The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation

Biochemical Pharmacology

Volumn 85, Issue 6, 2013, Pages 705-717

  Bryan, Holly K ^a   Olayanju, Adedamola ^a   Goldring, Christopher E ^a   Park, B Kevin ^a  

^a UNIVERSITY OF LIVERPOOL   (United Kingdom)

Author keywords

Cell defence; Keap1; Nrf2; Oxidative stress; Regulation

Indexed keywords

CASEIN KINASE II; CAVEOLIN 1; CYSTEINE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MICRORNA; PROTEASOME; TRANSCRIPTION FACTOR NRF2;

AUTOPHAGY; AUTOREGULATION; ENZYME DEGRADATION; HUMAN; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN DEGRADATION; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; REGULATORY MECHANISM; REVIEW; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION; UBIQUITINATION; UPREGULATION;

EID: 84874111758     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2012.11.016     Document Type: Note

References (126)

1. W.O. Osburn, and T.W. Kensler Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults Mutat Res 659 2008 31 39
2. W. Miao, L. Hu, P.J. Scrivens, and G. Batist Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes J Biol Chem 280 2005 20340 20348 (Pubitemid 40776732)
3. X.J. Wang, and D.D. Zhang Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level PLoS One 4 2009 e5492
4. Y. Li, J.D. Paonessa, and Y. Zhang Mechanism of chemical activation of Nrf2 PLoS One 7 2012 e35122
5. K. Chan, R. Lu, J.C. Chang, and Y.W.N.R.F2 Kan a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development Proc Natl Acad Sci USA 93 1996 13943 13948 (Pubitemid 26424225)
6. K. Itoh, K. Igarashi, N. Hayashi, M. Nishizawa, and M. Yamamoto Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins Mol Cell Biol 15 1995 4184 4193
7. J. Maher, and M. Yamamoto The rise of antioxidant signaling - the evolution and hormetic actions of Nrf2 Toxicol Appl Pharmacol 244 2010 4 15
8. N.R. Kitteringham, A. Abdullah, J. Walsh, L. Randle, R.E. Jenkins, and R. Sison Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver J Proteomics 73 2010 1612 1631
9. S. Shin, J. Wakabayashi, M.S. Yates, N. Wakabayashi, P.M. Dolan, and S. Aja Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide Eur J Pharmacol 620 2009 138 144
10. K.I. Tong, A. Kobayashi, F. Katsuoka, and M. Yamamoto Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism Biol Chem 387 2006 1311 1320 (Pubitemid 44691409)
11. T. Nguyen, P.J. Sherratt, and C.B. Pickett Regulatory mechanisms controlling gene expression mediated by the antioxidant response element Annu Rev Pharmacol Toxicol 43 2003 233 260 (Pubitemid 37372641)
12. K. Itoh, T. Chiba, S. Takahashi, T. Ishii, K. Igarashi, and Y. Katoh An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements Biochem Biophys Res Commun 236 1997 313 322 (Pubitemid 27373291)
13. J.D. Hayes, and L.I. McLellan Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress Free Radic Res 31 1999 273 300 (Pubitemid 29452854)
14. W. Lin, G. Shen, X. Yuan, M.R. Jain, S. Yu, and A. Zhang Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co-regulators J Biochem Mol Biol 39 2006 304 310 (Pubitemid 43854546)
15. T.W. Kensler, T.J. Curphey, Y. Maxiutenko, and B.D. Roebuck Chemoprotection by organosulfur inducers of phase 2 enzymes: dithiolethiones and dithiins Drug Metabol Drug Interact 17 2000 3 22 (Pubitemid 32047530)
16. E. Balogun, M. Hoque, P. Gong, E. Killeen, C.J. Green, and R. Foresti Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element Biochem J 371 2003 887 895 (Pubitemid 36578887)
17. R. Garg, S. Gupta, and G.B. Maru Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action Carcinogenesis 29 2008 1022 1032 (Pubitemid 351982248)
18. A. Kode, S. Rajendrasozhan, S. Caito, S.R. Yang, I.L. Megson, and I. Rahman Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells Am J Physiol Lung Cell Mol Physiol 294 2008 L478 L488
19. C.Y. Chen, J.H. Jang, M.H. Li, and Y.J. Surh Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells Biochem Biophys Res Commun 331 2005 993 1000
20. A. Singh, V. Misra, R.K. Thimmulappa, H. Lee, S. Ames, and M.O. Hoque Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer PLoS Med 3 2006 e420
21. T. Ohta, K. Iijima, M. Miyamoto, I. Nakahara, H. Tanaka, and M. Ohtsuji Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth Cancer Res 68 2008 1303 1309 (Pubitemid 351346836)
22. A. Lister, T. Nedjadi, N.R. Kitteringham, F. Campbell, E. Costello, and B. Lloyd Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy Mol Cancer 10 2011 37
23. G.M. DeNicola, F.A. Karreth, T.J. Humpton, A. Gopinathan, C. Wei, and K. Frese Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis Nature 475 2011 106 109
24. T.W. Kensler, N. Wakabayashi, and S. Biswal Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway Annu Rev Pharmacol Toxicol 47 2007 89 116
25. I.M. Copple The Keap1-Nrf2 cell defense pathway - a promising therapeutic target Adv Pharmacol 63 2012 43 79
26. M.I. Kang, A. Kobayashi, N. Wakabayashi, S.G. Kim, and M. Yamamoto Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes Proc Natl Acad Sci USA 101 2004 2046 2051 (Pubitemid 38229012)
27. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, and J.D. Engel Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain Genes Dev 13 1999 76 86 (Pubitemid 29045117)
28. S. Dhakshinamoorthy, and A.K. Jaiswal Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene Oncogene 20 2001 3906 3917 (Pubitemid 32646201)
29. L.M. Zipper, and R.T. Mulcahy The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm J Biol Chem 277 2002 36544 36552
30. K. Itoh, J. Mimura, and M. Yamamoto Discovery of the negative regulator of Nrf2, Keap1: a historical overview Antioxid Redox Signal 13 2010 1665 1678
31. N. Wakabayashi, K. Itoh, J. Wakabayashi, H. Motohashi, S. Noda, and S. Takahashi Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation Nat Genet 35 2003 238 245 (Pubitemid 37363177)
32. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, T. O'Connor, and M. Yamamoto Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles Genes Cells 8 2003 379 391 (Pubitemid 36504013)
33. J. Alam, E. Killeen, P. Gong, R. Naquin, B. Hu, and D. Stewart Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2 Am J Physiol Renal Physiol 284 2003 F743 F752
34. A. Kobayashi, M.I. Kang, H. Okawa, M. Ohtsuji, Y. Zenke, and T. Chiba Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 Mol Cell Biol 24 2004 7130 7139 (Pubitemid 39014439)
35. M. McMahon, K. Itoh, M. Yamamoto, and J.D. Hayes Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression J Biol Chem 278 2003 21592 21600 (Pubitemid 36792558)
36. M.K. Kwak, K. Itoh, M. Yamamoto, T.R. Sutter, and T.W. Kensler Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione Mol Med 7 2001 135 145 (Pubitemid 33702029)
37. T. Nguyen, P.J. Sherratt, H.C. Huang, C.S. Yang, and C.B. Pickett Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome J Biol Chem 278 2003 4536 4541 (Pubitemid 36800950)
38. M.K. Kwak, K. Itoh, M. Yamamoto, and T.W. Kensler Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter Mol Cell Biol 22 2002 2883 2892 (Pubitemid 34437448)
39. A.L. Levonen, A. Landar, A. Ramachandran, E.K. Ceaser, D.A. Dickinson, and G. Zanoni Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products Biochem J 378 2004 373 382 (Pubitemid 38367228)
40. S.K. Niture, A.K. Jain, and A.K. Jaiswal Antioxidant-induced modification of INrf2 cysteine 151 and PKC-delta-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance J Cell Sci 122 2009 4452 4464
41. A.L. Eggler, E. Small, M. Hannink, and A.D. Mesecar Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1 Biochem J 422 2009 171 180
42. L. Gao, J. Wang, K.R. Sekhar, H. Yin, N.F. Yared, and S.N. Schneider Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3 J Biol Chem 282 2007 2529 2537 (Pubitemid 47076775)
43. G. Rachakonda, Y. Xiong, K.R. Sekhar, S.L. Stamer, D.C. Liebler, and M.L. Freeman Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3 Chem Res Toxicol 21 2008 705 710 (Pubitemid 351498046)
44. D.D. Zhang, S.C. Lo, Z. Sun, G.M. Habib, M.W. Lieberman, and M. Hannink Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway J Biol Chem 280 2005 30091 30099 (Pubitemid 41216185)
45. T. Nguyen, P.J. Sherratt, P. Nioi, C.S. Yang, and C.B. Pickett Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1 J Biol Chem 280 2005 32485 32492 (Pubitemid 41361861)
46. Z. Sun, S. Zhang, J.Y. Chan, and D.D. Zhang Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2 Mol Cell Biol 27 2007 6334 6349 (Pubitemid 47435741)
47. Y. Watai, A. Kobayashi, H. Nagase, M. Mizukami, J. McEvoy, and J.D. Singer Subcellular localization and cytoplasmic complex status of endogenous Keap1 Genes Cells 12 2007 1163 1178 (Pubitemid 47500530)
48. I. Kim, S. Rodriguez-Enriquez, and J.J. Lemasters Selective degradation of mitochondria by mitophagy Arch Biochem Biophys 462 2007 245 253 (Pubitemid 46876640)
49. Y. Sakai, M. Oku, I.J. van der Klei, and J.A. Kiel Pexophagy: autophagic degradation of peroxisomes Biochim Biophys Acta 1763 2006 1767 1775 (Pubitemid 44880462)
50. V. Deretic Autophagy as an immune defense mechanism Curr Opin Immunol 18 2006 375 382 (Pubitemid 43947574)
51. N.A. Kaniuk, M. Kiraly, H. Bates, M. Vranic, A. Volchuk, and J.H. Brumell Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy Diabetes 56 2007 930 939 (Pubitemid 46525060)
52. P.K. Kim, D.W. Hailey, R.T. Mullen, and J. Lippincott-Schwartz Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes Proc Natl Acad Sci USA 105 2008 20567 20574
53. S. Pankiv, T.H. Clausen, T. Lamark, A. Brech, J.A. Bruun, and H. Outzen p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy J Biol Chem 282 2007 24131 24145 (Pubitemid 47328003)
54. M. Komatsu, H. Kurokawa, S. Waguri, K. Taguchi, A. Kobayashi, and Y. Ichimura The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 Nat Cell Biol 12 2010 213 223
55. A. Lau, X.J. Wang, F. Zhao, N.F. Villeneuve, T. Wu, and T. Jiang A noncanonical mechanism of Nrf2 activation by autophagy deficiency: Direct interaction between keap1 and p62 Mol Cell Biol 30 2010 3275 3285
56. A. Jain, T. Lamark, E. Sjøttem, K.B. Larsen, J.A. Awuh, and A. Øvervatn p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription J Biol Chem 285 2010 22576 22591
57. W. Fan, Z. Tang, D. Chen, D. Moughon, X. Ding, and S. Chen Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy Autophagy 6 2010 614 621
58. I.M. Copple, A. Lister, A.D. Obeng, N.R. Kitteringham, R.E. Jenkins, and R. Layfield Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway J Biol Chem 285 2010 16782 16788
59. Y. Inami, S. Waguri, A. Sakamoto, T. Kouno, K. Nakada, and O. Hino Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells J Cell Biol 193 2011 275 284
60. A. Miseta, and P. Csutora Relationship between the occurrence of cysteine in proteins and the complexity of organisms Mol Biol Evol 17 2000 1232 1239 (Pubitemid 30617150)
61. S.M. Marino, and V.N. Gladyshev Analysis and functional prediction of reactive cysteine residues J Biol Chem 287 2012 4419 4425
62. R. Holland, and J.C. Fishbein Chemistry of the cysteine sensors in Kelch-like ECH-associated protein 1 Antioxid Redox Signal 13 2010 1749 1761
63. G.H. Snyder, M.J. Cennerazzo, A.J. Karalis, and D. Field Electrostatic influence of local cysteine environments on disulfide exchange kinetics Biochemistry 20 1981 6509 6519
64. A.L. Eggler, G. Liu, J.M. Pezzuto, R.B. van Breemen, and A.D. Mesecar Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2 Proc Natl Acad Sci USA 102 2005 10070 10075 (Pubitemid 41023327)
65. A.T. Dinkova-Kostova, W.D. Holtzclaw, R.N. Cole, K. Itoh, N. Wakabayashi, and Y. Katoh Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants Proc Natl Acad Sci USA 99 2002 11908 11913 (Pubitemid 34994497)
66. R. Holland, A.E. Hawkins, A.L. Eggler, A.D. Mesecar, D. Fabris, and J.C. Fishbein Prospective type 1 and type 2 disulfides of Keap1 protein Chem Res Toxicol 21 2008 2051 2060
67. M. Kobayashi, L. Li, N. Iwamoto, Y. Nakajima-Takagi, H. Kaneko, and Y. Nakayama The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds Mol Cell Biol 29 2009 493 502
68. K. Takaya, T. Suzuki, H. Motohashi, K. Onodera, S. Satomi, and T.W. Kensler Validation of the multiple sensor mechanism of the Keap1-Nrf2 system Free Radic Biol Med 53 2012 817 827
69. T. Yamamoto, T. Suzuki, A. Kobayashi, J. Wakabayashi, J. Maher, and H. Motohashi Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity Mol Cell Biol 28 2008 2758 2770 (Pubitemid 351542373)
70. M. McMahon, D.J. Lamont, K.A. Beattie, and J.D. Hayes Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals Proc Natl Acad Sci USA 107 2010 18838 18843
71. S. Fujii, T. Sawa, H. Ihara, K.I. Tong, T. Ida, and T. Okamoto The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response J Biol Chem 285 2010 23970 23984
72. H.C. Um, J.H. Jang, D.H. Kim, C. Lee, and Y.J. Surh Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells Nitric Oxide 25 2011 161 168
73. A.J. Chia, C.E. Goldring, N.R. Kitteringham, S.Q. Wong, P. Morgan, and B.K. Park Differential effect of covalent protein modification and glutathione depletion on the transcriptional response of Nrf2 and NF-kappaB Biochem Pharmacol 80 2010 410 421
74. I.M. Copple, C.E. Goldring, R.E. Jenkins, A.J. Chia, L.E. Randle, and J.D. Hayes The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system Hepatology 48 2008 1292 1301
75. T.H. Rushmore, and A.N. Kong Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes Curr Drug Metab 3 2002 481 490 (Pubitemid 34987481)
76. T.H. Rushmore, R.G. King, K.E. Paulson, and C.B. Pickett Regulation of glutathione S-transferase Ya subunit gene expression: identification of a unique xenobiotic-responsive element controlling inducible expression by planar aromatic compounds Proc Natl Acad Sci USA 87 1990 3826 3830
77. T. Yamamoto, K. Yoh, A. Kobayashi, Y. Ishii, S. Kure, and A. Koyama Identification of polymorphisms in the promoter region of the human NRF2 gene Biochem Biophys Res Commun 321 2004 72 79 (Pubitemid 39055607)
78. J.M. Marzec, J.D. Christie, S.P. Reddy, A.E. Jedlicka, H. Vuong, and P.N. Lanken Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury FASEB J 21 2007 2237 2246 (Pubitemid 47026458)
79. C.P. Guan, M.N. Zhou, A.E. Xu, K.F. Kang, J.F. Liu, and X.D. Wei The susceptibility to vitiligo is associated with NF-E2-related factor2 (Nrf2) gene polymorphisms: a study on Chinese Han population Exp Dermatol 17 2008 1059 1062
80. S. Nair, S.T. Doh, J.Y. Chan, A.N. Kong, and L. Cai Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis Br J Cancer 99 2008 2070 2082
81. J.E. Kim, D.J. You, C. Lee, C. Ahn, J.Y. Seong, and J.I. Hwang Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation Cell Signal 22 2010 1645 1654
82. D.F. Lee, H.P. Kuo, M. Liu, C.K. Chou, W. Xia, and Y. Du KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta Mol Cell 36 2009 131 140
83. M. Yang, Y. Yao, G. Eades, Y. Zhang, and Q. Zhou MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism Breast Cancer Res Treat 129 2011 983 991
84. C. Sangokoya, and M.J. Telen Chi JT. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease Blood 116 2010 4338 4348
85. G. Eades, M. Yang, Y. Yao, Y. Zhang, and Q. Zhou miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells J Biol Chem 286 2011 40725 40733
86. N. Li, S. Muthusamy, R. Liang, H. Sarojini, and E. Wang Increased expression of miR-34a and miR-93 in rat liver during aging, and their impact on the expression of Mgst1 and Sirt1 Mech Ageing Dev 132 2011 75 85
87. W. Filipowicz, S.N. Bhattacharyya, and N. Sonenberg Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight Nat Rev Genet 9 2008 102 114
88. A.I. Rojo, O.N. Medina-Campos, P. Rada, A. Zuniga-Toala, A. Lopez-Gazcon, and S. Espada Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: role of glycogen synthase kinase-3 Free Radic Biol Med 52 2012 473 487
89. H.C. Huang, T. Nguyen, and C.B. Pickett Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription J Biol Chem 277 2002 42769 42774 (Pubitemid 35285650)
90. S. Numazawa, M. Ishikawa, A. Yoshida, S. Tanaka, and T. Yoshida Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress Am J Physiol Cell Physiol 285 2003 C334 C342
91. D.A. Bloom, and A.K. Jaiswal Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression J Biol Chem 278 2003 44675 44682 (Pubitemid 37377224)
92. M. Theodore, Y. Kawai, J. Yang, Y. Kleshchenko, S.P. Reddy, and F. Villalta Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2 J Biol Chem 283 2008 8984 8994
93. J. Pi, Y. Bai, J.M. Reece, J. Williams, D. Liu, and M.L. Freeman Molecular mechanism of human Nrf2 activation and degradation: role of sequential phosphorylation by protein kinase CK2 Free Radic Biol Med 42 2007 1797 1806 (Pubitemid 46754754)
94. P.L. Apopa, X. He, and Q. Ma Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells J Biochem Mol Toxicol 22 2008 63 76 (Pubitemid 351360163)
95. A.K. Jain, and A.K. Jaiswal Phosphorylation of tyrosine 568 controls nuclear export of Nrf2 J Biol Chem 281 2006 12132 12142 (Pubitemid 43855477)
96. A.K. Jain, and A.K. Jaiswal GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2 J Biol Chem 282 2007 16502 16510 (Pubitemid 47100395)
97. Y.S. Keum, S. Yu, P.P. Chang, X. Yuan, J.H. Kim, and C. Xu Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells Cancer Res 66 2006 8804 8813 (Pubitemid 44449198)
98. X. Yuan, C. Xu, Z. Pan, Y.S. Keum, J.H. Kim, and G. Shen Butylated hydroxyanisole regulates ARE-mediated gene expression via Nrf2 coupled with ERK and JNK signaling pathway in HepG2 cells Mol Carcinog 45 2006 841 850 (Pubitemid 44646336)
99. S.B. Cullinan, D. Zhang, M. Hannink, E. Arvisais, R.J. Kaufman, and J.A. Diehl Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival Mol Cell Biol 23 2003 7198 7209 (Pubitemid 37211002)
100. M. Salazar, A.I. Rojo, D. Velasco, R.M. de Sagarra, and A. Cuadrado Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2 J Biol Chem 281 2006 14841 14851 (Pubitemid 43855189)
101. P. Rada, A.I. Rojo, S. Chowdhry, M. McMahon, J.D. Hayes, and A. Cuadrado SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner Mol Cell Biol 31 2011 1121 1133
102. C.R. Beals, C.M. Sheridan, C.W. Turck, P. Gardner, and G.R. Crabtree Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3 Science 275 1997 1930 1934
103. J.R. Alt, J.L. Cleveland, M. Hannink, and J.A. Diehl Phosphorylation- dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation Genes Dev 14 2000 3102 3114 (Pubitemid 32015129)
104. V.V. Ogryzko, R.L. Schiltz, V. Russanova, B.H. Howard, and Y. Nakatani The transcriptional coactivators p300 and CBP are histone acetyltransferases Cell 87 1996 953 959 (Pubitemid 26404293)
105. S.Y. Roth, J.M. Denu, and C.D. Allis Histone acetyltransferases Annu Rev Biochem 70 2001 81 120 (Pubitemid 32662206)
106. Z. Sun, Y.E. Chin, and D.D. Zhang Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response Mol Cell Biol 29 2009 2658 2672
107. Y. Katoh, K. Itoh, E. Yoshida, M. Miyagishi, A. Fukamizu, and M. Yamamoto Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription Genes Cells 6 2001 857 868 (Pubitemid 33019739)
108. A.G. Ziady, A. Sokolow, S. Shank, D. Corey, R. Myers, and S. Plafker Interaction with CREB binding protein modulates the activities of Nrf2 and NF-kappaB in cystic fibrosis airway epithelial cells Am J Physiol Lung Cell Mol Physiol 302 2012 L1221 L1231
109. P. Rondou, G. Haegeman, P. Vanhoenacker, and K. Van Craenenbroeck BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase J Biol Chem 283 2008 11083 11096
110. C.M. Clements, R.S. McNally, B.J. Conti, T.W. Mak, and J.P. Ting DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2 Proc Natl Acad Sci USA 103 2006 15091 15096 (Pubitemid 44583169)
111. L. Gan, D.A. Johnson, and J.A. Johnson Keap1-Nrf2 activation in the presence and absence of DJ-1 Eur J Neurosci 31 2010 967 977
112. W. Chen, Z. Sun, X.J. Wang, T. Jiang, Z. Huang, and D. Fang Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response Mol Cell 34 2009 663 673
113. W. Li, H. Liu, J.S. Zhou, J.F. Cao, X.B. Zhou, and A.M. Choi Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45-related factor-2 (Nrf2) J Biol Chem 287 2012 20922 20930
114. Y. Zheng, A. Morris, M. Sunkara, J. Layne, M. Toborek, and B. Hennig Epigallocatechin-gallate stimulates NF-E2-related factor and heme oxygenase-1 via caveolin-1 displacement J Nutr Biochem 23 2012 163 168
115. W. Li, S.W. Yu, and A.N. Kong Nrf2 possesses a redox-sensitive nuclear exporting signal in the Neh5 transactivation domain J Biol Chem 281 2006 27251 27263 (Pubitemid 44401754)
116. B.K. Park, A. Boobis, S. Clarke, C.E. Goldring, D. Jones, and J.G. Kenna Managing the challenge of chemically reactive metabolites in drug development Nat Rev Drug Discov 10 2011 292 306
117. D. Papp, K. Lenti, D. Modos, D. Fazekas, Z. Dul, and D. Turei The NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops FEBS Lett 586 2012 1795 1802
118. J. Moscat, and M.T. Diaz-Meco p62 at the crossroads of autophagy, apoptosis, and cancer Cell 137 2009 1001 1004
119. C.E. Goldring, N.R. Kitteringham, R. Elsby, L.E. Randle, Y.N. Clement, and D.P. Williams Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice Hepatology 39 2004 1267 1276 (Pubitemid 38569048)
120. B.K. Park, N.R. Kitteringham, J.L. Maggs, M. Pirmohamed, and D.P. Williams The role of metabolic activation in drug-induced hepatotoxicity Annu Rev Pharmacol Toxicol 45 2005 177 202 (Pubitemid 40261802)
121. F. Hong, K.R. Sekhar, M.L. Freeman, and D.C. Liebler Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation J Biol Chem 280 2005 31768 31775 (Pubitemid 41291926)
122. Y. Luo, A.L. Eggler, D. Liu, G. Liu, A.D. Mesecar, and R.B. van Breemen Sites of alkylation of human Keap1 by natural chemoprevention agents J Am Soc Mass Spectrom 18 2007 2226 2232 (Pubitemid 350161332)
123. A.L. Eggler, Y. Luo, R.B. van Breemen, and A.D. Mesecar Identification of the highly reactive cysteine 151 in the chemopreventive agent-sensor Keap1 protein is method-dependent Chem Res Toxicol 20 2007 1878 1884
124. F. Hong, M.L. Freeman, and D.C. Liebler Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane Chem Res Toxicol 18 2005 1917 1926 (Pubitemid 43023050)
125. D.C. Liebler, F. Hong, K.R. Sekhar, M.L. Freeman, and C.F. James Chapter 3: Site-specific modification of the electrophile sensor protein Keap1 and activation of Nrf2-dependent gene expression Adv Mol Toxicol 1 2006 65 83
126. B.M. Dietz, D. Liu, G.K. Hagos, P. Yao, A. Schinkovitz, and S.M. Pro Angelica sinensis and its alkylphthalides induce the detoxification enzyme NAD(P)H: quinone oxidoreductase 1 by alkylating Keap1 Chem Res Toxicol 21 2008 1939 1948