B., Berry K.K., Qiu Y., Zusi F.C., et al. An inhibitor of IkappaB kinase, BMS-345541, blocks endothelial cell adhesion molecule expression and reduces the severity of dextran sulfate sodium-induced colitis in mice. Inflamm Res 52 (2003) 508-511
87. Ziegelbauer K., Gantner F., Lukacs N.W., Berlin A., Fuchikami K., Niki T., et al. A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity. Br J Pharmacol 145 (2005) 178-192
88. Olsen L.S., Hjarnaa P.J., Latini S., Holm P.K., Larsson R., Bramm E., et al. Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity. Int J Cancer 111 (2004) 198-205
89. Kamon J., Yamauchi T., Muto S., Takekawa S., Ito Y., Hada Y., et al. A novel IKKbeta inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance. Biochem Biophys Res Commun 323 (2004) 242-248
90. Gilmore T.D., and Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 25 (2006) 6887-6899
91. Chu L., Gu J., He Z., Xiao T., and Liu X. Adenoviral vector expressing CYLD augments antitumor activity of TRAIL by suppression of NF-kappaB survival signaling in hepatocellular carcinoma. Cancer Biol Ther 5 (2006) 615-622
92. Swinney D.C., Xu Y.Z., Scarafia L.E., Lee I., Mak A.Y., Gan Q.F., et al. A small molecule ubiquitination inhibitor blocks NF-kappa B-dependent cytokine expression in cells and rats. J Biol Chem 277 (2002) 23573-23581
93. Yuan M., Konstantopoulos N., Lee J., Hansen L., Li Z.W., Karin M., et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293 (2001) 1673-1677