Phosphorylation meets ubiquitination: The control of NF-κB activity

Annual Review of Immunology

Volumn 18, Issue , 2000, Pages 621-663

  Karin, Michael ^a   Ben Neriah, Yinon ^b  

^a San Diego   (United States)

^b HEBREW UNIVERSITY   (Israel)

Author keywords

IKK; IL 1; Proteasome; Protein kinase; TNF ; Ubiquitin

Indexed keywords

CYTOKINE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1; PROTEASOME; PROTEIN; PROTEIN I KAPPA B; PROTEIN I KAPPA B KINASE; PROTEIN KINASE; TUMOR NECROSIS FACTOR ALPHA; UBIQUITIN; UNCLASSIFIED DRUG;

DROSOPHILA; ENZYME ACTIVATION; ENZYME INACTIVATION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; STOICHIOMETRY;

AMINO ACID SEQUENCE; ANIMALS; DNA-BINDING PROTEINS; DOWN-REGULATION; HUMANS; I-KAPPA B KINASE; I-KAPPA B PROTEINS; MOLECULAR SEQUENCE DATA; NF-KAPPA B; NF-KAPPA B P50 SUBUNIT; PHOSPHORYLATION; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; UBIQUITINS;

EID: 0034084163     PISSN: 07320582     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.immunol.18.1.621     Document Type: Review

References (237)

1. Sen R, Baltimore D. 1986. Inducibility of the immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 47:921-8
2. Baldwin AS. 1996. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649-81
3. Ghosh S, May MJ, Kopp EB. 1998. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16:225-60
4. Miyamoto S, Verma IM. 1995. REl/NF-κB/IκB story. Adv. Cancer Res. 66:255-92
5. Siebenlist U, Franzoso G, Brown K. 1994. Structure, regulation and function of NF-κB. Annu. Rev. Cell. Biol. 10:405-55
6. Attar RM, Caamaño J, Carrasco D, Iotsova V, Ishikawa H, Ryseck RP, Weih F, Bravo R. 1997. Genetic approaches to study Rel/NF-κ B/I κ B function in mice. Semin. Cancer Biol. 8:93-101
7. Whiteside ST, Israël A. 1997. I κ B proteins: structure, function and regulation. Semin. Cancer Biol. 8:75-82
8. Arenzana-Seisdedos F, Turpin P, Rodriguez M, Thomas D, Hay RT, Virelizier JL, Dargemont C. 1997. Nuclear localization of IκBα promotes active transport of NF-κB from the nucleus to the cytoplasm. J. Cell Sci. 110:369-78
9. Klement JF, Rice NR, Car BD, Abbondanzo SJ, Powers GD, Bhatt PH, Chen CH, Rosen CA, Stewart CL. 1996. IκBα deficiency results in a sustained NF-κB response and severe widespread dermatitis in mice. Mol. Cell. Biol. 16:2341-49
10. Beg AA, Sha WC, Bronson RT, Baltimore D. 1995. Constitutive NF-κB activation, enhanced granulopoiesis, and neonatal lethality in IκBα-deficient mice. Genes Dev. 9:2736-46
11. Cheng JD, Ryseck RP, Attar RM, Dambach D, Bravo R. 1998. Functional redundancy of the nuclear factor κB inhibitors (IκBα) and (IκBβ). J. Exp. Med. 188:1055-62
12. Chen FE, Huang D-B, Chen Y-Q, Ghosh G. 1998. Crystal structure of p50/p65 heterodimer of transcription factor NF-κB bound to DNA. Nature 391:410-13
13. Chen YQ, Ghosh S, Ghosh G. 1998. A novel DNA recognition mode by the NF-κB p65 homodimer. Nat. Struct. Biol. 5:67-73
14. Ghosh G, Vanduyne G, Ghosh S, Sigler PB. 1995. Structure of NF-κB p50 homodimer bound to a IκB. Nature 373:303-10
15. Muller CW, Rey FA, Sodeoka M, Verdine GL, Harrison SC. 1995. Structure of the NF-κB homodimer bound to DNA. Nature 373:311-17
16. Huxford T, Huang DB, Malek S, Ghosh G. 1998. The crystal structure of the IκBα/NF-κB complex reveals mechanisms of NF-κB inactivation. Cell 95:759-70
17. Jacobs MD, Harrison SC. 1998. Structure of an IκBα/NF-κB complex. Cell 95:749-58
18. Baeuerle PA, Baichwal VR. 1997. NF-κ B as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv. Immunol. 65:111-37
19. Barnes PJ, Karin M. 1997. Nuclear factor-κB - a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336:1066-71
20. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. 1998. How cells respond to interferons. Annu. Rev. Biochem. 67:227-64
21. Boehm U, Klamp T, Groot M, Howard JC. 1997. Cellular responses to interferon-gamma. Annu. Rev. Immunol. 15: 749-95
22. Roulston A, Lin R, Beauparlant P, Wainberg MA, Hiscott J. 1995. Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-κ B/Rel transcription factors. Microbiol. Rev. 59:481-505
23. Bex F, Gaynor RB. 1998. Regulation of gene expression by HTLV-I Tax protein. Methods 16:83-94
24. Baichwal VR, Baeuerle PA. 1997. Activate NF-κB or die? Curr. Biol. 7:R94-96
25. Sonenshein GE. 1997. Rel/NF-κB transcription factors and the control of apoptosis. Semin. Cancer Biol. 8:113-19
26. Gilmore TD, Koedood M, Piffat KA, White DW. 1996. Rel/NF-κB/IκB proteins and cancer. Oncogene 13:1367-78
27. Luque I, Gélinas C. 1997. Rel/NF-κB and IκB factors in oncogenesis. Semin. Cancer Biol. 8:103-11
28. Grilli M, Memo M. 1999. NF-κB/Rel proteins: a point of convergence of signalling pathways relevant in neuronal function and dysfunction. Biochem. Pharmacol. 57:1-7
29. Lee SJ, Dimtchev A, Lavin MF, Dritschilo A, Jung M. 1998. A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB. Oncogene 17:1821-26
30. Foxwell B, Browne K, Bondeson J, Clarke C, de Martin R, Brennan F, Feldmann M. 1998. Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor alpha production in rheumatoid arthritis is NF-κB dependent. Proc. Natl. Acad. Sci. USA 95:8211-15
31. Barnes PJ, Adcock TM. 1998. Transcription factors and asthma. Eur. Respir. J. 12:221-34
32. Neurath MF, Becker C, Barbulescu K. 1998. Role of NF-κB in immune and inflammatory responses in the gut. Gut 43:856-60
33. Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY, Ballard DW. 1995. Coupling of a signal response domain in IκB to multiple pathways for NF-κB activation. Mol. Cell. Biol. 15:2809-18
34. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. 1995. Control of IκBα proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485-91
35. DiDonato JA, Mercurio F, Karin M. 1995. Phosphorylation of IκBα precedes but is not sufficient for its dissociation from NF-κB. Mol. Cell. Biol. 15:1302-11
36. DiDonato JA, Mercurio F, Rosette C, Wu-li J, Suyang H, Ghosh S, Karin M. 1996. Mapping of the inducible IκB phosphorylation sites that signal its ubiquitination and degradation. Mol. Cell. Biol. 16:1295-304
37. Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA. 1995. Phosphorylation of human IκB on serines 32 and 36 controls IκB proteolysis and NF-κB activation in response to diverse stimuli. EMBO J. 14:2876-83
38. Whiteside T, Ernst MK, LeBail O, Laurent-Winter C, Rice N, Israel A. 1995. N-and C-terminal sequences control degradation of MAD3/IκBα in response to inducers of NF-κB activity. Mol. Cell. Biol. 15:5339-45
39. Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben-Neriah Y. 1998. Identification of the receptor component of the IκBα-ubiquitin ligase. Nature 396:590-4
40. Laney JD, Hochstrasser M. 1999. Substrate targeting in the ubiquitin system. Cell 97:427-30
41. Maniatis T. 1999. A ubiquitin ligase complex essential for the NF-κB, Wnt/ Wingless, and Hedgehog signaling pathways. Genes Dev. 13:505-10
42. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T. 1995. Signal-induced site-specific phosphorylation targets IκB to the ubiquitin-proteasome pathway. Genes Dev. 9:1586-97
43. Scherer DC, Brockman J, Chen Z, Maniatis T, Ballard D. 1995. Signal-induced degradation of IκBα requires site-specific ubiquitination. Proc. Natl. Acad. Sci. USA 92:11259-63
44. Baldi L, Brown K, Franzoso G, Siebenlist U. 1996. Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of IκBα. J. Biol. Chem. 271:376-79
45. Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y. 1995. Stimulation-dependent IκBα phosphorylation marks the NF-κB inhibitor for degradation via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA 92:10599-603
46. Lin Y-C, Brown K, Siebenlist U. 1995. Activation of NF-κB requires proteolysis of the inhibitor IκB: Signal-induced phosphorylation of IκB alone does not release active NF-κB. Proc. Natl. Acad. Sci. USA 92:3003-9
47. Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner EB, Mueller-Dieckmann C, Farahifar D, Rossi B, Auberger P, Baeuerle PA, Peyron JF. 1996. Tyrosine phosphorylation of IκBα activates NF-κB without proteolytic degradation of IκBα. Cell 86:787-98
48. Beraud C, Henzel WJ, Baeuerle PA. 1999. Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-κB activation. Proc. Natl. Acad. Sci. USA 96:429-34
49. Bender K, Gottlicher M, Whiteside S, Rahmsdorf HJ, Herrlich P. 1998. Sequential DNA damage-independent and -dependent activation of NF-κB by UV. EMBO J. 17:5170-81
50. Li N, Karin M. 1998. Ionizing radiation and short wavelength UV activate NF-κB through two distinct mechanisms. Proc. Natl. Acad. Sci. USA 95:13012-17
51. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. 1997. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388:548-54
52. Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A. 1997. IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation. Science 278:860-66
53. Chen ZJ, Parent L, Maniatis T. 1996. Site-specific phosphorylation of IκBα by a novel ubiquitination-dependent protein kinase activity. Cell 84:853-62
54. Lee FS, Hagler J, Chen ZJ, Maniatis T. 1997. Activation of the IκBα kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88:213-22
55. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. 1997. The IκB kinase complex (IKK) contains two kinase subunits, IKKα and IKKβ, necessary for IκB phosphorylation and NF-κB activation. Cell 91:243-52
56. Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M. 1997. Identification and characterization of an IκB kinase. Cell 90:373-83
57. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV. 1997. IκB kinase-β; NF-κB activation and complex formation with IκB kinase-α and NIK. Science 278:866-69
58. Connelly MA, Marcu KB. 1995. CHUK, a new member of the helix-loop-helix and leucine zipper families of interacting proteins, contains a serine-threonine kinase catalytic domain. Cell. Mol. Biol. Res. 41:537-49
59. Rothwarf DM, Zandi E, Natoli G, Karin M. 1998. IKKγ is an essential regulatory subunit of the IκB kinase complex. Nature 395:297-300
60. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, Israel A. 1998. Complementation cloning of NEMO, a component of the IκB kinase complex essential for NF-κB activation. Cell 93:1231-40
61. Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM. 1999. IκB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Mol. Cell. Biol. 19:1526-38
62. Li Y, Kang J, Friedman J, Tarassishin L, Ye J, Kovalenko A, Wallach D, Horwitz MS. 1999. Identification of a cell protein (FIP-3) as a modulator of NF-κB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis. Proc. Natl. Acad. Sci. USA 96:1042-47
63. Gooding LR, Sofola IO, Tollefson AE, Duerksen-Hughes P, Wold WS. 1990. The adenovirus E3-14.7K protein is a general inhibitor of tumor necrosis factor-mediated cytolysis. J. Immunol. 145:3080-86
64. Cohen L, Henzel WJ, Baeuerle PA. 1998. IKAP is a scaffold protein of the IκB kinase complex. Nature 395:292-96
65. Heilker R, Freuler F, Pulfer R, Di Padova F, Eder J. 1999. All three IκB isoforms and most Rel family members are stably associated with the IκB kinase 1/2 complex. Eur. J. Biochem. 259:253-61
66. Otero G, Fellows J, Li Y, de Bizemont T, Dirac AM, Gustafsson CM, Erdjument-Bromage H, Tempst P, Svejstrup JQ. 1999. Elongator, a multisubunit component of a novel RNA polymerase II holo-enzyme for transcriptional elongation. Mol. Cell. 3:109-18
67. Database, YP. Yeast Protein Database http://www.com/database/YPD/blastsw/ yeast/human/IK13.html
68. Zandi E, Chen Y, Karin M. 1998. Direct phosphorylation of IκB by IKKα and IKKβ: discrimination between free and NF-κB-bound substrate. Science 281: 1360-63
69. Li Q, Van Antwerp D, Mercurio F, Lee K-F, Verma IM. 1999. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284:321-25
70. Li Z-W, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R, Karin M. 1999. The IKKβ subunit of IκB kinase (IKK) is essential for NF-κB activation and prevention of apoptosis. J. Exp. Med. 189:1839-45
71. Tanaka M, Fuentes ME, Yamaguchi K, Durnin MH, Dalrymple SA, Hardy KL, Goeddel DV. 1999. Embryonic lethality, liver degeneration, and impaired NF-κB activation in IKK-β-deficient mice. Immunity 10:421-29
72. Chu Z-L, Shin Y-A, Yang J-M, DiDonato JA, Ballard DW. 1999. IKKγ mediates the interaction of cellular IκB kinases with the tax transforming protein of human T cell leukemia virus type 1. J. Biol. Chem. 274:15297-300
73. Burke JR, Miller KR, Wood MK, Meyers CA. 1998. The multisubunit IκB kinase complex shows random sequential kinetics and is activated by the C-terminal domain of IκBα. J. Biol. Chem. 273:12041-46
74. Li J, Peet GW, Pullen SS, Schembri-King J, Warren TC, Marcu KB, Kehry MR, Barton R, Jakes S. 1998. Recombinant IκB kinases α and β are direct kinases of IκBα. J. Biol. Chem. 273:30736-41
75. Ling L, Cao Z, Goeddel DV. 1998. NF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176. Proc. Natl. Acad. Sci. USA 95:2791-97
76. Delhase M, Hayakawa M, Chen Y, Karin M. 1999. Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation. Science 284: 309-13
77. Johnson LN, Noble MEM, Owen DJ. 1996. Active and inactive protein kinases - structural basis for regulation. Cell 85:149-58
78. Lallena MJ, Diaz-Meco MT, Bren G, Payá CV, Moscat J. 1999. Activation of IκB kinase beta by protein kinase C isoforms. Mol. Cell. Biol. 19:2180-88
79. Lin X, Mu Y, Cunningham ET Jr, Marcu KB, Geleziunas R, Greene WC. 1998. Molecular determinants of NF-κB-inducing kinase action. Mol. Cell. Biol. 18:5899-907
80. Romashkova JA, Makarov SS. 1999. NF-κB is a target of AKT in anti-apoptotic PDGF signaling. Nature 401:86-90
81. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. 1999. NF-κB activation by tumor necrosis factor requires the AKT serine-threonine kinase. Nature 401:82-85
82. Nemoto S, DiDonato JA, Lin A. 1998. Coordinate regulation of IκB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-κB-inducing kinase. Mol. Cell. Biol. 18:7336-43
83. Lee FS, Peters RT, Dang LC, Maniatis T. 1998. MEKK1 activates both IκB kinase α and IκB kinase β. Proc. Natl. Acad. Sci. USA 95:9319-24
84. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J. 1999. Regulation of the MEF2 family of transcription factors by p38. Mol. Cell. Biol. 19:21-30
85. Lin X, Cunningham ET Jr, Mu Y, Geleziunas R, Greene WC. 1999. The protooncogene Cot kinase participates in CD3/ CD28 induction of NF-κB acting through the NF-κB-inducing kinase and IκB kinases. Immunity 10:271-80
86. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K. 1999. The kinase TAK1 can activate the NIK-I κB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398:252-56
87. Sakurai H, Miyoshi H, Toriumi W, Sugita T. 1999. Functional interactions of transforming growth factor beta-activated kinase 1 with IκB kinases to stimulate NF-κB activation. J. Biol. Chem. 274:10641-48
88. Malinin NL, Boldin MP, Kovalenko AV, Wallach D. 1997. MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature 385:540-44
89. Song HY, Régnier CH, Kirschning CJ, Goeddel DV, Rothe M. 1997. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-κB and c-jun N-terminal kinase (JNK/ SAPK) pathways at TNF receptor-associated factor 2. Proc. Natl. Acad. Sci. USA 94:9792-96
90. Baud V, Liu Z-G, Bennett B, Suzuki N, Xia Y, Karin M. 1999. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an N-terminal effector domain. Genes Dev. 13:1297-308
91. Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R, Karin M. 1999. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of the IκB kinase. Science 284:316-20
92. Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T, Sanjo H, Yoshikawa K, Terada N, Akira S. 1999. Limb and skin abnormalities in mice lacking IKKα. Science 284:313-16
93. Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M, Kogishi K, Serikawa T, Honjo T. 1999. Alymphoplasia is caused by a point mutation in the mouse gene encoding NF-κB-inducing kinase. Nat. Genet. 22:74-77
94. Eugster HP, Muller M, Karrer U, Car BD, Schnyder B, Eng VM, Woerly G, Le Hir M, di Padova F, Aguet M, Zinkernagel R, Bluethmann H, Ryffel B. 1996. Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-alpha double-deficient mice. Int. Immunol. 8:23-36
95. Xia Y, Wu Z, Su B, Murray B, Karin M. 1998. JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes Dev. 12:3369-81
96. Lee SY, Reichlin A, Santana A, Sokol KA, Nussenzweig MD, Choi Y. 1997. TRAF2 is essential for JNK but not NF-κB activation and regulates lymphocyte proliferation and survival. Immunity 7:703-13
97. Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, de la Pompa JL, Ferrick D, Hum B, Iscove N, Ohashi P, Rothe M, Goeddel DV, Mak TW. 1997. Early lethality, functional NF-κB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7:715-25
98. Seitz CS, Lin Q, Deng H, Khavari PA. 1998. Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB. Proc. Natl. Acad. Sci. USA 95:2307-12
99. Morisato D, Anderson KV. 1995. Signaling pathways that establish the dorsal-ventral pattern of the Drosophila embryo. Annu. Rev. Genet. 29:371-99
100. Pan DJ, Huang JD, Courey AJ. 1991. Functional analysis of the Drosophila twist promoter reveals a dorsal-binding ventral activator region. Genes Dev. 5:1892-901
101. Thisse C, Perrin-Schmitt F, Stoetzel C, Thisse B. 1991. Sequence-specific transactivation of the Drosophila twist gene by the dorsal gene product. Cell 65:1191-201
102. el Ghouzzi V, Le Merrer M, Perrin-Schmitt F, Lajeunie E, Benit P, Renier D, Bourgeois P, Bolcato-Bellemin AL, Munnich A, Bonaventure J. 1997. Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat. Genet. 15:42-46
103. Howard TD, Paznekas WA, Green ED, Chiang LC, Ma N, Ortiz de Luna RI, Garcia Delgado C, Gonzalez-Ramos M, Kline AD, Jabs EW. 1997. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat. Genet. 15:36-41
104. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. 1995. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376:167-69
105. Horwitz BH, Scott ML, Cherry SR, Bronson RT, Baltimore D. 1997. Failure of lymphopoiesis after adoptive transfer of NF-κ B-deficient fetal liver cells. Immunity 6:765-72
106. Doi TS, Marino MW, Takahashi T, Yoshida T, Sakakura T, Old LJ, Obata Y. 1999. Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc. Natl. Acad. Sci. USA 96:2994-99
107. Vandenabeele P, Declercg W, Beyaert R, Fiers W. 1995. Two tumour necrosis factor receptors: structure and function. Trends Cell. Biol. 5:392-99
108. Baker SJ, Reddy EP. 1998. Modulation of life and death by the TNF receptor superfamily. Oncogene 17:3261-70
109. Orlinick JR, Chao MV. 1998. TNF-related ligands and their receptors. Cell Signal. 10:543-51
110. Sims JE, Gayle MA, Slack JL, Alderson MR, Bird TA, Giri JG, Colotta F, Re F, Mantovani A, Shanebeck K, Grabstein KH, Dower SK. 1993. Interleukin 1 signaling occurs exclusively via the type I receptor. Proc. Natl. Acad. Sci. USA 90:6155-59
111. Auron PE. 1998. The interleukin 1 receptor: ligand interactions and signal transduction. Cytokine Growth Factor Rev. 9:221-37
112. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P. 1998. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8:297-303
113. Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA, Ju G. 1995. Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J. Biol. Chem. 270:13757-65
114. Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z. 1997. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837-47
115. Cao Z, Henzel WJ, Gao X. 1996. IRAK: a kinase associated with the interleukin-1 receptor. Science 271:1128-31
116. Muzio M, Ni J, Feng P, Dixit VM. 1997. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278:1612-15
117. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. 1996. TRAF6 is a signal transducer for interleukin-1. Nature 383:443-46
118. Arch RH, Gedrich RW, Thompson CB. 1998. Tumor necrosis factor receptor-associated factors (TRAFs) - a family of adapter proteins that regulates life and death. Genes Dev. 12:2821-30
119. Wajant H, Grell M, Scheurich P. 1999. TNF receptor associated factors in cytokine signaling. Cytokine Growth Factor Rev. 10:15-26
120. Park YC, Burkitt V, Villa AR, Tong L, Wu H. 1999. Structural basis for self-association and receptor recognition of human TRAF2. Nature 398:533-38
121. Rothe M, Sarma V, Dixit VM, Goeddel DV. 1995. TRAF-2-mediated activation of NF-κB by TNF receptor 2 and CD40. Science 269:1424-27
122. Liu Z-G, Hu H, Goeddel DV, Karin M. 1996. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis, while NF-κB activation prevents cell death. Cell 87:565-76
123. Takeuchi M, Rothe M, Goeddel DV. 1996. Anatomy of TRAF2: distinct domains for nuclear factor-κB activation and association with tumor necrosis factor signaling proteins. J. Biol. Chem. 16:19935-42
124. Nakano H, Oshima H, Chung W, Williams-Abbott L, Ware CF, Yagita H, Okumura K. 1996. TRAF5, an activator of NF-κB and putative signal transducer for the lymphotoxin-β receptor. J. Biol. Chem. 271:14661-64
125. Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW. 1999. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 13:1015-24
126. Yuasa T, Ohno S, Kehrl JH, Kyriakis JM. 1998. Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/ Jun NH2-terminal kinase (JNK) and p38. J. Biol. Chem. 273:22681-92
127. Shi CS, Kehrl JH. 1997. Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-κB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2-and germinal center kinase related-dependent pathway. J. Biol. Chem. 272:32102-7
128. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. 1997. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/ JNK and p38 signaling pathways. Science 275:90-94
129. Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H. 1998. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol. Cell. 2:389-95
130. Rusch J, Levine M. 1996. Threshold responses to the dorsal regulatory gradient and the subdivision of primary tissue territories in the Drosophila embryo. Curr. Opin. Genet. Dev. 6:416-23
131. Belvin MP, Anderson KV. 1996. A conserve signaling pathway: the Drosophila toll-dorsal pathway. Annu. Rev. Dev. Biol. 12:393-416
132. Drier EA, Steward R. 1997. The dorsoventral signal transduction pathway and the Rel-like transcription factors in Drosophila. Semin. Cancer Biol. 8:83-92
133. Reach M, Galindo RL, Towb P, Allen JL, Karin M, Wasserman SA. 1996. A gradient of cactus protein degradation establishes dorsoventral polarity in the Drosophila embryo. Dev. Biol. 180:353-64
134. Jiang J, Struhl G. 1998. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391:493-96
135. Knop J, Martin MU. 1999. Effects of IL-1 receptor-associated kinase (IRAK) expression on IL-1 signaling are independent of its kinase activity. FEBS Lett. 448:81-85
136. Maschera B, Ray K, Burns K, Volpe F. 1999. Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-κB. Biochem. J. 339:227-31
137. Kopp EB, Medzhitov R. 1999. The Toll-receptor family and control of innate immunity. Curr. Opin. Immunol. 11:13-18
138. Hoffmann JA, Kafatos FC, Janeway CAJ, Ezekowiz RAB. 1999. Phylogenetic perspectives in innate immunity. Science 284:1313-18
139. Wu LP, Anderson KV. 1998. Regulated nuclear import of Rel proteins in the Drosophila immune response. Nature 392:93-97
140. Dushay MS, Asling B, Hultmark D. 1996. Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila. Proc. Natl. Acad. Sci. USA 93:10343-47
141. Baumeister W, Walz J, Zuhl F, Seemuller E. 1998. The proteasome: paradigm of a self-compartmentalizing protease. Cell 92:367-80
142. Hochstrasser M. 1996. Ubiquitin-dependent protein degradation. Annu. Rev. Genet. 30:405-39
143. Hershko A, Ciechanover A. 1998. The ubiquitin system. Annu. Rev. Biochem. 67:425-79
144. Varshavsky A. 1997. The ubiquitin system. Trends Biochem. Sci. 22:383-87
145. Haas AL, Siepmann TJ. 1997. Pathways of ubiquitin conjugation. FASEB J. 11:1257-68
146. Varshavsky A. 1996. The N-end rule: functions, mysteries, uses. Proc. Natl. Acad. Sci. USA 93:12142-49
147. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. 1993. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495-505
148. Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D. 1997. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J. 16:6325-36
149. Scheffner M, Nuber U, Huibregtse JM. 1995. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature 373:81-83
150. Morgan DO. 1999. Regulation of the APC and the exit from mitosis. Nat. Cell Biol. 1:E47-E52
151. Zachariae W, Nosmyth K. 1999. Whose end is destruction: cell cycle division and the anaphase promoting complex. Genes Dev. 13:2039-58
152. Yamano H, Tsurumi C, Gannon J, Hunt T. 1998. The role of the destruction box and its neighbouring lysine residues in cyclin B for anaphase ubiquitin-dependent proteolysis in fission yeast: defining the D-box receptor. EMBO J. 17:5670-78
153. Fang G, Yu H, Kirschner MW. 1998. Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Mol. Cell. 2:163-71
154. Visintin R, Craig K, Hwang ES, Prinz S, Tyers M, Amon A. 1998. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol. Cell. 2:709-18
155. Peters JM. 1998. SCF and APC: the yin and yang of cell cycle regulated proteolysis. Curr. Opin. Cell. Biol. 10:759-68
156. Patton EE, Willems AR, Tyers M. 1998. Combinatorial control in ubiquitin-dependent proteolysis: Don't Skp the F-box hypothesis. Trends Genet. 14:236-43
157. Seol JH, Feldman RM, Zachariae W, Shevchenko A, Correll CC, Lyapina S, Chi Y, Galova M, Claypool J, Sandmeyer S, Nasmyth K, Deshaies RJ. 1999. Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34. Genes Dev. 13:1614-26
158. Ohta T, Michel JJ, Schottelius AJ, Xiong Y. 1999. ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol. Cell. 3:535-41
159. Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG Jr, Elledge SJ, Conaway RC, Harper JW, Conaway JW. 1999. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657-61
160. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. 1999. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271-75
161. Lonergan KM, Iliopoulos O, Ohh M, Kamura T, Conaway RC, Conaway JW, Kaelin WG Jr. 1998. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol. Cell. Biol. 18:732-41
162. Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC, Conaway JW, Elledge SJ, Harper JW. 1999. Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbxl. Science 284:662-65
163. Sun S, Elwood J, Greene WC. 1996. Both amino-and carboxyl-terminal sequences within I κ B alpha regulate its inducible degradation. Mol. Cell. Biol. 16:1058-65
164. Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S, Beyth S, Mercuric F, Manning AM, Ciechanover A, Ben-Neriah Y. 1997. Inhibition of NF-κB cellular function via specific targeting of the IκB-ubiquitin ligase. EMBO J. 16:6486-94
165. Scott ML, Fujita T, Liou HC, Nolan GP, Baltimore D. 1993. The p65 subunit of NF-κ B regulates IκB by two distinct mechanisms. Genes Dev. 7:1266-76
166. Rice NR, Ernst MK. 1993. In vivo control of NF-κ B activation by IκBα. EMBO J. 12:4685-95
167. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. 1997. Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16:3797-804
168. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. 1997. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 275:1790-92
169. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. 1997. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787-90
170. Palacios J, Gamallo C. 1998. Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res. 58:1344-47
171. Muller O, Nimmrich I, Finke U, Friedl W, Hoffmann I. 1998. A beta-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of beta-catenin germline mutations in FAP patients. Genes Chrom. Cancer 22:37-41
172. Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y. 1998. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 58:2524-27
173. Zurawel RH, Chiappa SA, Allen C, Raffel C. 1998. Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res. 58:896-99
174. Voeller HJ, Truica CI, Gelmann EP. 1998. Beta-catenin mutations in human prostate cancer. Cancer Res. 58:2520-23
175. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. 1998. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 58:1130-34
176. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C. 1998. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl. Acad. Sci. USA 95:8847-51
177. Chan EF, Gat U, McNiff JM, Fuchs E. 1999. A common human skin tumour is caused by activating mutations in beta-catenin. Nat. Genet. 21:410-13
178. Spevak W, Keiper BD, Stratowa C, Castanon MJ. 1993. Saccharomyces cerevisiae cdc15 mutants arrested at a late stage in anaphase are rescued by Xenopus cDNAs encoding N-ras or a protein with beta-transducin repeats. Mol. Cell. Biol. 13:4953-66. Erratum. 1993. 13(11):7199
179. Spevak W, Keiper BD, Stratowa C, Castanon MJ. 1993. Saccharomyces cerevisiae cdc15 mutants arrested at a late stage in anaphase are rescued by Xenopus cDNAs encoding N-ras or a protein with beta-transducin repeats. Mol. Cell. Biol. 13:4953-66. Erratum. 1993. 13(11):7199
180. Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R. 1998. A novel human WD protein, h-beta TrCP, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol. Cell. 1:565-74
181. Suzuki H, Chiba T, Kobayashi M, Takeuchi M, Suzuki T, Ichiyama A, Ikenoue T, Omata M, Furuichi K, Tanaka K. 1999. IκBα ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and beta-TrCP2. Biochem. Biophys. Res. Commun. 256:127-32
182. Hatakeyama S, Kitagawa M, Nakayama K, Shirane M, Matsumoto M, Hattori K, Higashi H, Nakano H, Okumura K, Onoe K, Good RA, Nakayama K. 1999. Ubiquitin-dependent degradation of IκBα is mediated by a ubiquitin ligase Skp1/Cu1 1/F-box protein FWD1. Proc. Natl. Acad. Sci. USA 96:3859-63
183. Kroll M, Margottin F, Kohl A, Renard P, Durand H, Concordet JP, Bachelerie F, Arenzana-Seisdedos F, Benarous R. 1999. Inducible degradation of IκBα by the proteasome requires interaction with the F-box protein h-betaTrCP. J. Biol. Chem. 274:7941-45
184. Spencer E, Jiang J, Chen ZJ. 1999. Signal-induced ubiquitination of IκBα by the F-box protein Slimb/β-TrCP. Genes Dev. 13:284-94
185. Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. 1999. The SCF β-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro. Genes Dev. 13:270-83
186. Fuchs SY, Chen A, Xiong Y, Pan Z-Q, Ronai Z. 1999. HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IκB and β-catenin. Oncogene 18:2039-46
187. Gaudet R, Bohm A, Sigler PB. 1996. Crystal structure at 2.4 angstroms resolution of the complex of transducin beta-gamma and its regulator, phosducin. Cell 87:577-88
188. Sondek J, Bohm A, Lambright DG, Hamm HE, Sigler PB. 1996. Crystal structure of a G-protein beta gamma dimer at 2.1A resolution. Nature 379:369-74.
189. Erratum. 1996. Nature 379(6568):847
190. Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, Tamura T, Tanaka K, Ichihara A. 1992. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 360:597-99
191. Fujiwara T, Suzuki M, Tanigami A, Ikenoue T, Omata M, Chiba T, Tanaka K. 1999. The BTRC gene, encoding a human F-Box/WD40-repeat protein, maps to chromosome 10q24-q25. Genomics 58:104-5
192. Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R, Polakis P. 1999. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr. Biol. 9:207-10
193. Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A, Nakayama K. 1999. An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO J. 18:2401-10
194. Latres E, Chiaur DS, Pagano M. 1999. The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene 18:849-54
195. Liu C, Kato Y, Zhang Z, Do VM, Yankner BA, He X. 1999. Beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation. Proc. Natl. Acad. Sci. USA 96:6273-78
196. Marikawa Y, Elinson RP. 1998. Beta-TrCP is a negative regulator of Wnt/beta-catenin signaling pathway and dorsal axis formation in Xenopus embryos. Mech. Dev. 77:75-80
197. Polakis P. 1997. The adenomatous polyposis coli (APC) tumor suppressor. Biochim. Biophys. Acta 1332:F127-47
198. Chernova O, Cowell JK. 1998. Molecular definition of chromosome translocations involving 10q24 and 19q13 in human malignant glioma cells. Cancer Genet. Cytogenet. 105:60-6
199. Prochownik EV, Eagle Grove L, Deubler D, Zhu XL, Stephenson RA, Rohr LR, Yin X, Brothman AR. 1998. Commonly occurring loss and mutation of the MXI1 gene in prostate cancer. Genes Chrom. Cancer. 22:295-304
200. Kim SK, Ro JY, Kemp BL, Lee JS, Kwon TJ, Hong WK, Mao L. 1998. Identification of two distinct tumor-suppressor loci on the long arm of chromosome 10 in small cell lung cancer. Oncogene 17:1749-53
201. Beg AA, Baltimore D. 1996. An essential role for NF-κB in preventing TNF-α induced cell death. Science 274:782-84
202. Wang C-Y, Mayo MW, Baldwin AS Jr. 1996. TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274:784-87
203. Lin L, DeMartino GN, Greene WC. 1998. Cotranslational biogenesis of NF-κB p50 by the 26S proteasome. Cell 92:819-28
204. Fan CM, Maniatis T. 1991. Generation of p50 subunit of NF-κB by processing of p105 through an ATP-dependent pathway. Nature 354:395-98
205. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. 1994. The ubiquitin-proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB. Cell 78:773-85
206. Orian A, Whiteside S, Israël A, Stancovski I, Schwartz AL, Ciechanover A. 1995. Ubiquitin-mediated processing of NF-κB transcriptional activator precursor p105: reconstitution of a cell-free system and identification of the ubiquitin-carrier protein, E2, and a novel ubiquitin-protein ligase, E3, involved in conjugation. J. Biol. Chem. 270:21707-14
207. Coux O, Goldberg AL. 1998. Enzymes catalyzing ubiquitination and proteolytic processing of the p105 precursor of nuclear factor-κB1. J. Biol. Chem. 273:8820-28
208. MacKichan ML, Logeat F, Israël A. 1996. Phosphorylation of p105 PEST sequence via a redox-insensitive pathway up-regulates processing of p50 NF-κB. J. Biol. Chem. 271:6084-91
209. Mellits KH, Hay RT, Goodbourn S. 1993. Proteolytic degradation of MAD-3 IκBα and enhanced processing of the NF-κB precursor p105 are obligatory steps in the activation of NF-κB. Nucleic Acids Res. 21:5059-66
210. Heissmeyer V, Krappman D, Wulczyn FG, Scheidereit C. 1999. NF-κB p105 is a target for IκB kinases and controls signal induction of Bcl-3-p50 complexes. EMBO J. 18:4766-78
211. Mercurio F, DiDonato J, Rosette C, Karin M. 1993. p105 and p98 precursor proteins play an active role in NF-κB mediated signal transduction. Genes. Dev. 7:705-18
212. Belich MP, Salmerön A, Johnston LH, Ley SC. 1999. TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105. Nature 397:363-68
213. Tamura N, Lottspeich F, Baumeister W, Tamura T. 1998. The role of tricorn protease and its aminopeptidase-interacting factors in cellular protein degradation. Cell 95:637-48
214. Lin L, Ghosh S. 1996. A glycine-rich region in NF-κB p105 functions as a processing signal for the generation of the p50 subunit. Mol. Cell Biol. 16:2248-54
215. Levitskaya J, Sharipo A, Leonchiks A, Ciechanover A, Masucci MG. 1997. Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Proc. Natl. Acad. Sci. USA 94:12616-21
216. Sharipo A, Imreh M, Leonchiks A, Imreh S, Masucci MG. 1998. A minimal glycine-alanine repeat prevents the interaction of ubiquitinated I κB alpha with the proteasome: a new mechanism for selective inhibition of proteolysis. Nat. Med. 4:939-44
217. Orian A, Schwartz AL, Israël A, Whiteside S, Kahana C, Ciechanover A. 1999. Structural motifs involved in ubiquitin-mediated processing of the NF-κB precursor p105: roles of the glycine-rich region and a downstream ubiquitination domain. Mol. Cell. Biol. 19:3664-73
218. Sears C, Olesen J, Rubin D, Finley D, Maniatis T. 1998. NF-κ B p105 processing via the ubiquitin-proteasome pathway. J. Biol. Chem. 273:1409-19
219. Wang D, Baldwin AS Jr. 1998. Activation of nuclear factor-κB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. J. Biol. Chem. 273:29411-16
220. Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S. 1997. The transcriptional activity of NF-κB is regulated by the IκB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 89:413-24
221. Drier EA, Huang LH, Steward R. 1999. Nuclear import of the Drosophila Rel protein dorsal is regulated by phosphorylation. Genes Dev. 13:556-68
222. Sachdev S, Hoffmann A, Hannink M. 1998. Nuclear localization of IκBα is mediated by the second ankyrin repeat: the IκBα ankyrin repeats define a novel class of cis-acting nuclear import sequences. Mol. Cell. Biol. 18:2524-34
223. Turpin P, Hay RT, Dargemont C. 1999. Characterization of IκBα nuclear import pathway. J. Biol. Chem. 274:6804-12
224. Arenzana-Seisdedos F, Thompson J, Rodriguez MS, Bachelerie F, Thomas D, Hay RT. 1995. Inducible nuclear expression of newly synthesized IκB alpha negatively regulates DNA-binding and transcriptional activities of NF-κB. Mol. Cell. Biol. 15:2689-96
225. Wen W, Meinkoth JL, Tsien RY, Taylor SS. 1995. Identification of a signal for rapid export of proteins from the nucleus. Cell 82:463-73
226. Johnson C, Van Antwerp D, Hope TJ. 1999. An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBα. EMBO J. 23:6682-93
227. Lin RT, Beauparlant P, Makris C, Meloche S, Hiscott J. 1996. Phosphorylation of IκBα in the C-terminal pest domain by casein kinase Iu affects intrinsic protein stability. Mol. Cell. Biol. 16:1401-9
228. McElhinny JA, Trushin SA, Bren GD, Chester N, Paya CV. 1996. Casein kinase Ii phosphorylates IκBα at S-283, S-289, S-293, and T-291 and is required for its degradation. Mol. Cell. Biol. 16:899-906
229. Schwarz EM, Vanantwerp D, Verma IM. 1996. Constitutive phosphorylation of IκBα by casein kinase Ii occurs preferentially at serine 293 - requirement for degradation of free IκBα. Mol. Cell. Biol. 16:3554-59
230. Suyang H, Phillips R, Douglas I, Ghosh S. 1996. Role of unphosphorylated, newly synthesized IκBβ in persistent activation of NF-κB. Mol. Cell. Biol. 16:5444-49
231. Tran K, Merika M, Thanos D. 1997. Distinct functional properties of IκBα and IκBβ. Mol. Cell. Biol. 17:5386-99
232. McKinsey TA, Chu ZL, Ballard DW. 1997. Phosphorylation of the PEST domain of IκBβ regulates the function of NF-κB/IκBβ complexes. J. Biol. Chem. 272:22377-80
233. Phillips RJ, Ghosh S. 1997. Regulation of IκB beta in WEHI 231 mature B cells. Mol. Cell. Biol. 17:4390-6
234. DeLuca C, Petropoulus L, Zmeureanu D, Hiscott J. 1999. Nuclear IκBβ maintains persistent NF-κB activation in HIV-1-infected myeloid cells. J. Biol. Chem. 274:13010-6
235. Baeuerle PA, Henkel T. 1994. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12:141-79
236. Chen F, Castranova V, Shi X, Demers LM. 1999. New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases. Clin. Chem. 45:7-17
237. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. 1995. Immuno-suppression by glucocorticoids: Inhibition of NF-κB activity through induction of IkB synthesis. Science 270:286-90