The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update

Medicinal Research Reviews

Volumn 36, Issue 5, 2016, Pages 924-963

  Lu, Meng Chen ^a   Ji, Jian Ai ^a   Jiang, Zheng Yu ^a   You, Qi Dong ^a  

^a CHINA PHARMACEUTICAL UNIVERSITY   (China)

Author keywords

Nrf2; Keap1; ARE; Oxidative Stress

Indexed keywords

BARDOXOLONE METHYL; CYSTEINE; FUMARIC ACID DIMETHYL ESTER; KELCH LIKE ECH ASSOCIATED PROTEIN 1; PROTEIN INHIBITOR; TRANSCRIPTION FACTOR NRF2;

ANTIOXIDANT RESPONSIVE ELEMENT; CANCER STAGING; DIABETIC NEPHROPATHY; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MULTIPLE SCLEROSIS; NONHUMAN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; RESPIRATORY TRACT DISEASE; REVIEW; SIGNAL TRANSDUCTION;

EID: 85028271428     PISSN: 01986325     EISSN: 10981128     Source Type: Journal    
DOI: 10.1002/med.21396     Document Type: Review

References (206)

1. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000;408(6809):239–247.
2. Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 2004;3(3):205–214.
3. Hu R, Saw CL, Yu R, Kong AN. Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: Antioxidant coupled with antiinflammatory. Antioxid Redox Signal 2010;13(11):1679–1698.
4. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007;47:89–116.
5. Benz CC, Yau C. Ageing, oxidative stress and cancer: Paradigms in parallax. Nat Rev Cancer 2008;8(11):875–879.
6. Kobayashi M, Yamamoto M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 2005;7(3-4):385–394.
7. Stepkowski TM, Kruszewski MK. Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. Free Radic Biol Med 2011;50(9):1186–1195.
8. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011;16(2):123–140.
9. Hur W, Gray NS. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol 2011;15(1):162–173.
10. Sporn MB, Liby KT. NRF2 and cancer: The good, the bad and the importance of context. Nat Rev Cancer 2012;12(8):564–571.
11. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 2013;12(12):931–947.
12. Magesh S, Chen Y, Hu L. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 2012;32(4):687–726.
13. Wilson AJ, Kerns JK, Callahan JF, Moody CJ. Keap calm, and carry on covalently. J Med Chem 2013;56(19):7463–7476.
14. Zhuang C, Narayanapillai S, Zhang W, Sham YY, Xing C. Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search. J Med Chem 2014;57(3):1121–1126.
15. Richardson BG, Jain AD, Speltz TE, Moore TW. Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway. Bioorg Med Chem Lett 2015;25(11):2261–2268.
16. Wells G. Peptide and small molecule inhibitors of the Keap1-Nrf2 protein-protein interaction. Biochem Soc Trans 2015;43(4):674–679.
17. Abed DA, Goldstein M, Albanyan H, Jin H, Hu L. Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents. Acta Pharm Sin B 2015;5(4):285–299.
18. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 1999;13(1):76–86.
19. Nioi P, Nguyen T, Sherratt PJ, Pickett CB. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 2005;25(24):10895–10906.
20. Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 2001;6(10):857–868.
21. Zhang J, Ohta T, Maruyama A, Hosoya T, Nishikawa K, Maher JM, Shibahara S, Itoh K, Yamamoto M. BRG1 interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress. Mol Cell Biol 2006;26(21):7942–7952.
22. Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, Xue P, Pi J, Kleeberger SR, Bell DA. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res 2012;40(15):7416–7429.
23. Hirotsu Y, Katsuoka F, Funayama R, Nagashima T, Nishida Y, Nakayama K, Engel JD, Yamamoto M. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res 2012;40(20):10228–10239.
24. Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, Shyr C, Wakabayashi N, Kensler TW, Wasserman WW, Biswal S. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 2010;38(17):5718–5734.
25. Yates MS, Tran QT, Dolan PM, Osburn WO, Shin S, McCulloch CC, Silkworth JB, Taguchi K, Yamamoto M, Williams CR, Liby KT, Sporn MB, Sutter TR, Kensler TW. Genetic versus chemoprotective activation of Nrf2 signaling: Overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 2009;30(6):1024–1031.
26. Gill R, Tsung A, Billiar T. Linking oxidative stress to inflammation: Toll-like receptors. Free Radic Biol Med 2010;48(9):1121–1132.
27. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med 2010;49(11):1603–1616.
28. Iida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, Shimazui T, Akaza H, Yamamoto M. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res 2004;64(18):6424–6431.
29. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 2001;98(6):3410–3415.
30. Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA 1999;96(22):12731–12736.
31. Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, Kleeberger SR. Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 2002;26(2):175–182.
32. Cho HY, Reddy SP, Yamamoto M, Kleeberger SR. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J 2004;18(11):1258–1260.
33. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 2006;116(4):984–995.
34. Itoh K, Mimura J, Yamamoto M. Discovery of the negative regulator of Nrf2, Keap1: A historical overview. Antioxid Redox Signal 2010;13(11):1665–1678.
35. Mitsuishi Y, Motohashi H, Yamamoto M. The Keap1-Nrf2 system in cancers: Stress response and anabolic metabolism. Front Oncol 2012;2:200.
36. Pintard L, Willis JH, Willems A, Johnson J-LF, Srayko M, Kurz T, Glaser S, Mains PE, Tyers M, Bowerman B. The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 2003;425(6955):311–316.
37. Xu L, Wei Y, Reboul J, Vaglio P, Shin T-H, Vidal M, Elledge SJ, Harper JW. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 2003;425(6955):316–321.
38. Zipper LM, Mulcahy RT. The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem 2002;277(39):36544–36552.
39. Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol 2007;27(21):7511–7521.
40. Tong KI, Kobayashi A, Katsuoka F, Yamamoto M. Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism. Biol Chem 2006;387(10–11):1311–1320.
41. Baird L, Lleres D, Swift S, Dinkova-Kostova AT. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci USA 2013;110(38):15259–15264.
42. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism. J Biol Chem 2006;281(34):24756.
43. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: Characterization of the two-site molecular recognition model. Mol Cell Biol 2006;26(8):2887–2900.
44. Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, Yamamoto M. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci USA 2010;107(7):2842–2847.
45. Baird L, Swift S, Lleres D, Dinkova-Kostova AT. Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol Adv 2014;32(6):1133–1144.
46. Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 2004;24(24):10941–10953.
47. Baird L, Dinkova-Kostova AT. Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells. Biochem Biophys Res Commun 2013;433(1):58–65.
48. Tian H, Zhang B, Di J, Jiang G, Chen F, Li H, Li L, Pei D, Zheng J. Keap1: One stone kills three birds Nrf2, IKKbeta and Bcl-2/Bcl-xL. Cancer Lett 2012;325(1):26–34.
49. Bryan HK, Olayanju A, Goldring CE, Park BK. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol 2013;85(6):705–717.
50. Qin S, Deng F, Wu W, Jiang L, Yamashiro T, Yano S, Hou DX. Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms. Arch Biochem Biophys 2014;559:53–61.
51. Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA. Nrf2, a multi-organ protector? FASEB J 2005;19(9):1061–1066.
52. Copple IM. The Keap1-Nrf2 cell defense pathway – A promising therapeutic target? Adv Pharmacol 2012;63:43–79.
53. Kensler TW, Wakabayashi N. Nrf2: Friend or foe for chemoprevention? Carcinogenesis 2010;31(1):90–99.
54. Zhang DD. The Nrf2-Keap1-ARE signaling pathway: The regulation and dual function of Nrf2 in cancer. Antioxid Redox Signal 2010;13(11):1623–1626.
55. Giudice A, Montella M. Activation of the Nrf2–ARE signaling pathway: A promising strategy in cancer prevention. Bioessays 2006;28(2):169–181.
56. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 2010;13(11):1713–1748.
57. Kensler TW, Egner PA, Agyeman AS, Visvanathan K, Groopman JD, Chen JG, Chen TY, Fahey JW, Talalay P. Keap1-nrf2 signaling: A target for cancer prevention by sulforaphane. Top Curr Chem 2013;329:163–177.
58. Shelton P, Jaiswal AK. The transcription factor NF-E2-related factor 2 (Nrf2): A protooncogene? FASEB J 2013;27(2):414–423.
59. Hayes JD, McMahon M. NRF2 and KEAP1 mutations: Permanent activation of an adaptive response in cancer. Trends Biochem Sci 2009;34(4):176–188.
60. Cheng IC, Chen YJ, Ku CW, Huang YW, Yang CN. Structural and dynamic characterization of mutated Keap1 for varied affinity toward Nrf2: A molecular dynamics simulation study. J Chem Inf Model 2015;55(10):2178–2186.
61. Solis LM, Behrens C, Dong W, Suraokar M, Ozburn NC, Moran CA, Corvalan AH, Biswal S, Swisher SG, Bekele BN, Minna JD, Stewart DJ, Wistuba II. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res 2010;16(14):3743–3753.
62. Konstantinopoulos PA, Spentzos D, Fountzilas E, Francoeur N, Sanisetty S, Grammatikos AP, Hecht JL, Cannistra SA. Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer Res 2011;71(15):5081–5089.
63. Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev 2013;27(20):2179–2191.
64. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Bruck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134(Pt 3):678–692.
65. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. New Engl J Med 2012;367(12):1098–1107.
66. Scannevin RH, Chollate S, Jung M-Y, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 2012;341(1):274–284.
67. Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: The need for effective antioxidant therapy. J Neurol 2004;251(3):261–268.
68. de Vries HE, Witte M, Hondius D, Rozemuller AJ, Drukarch B, Hoozemans J, van Horssen J. Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radic Biol Med 2008;45(10):1375–1383.
69. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, Johnson JA. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 2009;11(3):497–508.
70. Kanninen K, Malm TM, Jyrkkanen HK, Goldsteins G, Keksa-Goldsteine V, Tanila H, Yamamoto M, Yla-Herttuala S, Levonen AL, Koistinaho J. Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci 2008;39(3):302–313.
71. Tufekci KU, Civi Bayin E, Genc S, Genc K. The Nrf2/ARE pathway: A promising target to counteract mitochondrial dysfunction in Parkinson's disease. Parkinsons Dis 2011;2011:314082.
72. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging 2001;22(6):993–1005.
73. van Muiswinkel FL, de Vos RA, Bol JG, Andringa G, Jansen Steur EN, Ross D, Siegel D, Drukarch B. Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol Aging 2004;25(9):1253–1262.
74. Cachofeiro V, Goicochea M, de Vinuesa SG, Oubina P, Lahera V, Luno J. Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease. Kidney Int Suppl 2008(111):S4–9.
75. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG, Investigators BS. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011;365(4):327–336.
76. Pergola PE, Krauth M, Huff JW, Ferguson DA, Ruiz S, Meyer CJ, Warnock DG. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am J Nephrol 2011;33(5):469–476.
77. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM, Investigators BT. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369(26):2492–2503.
78. Tayek JA, Kalantar-Zadeh K. The extinguished BEACON of bardoxolone: Not a Monday morning quarterback story. Am J Nephrol 2013;37(3):208–211.
79. Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system. Free Radic Biol Med 2015.
80. Chin M, Lee CY, Chuang JC, Bumeister R, Wigley WC, Sonis ST, Ward KW, Meyer C. Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of type 2 diabetes and obesity. Am J Physiol Renal Physiol 2013;304(12):F1438–1446.
81. Shelton LM, Lister A, Walsh J, Jenkins RE, Wong MH, Rowe C, Ricci E, Ressel L, Fang Y, Demougin P, Vukojevic V, O'Neill PM, Goldring CE, Kitteringham NR, Park BK, Odermatt A, Copple IM. Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney. Kidney Int 2015;88(6):1261–1273.
82. Noel S, Hamad AR, Rabb H. Reviving the promise of transcription factor Nrf2-based therapeutics for kidney diseases. Kidney Int 2015;88(6):1217–1218.
83. Aleksunes LM, Reisman SA, Yeager RL, Goedken MJ, Klaassen CD. Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice. J Pharmacol Exp Ther 2010;333(1):140–151.
84. Bitar MS, Al-Mulla F. A defect in Nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes. Am J Physiol Endocrinol Metab 2011;301(6):E1119–1129.
85. Cheng X, Siow RC, Mann GE. Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: A role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway. Antioxid Redox Signal 2011;14(3):469–487.
86. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006;440(7086):944–948.
87. Rochette L, Zeller M, Cottin Y, Vergely C. Diabetes, oxidative stress and therapeutic strategies. Biochim Biophys Acta 2014;1840(9):2709–2729.
88. Bhakkiyalakshmi E, Sireesh D, Rajaguru P, Paulmurugan R, Ramkumar KM. The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes. Pharmacol Res 2015;91:104–114.
89. He HJ, Wang GY, Gao Y, Ling WH, Yu ZW, Jin TR. Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World J Diabetes 2012;3(5):94–104.
90. Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology 2008;149(7):3549–3558.
91. Bagul PK, Middela H, Matapally S, Padiya R, Bastia T, Madhusudana K, Reddy BR, Chakravarty S, Banerjee SK. Attenuation of insulin resistance, metabolic syndrome and hepatic oxidative stress by resveratrol in fructose-fed rats. Pharmacol Res 2012;66(3):260–268.
92. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414(6865):782–787.
93. Ungvari Z, Bailey-Downs L, Gautam T, Jimenez R, Losonczy G, Zhang C, Ballabh P, Recchia FA, Wilkerson DC, Sonntag WE, Pearson K, de Cabo R, Csiszar A. Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 2011;300(4):H1133–1140.
94. Xue M, Qian Q, Adaikalakoteswari A, Rabbani N, Babaei-Jadidi R, Thornalley PJ. Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 2008;57(10):2809–2817.
95. He X, Kan H, Cai L, Ma Q. Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. J Mol Cell Cardiol 2009;46(1):47–58.
96. Tan SM, Sharma A, Stefanovic N, Yuen DY, Karagiannis TC, Meyer C, Ward KW, Cooper ME, de Haan JB. Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-associated atherosclerosis and improves diabetic kidney disease. Diabetes 2014;63(9):3091–3103.
97. Xu J, Kulkarni SR, Donepudi AC, More VR, Slitt AL. Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes 2012;61(12):3208–3218.
98. Wang X, Hai CX. ROS acts as a double-edged sword in the pathogenesis of type 2 diabetes mellitus: Is Nrf2 a potential target for the treatment? Mini Rev Med Chem 2011;11(12):1082–1092.
99. Freigang S, Ampenberger F, Spohn G, Heer S, Shamshiev AT, Kisielow J, Hersberger M, Yamamoto M, Bachmann MF, Kopf M. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur J Immunol 2011;41(7):2040–2051.
100. Harada N, Ito K, Hosoya T, Mimura J, Maruyama A, Noguchi N, Yagami K, Morito N, Takahashi S, Maher JM, Yamamoto M, Itoh K. Nrf2 in bone marrow-derived cells positively contributes to the advanced stage of atherosclerotic plaque formation. Free Radic Biol Med 2012;53(12):2256–2262.
101. Sussan TE, Jun J, Thimmulappa R, Bedja D, Antero M, Gabrielson KL, Polotsky VY, Biswal S. Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice. PLoS One 2008;3(11):e3791.
102. Yin J, Wang L, Wang X, Zheng L, Shi Y, Shao A, Tang W, Ding G, Liu C, Liu R, Chen S, Gu H. NQO1 rs1800566 C>T polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. Scand J Gastroenterol 2014;49(3):317–322.
103. Cho HY, Kleeberger SR. Nrf2 protects against airway disorders. Toxicol Appl Pharmacol 2010;244(1):43–56.
104. Adenuga D, Caito S, Yao H, Sundar IK, Hwang JW, Chung S, Rahman I. Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction. Biochem Biophys Res Commun 2010;403(3-4):452–456.
105. Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, Sporn MB, Yamamoto M, Kensler TW, Biswal S. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun 2006;351(4):883–889.
106. Iizuka T, Ishii Y, Itoh K, Kiwamoto T, Kimura T, Matsuno Y, Morishima Y, Hegab AE, Homma S, Nomura A, Sakamoto T, Shimura M, Yoshida A, Yamamoto M, Sekizawa K. Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells 2005;10(12):1113–1125.
107. Singh A, Ling G, Suhasini AN, Zhang P, Yamamoto M, Navas-Acien A, Cosgrove G, Tuder RM, Kensler TW, Watson WH, Biswal S. Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs. Free Radic Biol Med 2009;46(3):376–386.
108. Suzuki M, Betsuyaku T, Ito Y, Nagai K, Nasuhara Y, Kaga K, Kondo S, Nishimura M. Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2008;39(6):673–682.
109. Goven D, Boutten A, Lecon-Malas V, Marchal-Somme J, Amara N, Crestani B, Fournier M, Leseche G, Soler P, Boczkowski J, Bonay M. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax 2008;63(10):916–924.
110. Hubner RH, Schwartz JD, De Bishnu P, Ferris B, Omberg L, Mezey JG, Hackett NR, Crystal RG. Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking. Mol Med 2009;15(7-8):203–219.
111. Sandford AJ, Silverman EK. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype-environment interaction. Thorax 2002;57(8):736–741.
112. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S. Expression of concern: Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 2008;178(6):592–604.
113. Boutten A, Goven D, Artaud-Macari E, Boczkowski J, Bonay M. NRF2 targeting: A promising therapeutic strategy in chronic obstructive pulmonary disease. Trends Mol Med 2011;17(7):363–371.
114. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342(18):1334–1349.
115. Reddy NM, Potteti HR, Mariani TJ, Biswal S, Reddy SP. Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am J Respir Cell Mol Biol 2011;45(6):1161–1168.
116. Jin W, Wang H, Ji Y, Zhu L, Yan W, Qiao L, Yin H. Genetic ablation of Nrf2 enhances susceptibility to acute lung injury after traumatic brain injury in mice. Exp Biol Med (Maywood) 2009;234(2):181–189.
117. Reddy NM, Suryanaraya V, Yates MS, Kleeberger SR, Hassoun PM, Yamamoto M, Liby KT, Sporn MB, Kensler TW, Reddy SP. The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice. Am J Respir Crit Care Med 2009;180(9):867–874.
118. Chen T, Mou Y, Tan J, Wei L, Qiao Y, Wei T, Xiang P, Peng S, Zhang Y, Huang Z, Ji H. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol 2015;25(1):55–64.
119. Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I. 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 2008;294(3):L478–488.
120. Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2 – An update. Free Radic Biol Med 2014;66:36–44.
121. Gill AJ, Kolson DL. Dimethyl fumarate modulation of immune and antioxidant responses: Application to HIV therapy. Crit Rev Immunol 2013;33(4):307–359.
122. Reisman SA, Chertow GM, Hebbar S, Vaziri ND, Ward KW, Meyer CJ. Bardoxolone methyl decreases megalin and activates Nrf2 in the kidney. J Am Soc Nephrol 2012;23(10):1663–1673.
123. Sporn MB, Liby KT, Yore MM, Fu L, Lopchuk JM, Gribble GW. New synthetic triterpenoids: Potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 2011;74(3):537–545.
124. Honda T, Rounds BV, Gribble GW, Suh N, Wang Y, Sporn MB. Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett 1998;8(19):2711–2714.
125. Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF, Maue RA, Place AE, Porter DM, Spinella MJ, Williams CR, Wu G, Dannenberg AJ, Flanders KC, Letterio JJ, Mangelsdorf DJ, Nathan CF, Nguyen L, Porter WW, Ren RF, Roberts AB, Roche NS, Subbaramaiah K, Sporn MB. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res 1999;59(2):336–341.
126. Liby KT, Sporn MB. Synthetic oleanane triterpenoids: Multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 2012;64(4):972–1003.
127. Zheng S, Santosh Laxmi YR, David E, Dinkova-Kostova AT, Shiavoni KH, Ren Y, Zheng Y, Trevino I, Bumeister R, Ojima I, Wigley WC, Bliska JB, Mierke DF, Honda T. Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents(1). J Med Chem 2012;55(10):4837–4846.
128. Dinkova-Kostova AT, Talalay P, Sharkey J, Zhang Y, Holtzclaw WD, Wang XJ, David E, Schiavoni KH, Finlayson S, Mierke DF, Honda T. An exceptionally potent inducer of cytoprotective enzymes. J Biol Chem 2010;285(44):33747–33755.
129. Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, Callahan JF, Carr R, Concha N, Kerns JK, Qi H, Sweitzer T, Ward P, Davies TG. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS One 2014;9(6):e98896.
130. Li W, Zheng S, Higgins M, Morra RP Jr., Mendis AT, Chien CW, Ojima I, Mierke DF, Dinkova-Kostova AT, Honda T. New monocyclic, bicyclic, and tricyclic ethynylcyanodienones as activators of the Keap1/Nrf2/ARE pathway and inhibitors of inducible nitric oxide synthase. J Med Chem 2015;58(11):4738–4748.
131. Xi MY, Jia JM, Sun HP, Sun ZY, Jiang JW, Wang YJ, Zhang MY, Zhu JF, Xu LL, Jiang ZY, Xue X, Ye M, Yang X, Gao Y, Tao L, Guo XK, Xu XL, Guo QL, Zhang XJ, Hu R, You QD. 3-Aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as potent Nrf2/ARE inducers in human cancer cells and AOM-DSS treated mice. J Med Chem 2013;56(20):7925–7938.
132. You R, Long W, Lai Z, Sha L, Wu K, Yu X, Lai Y, Ji H, Huang Z, Zhang Y. Discovery of a potential anti-inflammatory agent: 3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile. J Med Chem 2013;56(5):1984–1995.
133. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. New Engl J Med 2011;365(4):327–336.
134. Kern JT, Hannink M, Fred Hess J. Disruption of the Keap1-containing ubiquitination complex as an antioxidant therapy. Curr Top Med Chem 2007;7(10):972–978.
135. Furukawa M, Xiong Y. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol 2005;25(1):162–171.
136. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 2004;24(16):7130–7139.
137. Sola M, de Paola I, Pirone L, Palmieri M, Balasco N, Esposito L, Russo L, Mazzà D, Di Marcotullio L, Di Gaetano S, Malgieri G, Vitagliano L, Pedone E, Zaccaro L. Cullin3-BTB interface: A novel target for stapled peptides. PLoS One 2015;10(4):e0121149.
138. Beamer LJ, Li X, Bottoms CA, Hannink M. Conserved solvent and side-chain interactions in the 1.35 Angstrom structure of the Kelch domain of Keap1. Acta Crystallogr D Biol Crystallogr 2005;61(Pt 10):1335–1342.
139. Horer S, Reinert D, Ostmann K, Hoevels Y, Nar H. Crystal-contact engineering to obtain a crystal form of the Kelch domain of human Keap1 suitable for ligand-soaking experiments. Acta Crystallogr Sect F Struct Biol Cryst Commun 2013;69(Pt 6):592–596.
140. Lo S-C, Li X, Henzl MT, Beamer LJ, Hannink M. Structure of the Keap1: Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 2006;25(15):3605–3617.
141. Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang M-I, Kobayashi A, Yokoyama S, Yamamoto M. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 2006;21(5):689–700.
142. Jiang Z-Y, Xu L-L, Lu M-C, Pan Y, Huang H-Z, Zhang X-J, Sun H-P, You Q-D. Investigation of the intermolecular recognition mechanism between the E3 ubiquitin ligase Keap1 and substrate based on multiple substrates analysis. J Comput Aided Mol Des 2014;28(12):1233–1245.
143. Schneekloth JS, Crews CM. Natural product inhibitors of the ubiquitin-proteasome pathway. Curr Drug Targets 2011;12(11):1581–1594.
144. Chen Y, Inoyama D, Kong ANT, Beamer LJ, Hu L. Kinetic analyses of Keap1-Nrf2 interaction and determination of the minimal Nrf2 peptide sequence required for Keap1 binding using surface plasmon resonance. Chem Biol Drug Des 2011;78(6):1014–1021.
145. Inoyama D, Chen Y, Huang X, Beamer LJ, Kong AN, Hu L. Optimization of fluorescently labeled Nrf2 peptide probes and the development of a fluorescence polarization assay for the discovery of inhibitors of Keap1-Nrf2 interaction. J Biomol Screen 2012;17(4):435–447.
146. Lu M-C, Chen Z-Y, Wang Y-L, Jiang Y-L, Yuan Z-W, You Q-D, Jiang Z-Y. Binding thermodynamics and kinetics guided optimization of potent Keap1-Nrf2 peptide inhibitors. RSC Advances 2015;5(105):85983–85987.
147. Hancock R, Bertrand HC, Tsujita T, Naz S, El-Bakry A, Laoruchupong J, Hayes JD, Wells G. Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radic Biol Med 2012;52(2):444–451.
148. Zhuang C, Miao Z, Sheng C, Zhang W. Updated research and applications of small molecule inhibitors of Keap1-Nrf2 protein-protein interaction: A review. Curr Med Chem 2014;21(16):1861–1870.
149. Steel R, Cowan J, Payerne E, O'Connell MA, Searcey M. Anti-inflammatory effect of a cell-penetrating peptide targeting the Nrf2/Keap1 interaction. ACS Med Chem Lett 2012;3(5):407–410.
150. Guntas G, Lewis SM, Mulvaney KM, Cloer EW, Tripathy A, Lane TR, Major MB, Kuhlman B. Engineering a genetically encoded competitive inhibitor of the KEAP1-NRF2 interaction via structure-based design and phage display. Protein Eng Des Sel 2016;29(1):1–9.
151. Bowman AL, Nikolovska-Coleska Z, Zhong H, Wang S, Carlson HA. Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models. J Am Chem Soc 2007;129(42):12809–12814.
152. Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, Khodier C, Inoyama D, Beamer LJ, Emge TJ, Shen J, Kerrigan JE, Kong AN, Dandapani S, Palmer M, Schreiber SL, Munoz B. Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett 2013;23(10):3039–3043.
153. Wen X, Thorne G, Hu L, Joy MS, Aleksunes LM. Activation of NRF2 signaling in HEK293 cells by a first-in-class direct KEAP1-NRF2 inhibitor. J Biochem Mol Toxicol 2015;29(6):261–266.
154. Jnoff E, Albrecht C, Barker JJ, Barker O, Beaumont E, Bromidge S, Brookfield F, Brooks M, Bubert C, Ceska T, Corden V, Dawson G, Duclos S, Fryatt T, Genicot C, Jigorel E, Kwong J, Maghames R, Mushi I, Pike R, Sands ZA, Smith MA, Stimson CC, Courade JP. Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex. Chemmedchem 2014;9(4):699–705.
155. Marcotte D, Zeng W, Hus J-C, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H, Wang D, Atmanene C, Roecklin D, Vecchi M, Vivat V, Kraemer J, Winkler D, Hong V, Chao J, Lukashev M, Silvian L. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 2013;21(14):4011–4019.
156. Nasiri HR, Linge S, Ullmann D. Thermodynamic profiling of inhibitors of Nrf2: Keap1 interactions. Bioorg Med Chem Lett 2015;26(2):526–529.
157. Sun H-P, Jiang Z-Y, Zhang M-Y, Lu M-C, Yang T-T, Pan Y, Huang H-Z, Zhang X-J, You Q-d. Novel protein-protein interaction inhibitor of Nrf2-Keap1 discovered by structure-based virtual screening. MedChemComm 2014;5(1):93–98.
158. Baell J, Walters MA. Chemistry: Chemical con artists foil drug discovery. Nature 2014;513(7519):481–483.
159. Jiang Z-Y, Lu M-C, Xu LL, Yang T-T, Xi M-Y, Xu X-L, Guo X-K, Zhang X-J, You Q-D, Sun H-P. Discovery of potent Keap1–Nrf2 protein–protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem 2014;57(6):2736–2745.
160. Jiang Z-Y, Xu LL, Lu M-C, Chen Z-Y, Yuan Z-W, Xu X-L, Guo X-K, Zhang X-J, Sun H-P, You Q-D. Structure–activity and structure–property relationship and exploratory in vivo evaluation of the nanomolar keap1–nrf2 protein–protein interaction inhibitor. J Med Chem 2015;58(16):6410–6421.
161. Jain AD, Potteti H, Richardson BG, Kingsley L, Luciano JP, Ryuzoji AF, Lee H, Krunic A, Mesecar AD, Reddy SP, Moore TW. Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. Eur J Med Chem 2015;103:252–268.
162. Bertrand HC, Schaap M, Baird L, Georgakopoulos ND, Fowkes A, Thiollier C, Kachi H, Dinkova-Kostova AT, Wells G. Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction. J Med Chem 2015;58(18):7186–7194.
163. Xu LL, Zhu JF, Xu XL, Zhu J, Li L, Xi MY, Jiang ZY, Zhang MY, Liu F, Lu MC, Bao QC, Li Q, Zhang C, Wei JL, Zhang XJ, Zhang LS, You QD, Sun HP. Discovery and modification of in vivo active Nrf2 activators with 1,2,4-oxadiazole core: Hits identification and structure-activity relationship study. J Med Chem 2015;58(14):5419–5436.
164. Satoh M, Saburi H, Tanaka T, Matsuura Y, Naitow H, Shimozono R, Yamamoto N, Inoue H, Nakamura N, Yoshizawa Y, Aoki T, Tanimura R, Kunishima N. Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation. FEBS Open Bio 2015;5:557–570.
165. Winkel AF, Engel CK, Margerie D, Kannt A, Szillat H, Glombik H, Kallus C, Ruf S, Gussregen S, Riedel J, Herling AW, von Knethen A, Weigert A, Brune B, Schmoll D. Characterization of RA839, a noncovalent small molecule binder to Keap1 and selective activator of Nrf2 signaling. J Biol Chem 2015;290(47):28446–28455.
166. Wang XJ, Hayes JD, Henderson CJ, Wolf CR. Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci USA 2007;104(49):19589–19594.
167. Tarumoto T, Nagai T, Ohmine K, Miyoshi T, Nakamura M, Kondo T, Mitsugi K, Nakano S, Muroi K, Komatsu N, Ozawa K. Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol 2004;32(4):375–381.
168. Tang X, Wang H, Fan L, Wu X, Xin A, Ren H, Wang XJ. Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med 2011;50(11):1599–1609.
169. Boettler U, Sommerfeld K, Volz N, Pahlke G, Teller N, Somoza V, Lang R, Hofmann T, Marko D. Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression. J Nutr Biochem 2011;22(5):426–440.
170. Hayes AJ, Skouras C, Haugk B, Charnley RM. Keap1-Nrf2 signalling in pancreatic cancer. Int J Biochem Cell Biol 2015;65:288–299.
171. Bollong MJ, Yun H, Sherwood L, Woods AK, Lairson LL, Schultz PG. A small molecule inhibits deregulated NRF2 transcriptional activity in cancer. ACS Chem Biol 2015;10(10):2193–2198.
172. Lee S, Lim MJ, Kim MH, Yu CH, Yun YS, Ahn J, Song JY. An effective strategy for increasing the radiosensitivity of human lung cancer cells by blocking Nrf2-dependent antioxidant responses. Free Radic Biol Med 2012;53(4):807–816.
173. Ahn J, Nam K-Y, Lee S-L-O, Ryu H, Choi HK, Song J-Y. Synthesis and biological evaluation of novel IM3829 (4-(2-cyclohexylethoxy)aniline) derivatives as potent radiosensitizers. Bull Korean Chem Soc 2014;35(12):3623–3626.
174. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, Zhang DD. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci USA 2011;108(4):1433–1438.
175. Olayanju A, Copple IM, Bryan HK, Edge GT, Sison RL, Wong MW, Lai ZQ, Lin ZX, Dunn K, Sanderson CM, Alghanem AF, Cross MJ, Ellis EC, Ingelman-Sundberg M, Malik HZ, Kitteringham NR, Goldring CE, Park BK. Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2. Free Radic Biol Med 2015;78:202–212.
176. Vartanian S, Ma TP, Lee J, Haverty PM, Kirkpatrick DS, Yu K, Stokoe D. Application of mass spectrometry profiling to establish brusatol as an inhibitor of global protein synthesis. Mol Cell Proteomics 2016;15(4):1220–1231.
177. Huang HC, Nguyen T, Pickett CB. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci USA 2000;97(23):12475–12480.
178. Huang HC, Nguyen T, Pickett CB. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem 2002;277(45):42769–42774.
179. Bloom DA, Jaiswal AK. 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 2003;278(45):44675–44682.
180. Numazawa S, Ishikawa M, Yoshida A, Tanaka S, Yoshida T. Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress. Am J Physiol Cell Physiol 2003;285(2):C334–342.
181. Niture SK, Jain AK, Jaiswal AK. 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 2009;122(Pt 24):4452–4464.
182. Boesch-Saadatmandi C, Wagner AE, Graeser AC, Hundhausen C, Wolffram S, Rimbach G. Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells. J Anim Physiol Anim Nutr (Berl) 2009;93(5):547–554.
183. Kumar R, Ansari KM, Chaudhari BP, Dhawan A, Dwivedi PD, Jain SK, Das M. Topical application of ochratoxin A causes DNA damage and tumor initiation in mouse skin. PLoS One 2012;7(10):e47280.
184. Boesch-Saadatmandi C, Loboda A, Jozkowicz A, Huebbe P, Blank R, Wolffram S, Dulak J, Rimbach G. Effect of ochratoxin A on redox-regulated transcription factors, antioxidant enzymes and glutathione-S-transferase in cultured kidney tubulus cells. Food Chem Toxicol 2008;46(8):2665–2671.
185. Cavin C, Delatour T, Marin-Kuan M, Holzhauser D, Higgins L, Bezencon C, Guignard G, Junod S, Richoz-Payot J, Gremaud E, Hayes JD, Nestler S, Mantle P, Schilter B. Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. Toxicol Sci 2007;96(1):30–39.
186. Limonciel A, Jennings P. A review of the evidence that ochratoxin A is an Nrf2 inhibitor: Implications for nephrotoxicity and renal carcinogenicity. Toxins (Basel) 2014;6(1):371–379.
187. Nioi P, Nguyen T. A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun 2007;362(4):816–821.
188. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P. Protection against electrophile and oxidant stress by induction of the phase 2 response: Fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci USA 2004;101(7):2040–2045.
189. Zhang DD, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 2003;23(22):8137–8151.
190. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science 2006;314(5797):268–274.
191. Nioi P, Nguyen T. A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun 2007;362(4):816–821.
192. Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman ML. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol 2008;21(3):705–710.
193. Serafimova IM, Pufall MA, Krishnan S, Duda K, Cohen MS, Maglathlin RL, McFarland JM, Miller RM, Frodin M, Taunton J. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat Chem Biol 2012;8(5):471–476.
194. Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. Drug-protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 2004;17(1):3–16.
195. Park BK, Boobis A, Clarke S, Goldring CE, Jones D, Kenna JG, Lambert C, Laverty HG, Naisbitt DJ, Nelson S, Nicoll-Griffith DA, Obach RS, Routledge P, Smith DA, Tweedie DJ, Vermeulen N, Williams DP, Wilson ID, Baillie TA. Managing the challenge of chemically reactive metabolites in drug development. Nat Rev Drug Discov 2011;10(4):292–306.
196. Uetrecht J. Idiosyncratic drug reactions: Past, present, and future. Chem Res Toxicol 2008;21(1):84–92.
197. Jiang Z-Y, Chu H-X, Xi M-Y, Yang T-T, Jia J-M, Huang J-J, Guo X-K, Zhang X-J, You Q-D, Sun H-P. Insight into the intermolecular recognition mechanism between Keap1 and IKKβ combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation. PLoS One 2013;8(9):e75076.
198. Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, Shen J, Chen CT, Huo L, Hsu MC, Li CW, Ding Q, Liao TL, Lai CC, Lin AC, Chang YH, Tsai SF, Li LY, Hung MC. KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell 2009;36(1):131–140.
199. Lo SC, Hannink M. PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex. J Biol Chem 2006;281(49):37893–37903.
200. Niture SK, Jaiswal AK. INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis. Cell Death Differ 2011;18(3):439–451.
201. Niture SK, Jaiswal AK. Hsp90 interaction with INrf2(Keap1) mediates stress-induced Nrf2 activation. J Biol Chem 2010;285(47):36865–36875.
202. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 2006;103(41):15091–15096.
203. Bitar MS, Liu C, Ziaei A, Chen Y, Schmedt T, Jurkunas UV. Decline in DJ-1 and decreased nuclear translocation of Nrf2 in Fuchs endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2012;53(9):5806–5813.
204. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 2010;12(3):213–223.
205. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, Hoshii T, Hirao A, Takagi K, Mizushima T, Motohashi H, Lee MS, Yoshimori T, Tanaka K, Yamamoto M, Komatsu M. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell 2013;51(5):618–631.
206. Yu M, Li H, Liu Q, Liu F, Tang L, Li C, Yuan Y, Zhan Y, Xu W, Li W, Chen H, Ge C, Wang J, Yang X. Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal 2011;23(5):883–892.