Cancer chemoprevention mechanisms mediated through the keap1-Nrf2 pathway

Antioxidants and Redox Signaling

Volumn 13, Issue 11, 2010, Pages 1713-1748

  Hayes, John D ^a   McMahon, Michael ^a   Chowdhry, Sudhir ^a   Dinkova Kostova, Albena T ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BETULIC ACID; BUTYLATED HYDROXYANISOLE; BUTYLCRESOL; CAFFEIC ACID PHENETHYL ESTER; CARNOSOL; CAROTENOID; COUMARIN; CURCUMIN; DITERPENE; ETHOXYQUIN; FLAVONOID; FUMARIC ACID DIMETHYL ESTER; HEME OXYGENASE 1; INDOLE DERIVATIVE; ISOTHIOCYANIC ACID DERIVATIVE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MACROLIDE; NUCLEAR PROTEIN; OLEANOLIC ACID; OLTIPRAZ; QUERCETIN; SULFIDE; TP 225; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG;

ANTIOXIDANT RESPONSIVE ELEMENT; BINDING SITE; CANCER PREVENTION; CELL PROLIFERATION; CELL PROTECTION; DETOXIFICATION; DIMERIZATION; DISULFIDE BOND; DRUG DETOXIFICATION; ENZYME REPRESSION; GENE CONTROL; GENETIC TRANSCRIPTION; GENOTOXICITY; HUMAN; IN VIVO STUDY; METAL BINDING; MICHAEL ADDITION; MODULATION; NONHUMAN; OXIDATION REDUCTION REACTION; PHYTOCHEMISTRY; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; REVIEW; SENSITIVITY ANALYSIS; SIGNAL TRANSDUCTION; UPREGULATION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANTICARCINOGENIC AGENTS; ANTIOXIDANTS; CARRIER PROTEINS; CELL PROLIFERATION; CULLIN PROTEINS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NEOPLASMS; NF-E2-RELATED FACTOR 2; RESPONSE ELEMENTS; SIGNAL TRANSDUCTION; TRANS-ACTIVATORS; TRANSCRIPTION FACTORS; VESICULAR TRANSPORT PROTEINS;

EID: 77958130983     PISSN: 15230864     EISSN: None     Source Type: Journal    
DOI: 10.1089/ars.2010.3221     Document Type: Review

References (356)

1. Ainbinder E, Bergelson S, Pinkus R, and Daniel V. Reg-ulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione S-transferase gene ex-pression by chemical agents. Eur J Biochem 243: 49-57,1997.
2. Alam J. Multiple elements within the 5' distal enhancer of the mouse heme oxygenase-1 gene mediate induction by heavy metals. J Biol Chem 269: 25049-25056, 1994.
3. Alam J, Camhi S, and Choi AM. Identification of a second region upstream of the mouse heme oxygenase-1 gene that functions as a basal level and inducer-dependent tran-scription enhancer. J Biol Chem 270: 11977-11984, 1995.
4. Alam J, Wicks C, Stewart D, Gong P, Touchard C, Otterbein S, Choi AM, Burow ME, and Tou J. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mam-mary epithelial cells. Role of p38 kinase and Nrf2 tran-scription factor. J Biol Chem 275: 27694-27702, 2000.
5. Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P, Wassilew SW, Horn T, Kreysel HW, Lutz G, et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol 30: 977-981, 1994.
6. Andreadi CK, Howells LM, Atherfold PA, and Manson MM. Involvement of Nrf2, p38, B-Raf, and nuclear factor-?B, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols. Mol Pharmacol 69: 1033-1040, 2006.
7. Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, and Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49: 729-739, 1987.
8. Ansell PJ, Lo SC, Newton LG, Espinosa-Nicholas C, Zhang DD, Liu JH, Hannink M, and Lubahn DB. Repression of cancer protective genes by 17/ï-estradiol: Ligand-dependent interaction between human Nrf2 and estrogen receptor α. Mol Cell Endocrinol 243: 27-34, 2005.
9. Aoki Y, Sato H, Nishimura N, Takahashi S, Itoh K, and Yamamoto M. Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel ex-haust. Toxicol Appl Pharmacol 173: 154-160, 2001.
10. Aoki Y, Hashimoto AH, Amanuma K, Matsumoto M, Hiyoshi K, Takano H, Masumura K, Itoh K, Nohmi T, and Yamamoto M. Enhanced spontaneous and benzo[a]pyrene-induced mutations in the lung of Nrf2-deficient gpt ß mice. Cancer Res 67: 5643-5648, 2007.
11. Balla J, Nath KA, Balla G, Juckett MB, Jacob HS, and Ver-cellotti GM. Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo. Am J Physiol 268: L321-327, 1995.
12. Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J, and Motterlini R. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxi-dant-responsive element. Biochem J 371: 887-895, 2003.
13. Banning A, Deubel S, Kluth D, Zhou Z, and Brigelius-Flohé R. The GI-GPx gene is a target for Nrf2. Mol Cell Biol 25: 4914-4923, 2005.
14. Batzinger RP, Ou SY, and Bueding E. Antimutagenic effects of 2(3)-tert-butyl-4-hydroxyanisole and of antimicrobial agents. Cancer Res 38: 4478-4485, 1978.
15. Benson AM, Batzinger RP, Ou SY, Bueding E, Cha YN, and Talalay P. Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites of benzo(a)pyrene by dietary antioxidants. Cancer Res 38: 4486-4495, 1978.
16. Benson AM, Cha YN, Bueding E, Heine HS, and Talalay P. Elevation of extrahepatic glutathione S-transferase and epoxide hydratase activities by 2(3)-tert-butyl-4-hydro-xyanisole. Cancer Res 39: 2971-2977, 1979. (Pubitemid 9226904)
17. Benson AM, Hunkeler MJ, and Talalay P. Increase of NAD(P)H:quinone reductase by dietary antioxidants: Pos-sible role in protection against carcinogenesis and toxicity. Proc Natl Acad Sci USA 77: 5216-5220, 1980.
18. Bergelson S, Pinkus R, and Daniel V. Induction of AP-1 (Fos/Jun) by chemical agents mediates activation of gluta-thione S-transferase and quinone reductase gene expres-sion. Oncogene 9: 565-571, 1994.
19. Beyer TA, Xu W, Teupser D, auf dem Keller U, Bugnon P, Hildt E, Thiery J, Kan YW, Werner S. Impaired liver regeneration in Nrf2 knockout mice: Role of ROS-mediated insulin/IGF-1 resistance. EMBO J 27: 212-223, 2008.
20. Bizzozero OA, Bixler HA, and Pastuszyn A. Structural de-terminants influencing the reaction of cysteine-containing peptides with palmitoyl-coenzyme A and other thioesters. Biochim Biophys Acta 1545: 278-288, 2001.
21. Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, and Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171: 603-614, 2005.
22. Bodreddigari S, Jones LK, Egner PA, Groopman JD, Sutter CH, Roebuck BD, Guengerich FP, Kensler TW, and Sutter TR. Protection against aflatoxin B1-induced cytotoxicity by expression of the cloned aflatoxin B1-aldehyde reductases rat AKR7A1 and human AKR7A3. Chem Res Toxicol 21: 1134-1142, 2008.
23. Bones AM, and Rossiter JT. The enzymic and chemically induced decomposition of glucosinolates. Phytochemistry 67: 1053-1067, 2006.
24. Bonnesen C, Eggleston IM, and Hayes JD. Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer pro-tection against DNA damage in human colon cell lines. Cancer Res 61: 6120-6130, 2001.
25. Borroz KI, Buetler TM, and Eaton DL. Modulation of y-glutamylcysteine synthetase large subunit mRNA expres-sion by butylated hydroxyanisole. Toxicol Appl Pharmacol 126: 150-155, 1994.
26. Brooks JD, Paton VG, Vidanes G. Potent induction of phase 2 enzymes in human prostate cells by sulforaphane. Cancer Epidemiol Biomarkers Prev 10: 949-954, 2001.
27. Brown SL, Sekhar KR, Rachakonda G, Sasi S, and Freeman ML. Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res 68: 364-368, 2008.
28. Burczynski ME, Lin HK, and Penning TM. Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxida-tive stress: implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydroge-nase. Cancer Res 59: 607-614, 1999.
29. Burhans WC and Heintz NH. The cell cycle is a redox cycle: Linking phase-specific targets to cell fate. Free Radic Biol Med 47: 1282-1293, 2009.
30. Cabral JR and Neal GE. The inhibitory effects of ethoxyquin on the carcinogenic action of aflatoxin B1 in rats. Cancer Lett 19: 125-132, 1983.
31. Cha YN, Martz F, and Bueding E. Enhancement of liver microsome epoxide hydratase activity in rodents by treat-ment with 2(3)-tert-butyl-4- hydroxyanisole. Cancer Res 38: 4496-4498, 1978.
32. Chambers KF, Bacon JR, Kemsley EK, Mills RD, Ball RY, Mithen RF, and Traka MH. Gene expression profile of pri-mary prostate epithelial and stromal cells in response to sulforaphane or iberin exposure. Prostate 69:1411-1421,2009.
33. Chanas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, Yamamoto M, and Hayes JD. Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and in-ducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3, and Gstm4 genes in the livers of male and female mice. Biochem J 365: 405-416, 2002.
34. Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, and Zhang DD. Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxi-dant response. Mol Cell 34: 663-673, 2009.
35. Cho HY, Reddy SP, Debiase A, Yamamoto M, and Klee-berger SR. Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic Biol Med 38: 325-343, 2005. (Pubitemid 40081112)
36. Cho HY and Kleeberger SR. Nrf2 protects against airway disorders. Toxicol Appl Pharmacol 244: 43-56, 2010.
37. Choi HS and Moore DD. Induction of c-fos and c-jun gene expression by phenolic antioxidants. Mol Endocrinol 7: 1596-1602, 1993.
38. Chowdhury I, Mo Y, Gao L, Kazi A, Fisher AB, and Fein-stein SI. Oxidant stress stimulates expression of the human peroxiredoxin 6 gene by a transcriptional mechanism in-volving an antioxidant response element. Free Radic Biol Med 46: 146-153, 2009.
39. Ciaccio PJ, Jaiswal AK, and Tew KD. Regulation of human dihydrodiol dehydrogenase by Michael acceptor xenobi-otics. J Biol Chem 269: 15558-15562, 1994.
40. Collings AJ and Sharratt M. The BHT content of human adipose tissue. Food Cosmet Toxicol 8: 409-412, 1970.
41. Conaway CC, Jiao D, and Chung FL. Inhibition of rat liver cytochrome P450 isozymes by isothiocyanates and their conjugates: A structure-activity relationship study. Carci-nogenesis 17: 2423-2427, 1996.
42. Conaway CC, Wang CX, Pittman B, Yang YM, Schwartz JE, Tian D, McIntee EJ, Hecht SS, and Chung FL. Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice. Cancer Res 65: 8548-8557, 2005.
43. Copple IM, Goldring CE, Jenkins RE, Chia AJ, Randle LE, Hayes JD, Kitteringham NR, and Park BK. The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system. Hepatology 48: 1292-1301, 2008.
44. Cullinan SB and Diehl JA. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279: 20108-20117, 2004.
45. Cullinan SB, Gordan JD, Jin J, Harper JW, and Diehl JA. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: Oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol 24: 8477-8486, 2004.
46. Dalton T, Palmiter RD, and Andrews GK. Transcriptional induction of the mouse metallothionein-I gene in hydrogen peroxide-treated Hepa cells involves a composite major late transcription factor/antioxidant response element and me-tal response promoter elements. Nucleic Acids Res 22: 5016-5023, 1994.
47. De Long MJ, Prochaska HJ, and Talalay P. Tissue-specific induction patterns of cancer-protective enzymes in mice by tert-Butyl-4-hydroxyanisole and related substituted phe-nols. Cancer Res 45: 546-551, 1985.
48. De Long MJ, Prochaska HJ, and Talalay P. Induction of NAD(P)H:quinone reductase in murine hepatoma cells by phenolic antioxidants, azo dyes, and other chemoprotec-tors: A model system for the study of anticarcinogens. Proc Natl Acad Sci USA 83: 787-791, 1986.
49. Deveaux S, Cohen-Kaminsky S, Shivdasani RA, Andrews NC, Filipe A, Kuzniak I, Orkin SH, Roméo PH, and Mignotte V. p45 NF-E2 regulates expression of thromboxane synthase in megakaryocytes. EMBO J 16: 5654-5661, 1997.
50. Devling TW, Lindsay CD, McLellan LI, McMahon M, and Hayes JD. Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype. Proc Natl Acad Sci USA 102: 7280-7285A, 2005.
51. 412-hydroxydehydrogenase/15-oxoprostaglandin 13-reductase. J Biol Chem 276: 40803-40810, 2001.
52. Dickinson SE, Melton TF, Olson ER, Zhang J, Saboda K, and Bowden GT. Inhibition of activator protein-1 by sul-foraphane involves interaction with cysteine in the cFos DNA-binding domain: Implications for chemoprevention of UVB-induced skin cancer. Cancer Res 69: 7103-7110, 2009.
53. Dinkova-Kostova AT, Abeygunawardana C, and Talalay P. Chemoprotective properties of phenylpropenoids, bis(-benzylidene)cycloalkanones, and related Michael reaction acceptors: Correlation of potencies as phase 2 enzyme in-ducers and radical scavengers. J Med Chem 41: 5287-5296, 1998.
54. Dinkova-Kostova AT and Talalay P. Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes. Carcinogenesis 20: 911-914, 1999.
55. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, and Talalay P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci USA 98: 3404-3409, 2001.
56. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, and Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that pro-tect against carcinogens and oxidants. Proc Natl Acad Sci USA 99: 11908-11913, 2002.
57. Dinkova-Kostova AT, Fahey JW, and Talalay P. Chemical structures of inducers of nicotinamide quinone oxidore-ductase 1 (NQO1). Methods Enzymol 382: 423-448, 2004.
58. Dinkova-Kostova AT, Holtzclaw WD, and Wakabayashi N. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 44: 6889-6899, 2005.
59. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, and Talalay P. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102: 4584-4589, 2005.
60. Dinkova-Kostova AT, Jenkins SN, Fahey JW, Ye L, Wehage SL, Liby KT, Stephenson KK, Wade KL, and Talalay P. Protection against UV-light-induced skin carcinogenesis in SKH-1 high-risk mice by sulforaphane-containing broccoli sprout extracts. Cancer Lett 240: 243-252, 2006.
61. Dinkova-Kostova AT, Fahey JW, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ, Kerns ML, and Talalay P. Induction of the phase 2 response in mouse and human skin by sul-foraphane-containing broccoli sprout extracts. Cancer Epi-demiol Biomarkers Prev 16: 847-851, 2007.
62. Dinkova-Kostova AT, Jenkins SN, Wehage SL, Huso DL, Benedict AL, Stephenson KK, Fahey JW, Liu H, Liby KT, Honda T, Gribble GW, Sporn MB, and Talalay P. A di-cyanotriterpenoid induces cytoprotective enzymes and re-duces multiplicity of skin tumors in UV-irradiated mice. Biochem Biophys Res Commun 367: 859-865, 2008.
63. Dohi Y, Alam J, Yoshizumi M, Sun J, and Igarashi K. Heme oxygenase-1 gene enhancer manifests silencing activity in a chromatin environment prior to oxidative stress. Antioxid Redox Signal 8: 60-67, 2006.
64. Eaton DL and Gallagher EP. Mechanisms of aflatoxin carcinogenesis. Annu Rev Pharmacol Toxicol 34: 135-172, 1994.
65. Eggler AL, Liu G, Pezzuto JM, van Breemen RB, and Me-secar AD. 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: 10070-10075, 2005.
66. Eggler AL, Luo Y, van Breemen RB, and Mesecar AD. Identification of the highly reactive cysteine 151 in the chemopreventive agent-sensor Keap1 protein is method-dependent. Chem Res Toxicol 20: 1878-1884, 2007.
67. Eggler AL, Small E, Hannink M, and Mesecar AD. 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: 171-180, 2009.
68. Ellis EM, Judah DJ, Neal GE, and Hayes JD. An ethoxyquin-inducible aldehyde reductase from rat liver that metabolizes aflatoxin B1 defines a subfamily of aldo-keto reductases. Proc Natl Acad Sci USA 90: 10350-10354, 1993.
69. Ellis EM. Protection against aflatoxin B1 in rat\A new look at the link between toxicity, carcinogenicity, and metabo-lism. Toxicol Sci 109:1-3, 2009.
70. Erickson AM, Nevarea Z, Gipp JJ, and Mulcahy RT. Iden-tification of a variant antioxidant response element in the promoter of the human glutamate-cysteine ligase modifier subunit gene. Revision of the ARE consensus sequence. J Biol Chem 277: 30730-30737, 2002.
71. Fahey JW, Zhang Y, and Talalay P. Broccoli sprouts: An exceptionally rich source of inducers of enzymes that pro-tect against chemical carcinogens. Proc Natl Acad Sci USA 94: 10367-10372, 1997.
72. Fahey JW, Zalcmann AT, and Talalay P. The chemical di-versity and distribution of glucosinolates and iso-thiocyanates among plants. Phytochemistry 56: 5-51, 2001.
73. Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, and Lozniewski A. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci USA 99: 7610-7615, 2002.
74. Fahey JW, Dinkova-Kostova AT, Stephenson KK, and Talalay P. The "Prochaska" microtiter plate bioassay for inducers of NQO1. Methods Enzymol 382: 243-258, 2004.
75. Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M, Russo T, and Cimino F. p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 281: 39776-39784, 2006.
76. Farber E. Cellular biochemistry of the stepwise develop-ment of cancer with chemicals: G. H. A. Clowes memorial lecture. Cancer Res 44: 5463-5474, 1984.
77. Favreau LV and Pickett CB. Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. J Biol Chem 266: 4556-4561, 1991.
78. Favreau LV and Pickett CB. The rat quinone reductase an-tioxidant response element. Identification of the nucleotide sequence required for basal and inducible activity and detection of antioxidant response element-binding proteins in hepatoma and non-hepatoma cell lines. J Biol Chem 270: 24468-24474, 1995.
79. Feuer G, Kellen JA, and Kovacs K. Suppression of 7,12-dimethylbenz[a] anthracene-induced breast carcinoma by coumarin in the rat. Oncology 33, 35-39, 1976.
80. Fields WR, Morrow CS, Doehmer J, Townsend AJ. Expression of stably transfected murine glutathione S-transferase A3-3 protects against nucleic acid alkylation and cytotoxicity by aflatoxin B1 in hamster V79 cells expressing rat cytochrome P450-2B1. Carcinogenesis 20: 1121-1125, 1999.
81. Foresti R, Hoque M, Monti D, Green CJ, and Motterlini R. Differential activation of heme oxygenase-1 by chalcones and rosolic acid in endothelial cells. J Pharmacol Exp Ther 312: 686-693, 2005.
82. 2 involves KEAP1 disulfide formation. J Biol Chem 285:8463-8471, 2010.
83. Friling RS, Bensimon A, Tichauer Y, and Daniel V. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Natl Acad Sci USA 87: 6258-6262, 1990.
84. Friling RS, Bergelson S, and Daniel V. Two adjacent AP-1-like binding sites form the electrophile-responsive element of the murine glutathione S-transferase Ya subunit gene. Proc Natl Acad Sci USA 89: 668-672, 1992.
85. Furukawa M and Xiong Y. BTB protein Keap1 targets an-tioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol 25: 162-171, 2005.
86. Gamet-Payrastre L, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, Gasc N, Tulliez J, and Tercé F. Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle ar-rest and apoptosis in HT29 human colon cancer cells. Cancer Res 60: 1426-1433, 2000.
87. Gasper AV, Traka M, Bacon JR, Smith JA, Taylor MA, Hawkey CJ, Barrett DA, and Mithen RF. Consuming broccoli does not induce genes associated with xenobiotic metabolism and cell cycle control in human gastric mucosa. J Nutr 137: 1718-1724, 2007.
88. Gao X, Dinkova-Kostova AT, and Talalay P. Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxi-dative damage: The indirect antioxidant effects of sulfor-aphane. Proc Natl Acad Sci USA 98: 15221-15226, 2001.
89. Geetha T and Wooten MW. Structure and functional properties of the ubiquitin binding protein p62. FEBS Lett 512: 19-24, 2002.
90. Gibbs A, Schwartzman J, Deng V, and Alumkal J. Sulfor-aphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 6. Proc Natl Acad Sci USA 106: 16663-16668, 2009.
91. Gills JJ, Jeffery EH, Matusheski NV, Moon RC, Lantvit DD, and Pezzuto JM. Sulforaphane prevents mouse skin tu-morigenesis during the stage of promotion. Cancer Lett 236: 72-79, 2006.
92. Gong P, Hu B, Stewart D, Ellerbe M, Figueroa YG, Blank V, Beckman BS, and Alam J. Cobalt induces heme oxygenase-1 expression by a hypoxia-inducible factor-independent mechanism in Chinese hamster ovary cells: Regulation by Nrf2 and MafG transcription factors. J Biol Chem 276: 27018-27025, 2001.
93. 2 is mediated by the stress re-sponse elements and transcription factor Nrf2. Antioxid Redox Signal 4: 249-257, 2002.
94. Gong P, Stewart D, Hu B, Vinson C, and Alam J. Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite. Arch Biochem Biophys 405: 265-274, 2002.
95. Grantham PH, Weisburger JH, and Weisburger EK. Effect of the antioxidant butylated hydroxytoluene (BHT) on the metabolism of the carcinogens N-2-fluorenylacetamide and N-hydroxy-N-2-fluorenylacetamide. Food Cosmet Toxicol 11: 209-217, 1973.
96. Greenwald P. Cancer chemoprevention. BMJ 324: 714-718, 2002.
97. Guengerich FP, Cai H, McMahon M, Hayes JD, Sutter TR, Groopman JD, Deng Z, and Harris TM. Reduction of afla-toxin B1 dialdehyde by rat and human aldo-keto reduc-tases. Chem Res Toxicol 14: 727-737, 2001.
98. Han ES, Muller FL, Pérez VI, Qi W, Liang H, Xi L, Fu C, Doyle E, Hickey M, Cornell J, Epstein CJ, Roberts LJ, Van Remmen H, and Richardson A. The in vivo gene expression signature of oxidative stress. Physiol Genomics 34:112-126,2008.
99. Harada H, Sugimoto R, Watanabe A, Taketani S, Okada K, Warabi E, Siow R, Itoh K, Yamamoto M, and Ishii T. Dif-ferential roles for Nrf2 and AP-1 in upregulation of HO-1 expression by arsenite in murine embryonic fibroblasts. Free Radic Res 42: 297-304, 2008.
100. Harvey CJ, Thimmulappa RK, Singh A, Blake DJ, Ling G, Wakabayashi N, Fujii J, Myers A, and Biswal S. Nrf2-regulated glutathione recycling independent of biosynthe-sis is critical for cell survival during oxidative stress. Free Radic Biol Med 46: 443-453, 2009.
101. Hatcher H, Planalp R, Cho J, Torti FM, and Torti SV. Curcumin: From ancient medicine to current clinical trials. Cell Mol Life Sci 65: 1631-1652, 2008.
102. 2, which pos-sesses high catalytic activity for aflatoxin B1-8,9-epoxide. Biochem J 279: 385-398, 1991.
103. Hayes JD, Judah DJ, Neal GE, and Nguyen T. Molecular cloning and heterologous expression of a cDNA encoding a mouse glutathione S-transferase Yc subunit possessing high catalytic activity for aflatoxin B1-8,9-epoxide. Biochem J 285: 173-180, 1992.
104. Hayes JD, Judah DJ, and Neal GE. Resistance to aflatoxin B1 is associated with the expression of a novel aldo-keto re-ductase which has catalytic activity towards a cytotoxic aldehyde-containing metabolite of the toxin. Cancer Res 53: 3887-3894, 1993.
105. 2 subunit is expressed in adult rat liver resistant to the hepatocarcino-gen aflatoxin B1. J Biol Chem 269: 20707-20717, 1994.
106. Hayes JD and Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30: 445-600, 1995.
107. Hayes JD, Pulford DJ, Ellis EM, McLeod R, James RF, Sei-dega°rd J, Mosialou E, Jernström B, and Neal GE. Regulation of rat glutathione S-transferase A5 by cancer chemo-preventive agents: mechanisms of inducible resistance to aflatoxin B1. Chem Biol Interact 111-112: 51-67, 1998.
108. Hayes JD, Ellis EM, Neal GE, Harrison DJ, and Manson MM. Cellular response to cancer chemopreventive agents: Contribution of the antioxidant responsive element to the adaptive response to oxidative and chemical stress. Biochem Soc Symp 64: 141-168, 1999.
109. Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, and Yamamoto M. The Nrf2 tran-scription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their in-duction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin. Biochem Soc Trans 28: 33-41, 2000.
110. Hayes JD and McMahon M. The double-edged sword of Nrf2: Subversion of redox homeostasis during the evolu-tion of cancer. Mol Cell 21:732-734, 2006.
111. Hayes JD, Kelleher MO, and Eggleston IM. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. Eur J Nutr 47 Suppl 2: 73-88, 2008.
112. Hayes JD and McMahon M. NRF2 and KEAP1 mutations: Permanent activation of an adaptive response in cancer. Trends Biochem Sci 34: 176-188, 2009.
113. He X and Ma Q. NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degrada-tion, and transcription activation. Mol Pharmacol 76: 1265-1278, 2009.
114. Higgins LG, Cavin C, Itoh K, Yamamoto M, and Hayes JD. Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein. Toxicol Appl Pharmacol 226: 328-337, 2008.
115. Higgins LG, Kelleher MO, Eggleston IM, Itoh K, Yamamoto M, and Hayes JD. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, per-oxides and redox-cycling agents. Toxicol Appl Pharmacol 237: 267-280, 2009.
116. Hintze KJ and Theil EC DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression. Proc Natl Acad Sci USA 102: 15048-15052, 2005.
117. Hirvonen T, Virtamo J, Korhonen P, Albanes D, and Pie-tinen P. Flavonol and flavone intake and the risk of cancer in male smokers (Finland). Cancer Causes Control 12: 789-796, 2001. (Pubitemid 33010616)
118. Holland R, Navamal M, Velayutham M, Zweier JL, Kensler TW, and Fishbein JC. Hydrogen peroxide is a second messenger in phase 2 enzyme induction by cancer chemopre-ventive dithiolethiones. Chem Res Toxicol 22: 1427-1434, 2009.
119. Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, Itoh K, Yamamoto M. Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15: 3423-3432, 2009.
120. Hong F, Freeman ML, and Liebler DC Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 18: 1917-1926, 2005.
121. Hong F, Sekhar KR, Freeman ML, and Liebler DC Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation. J Biol Chem 280: 31768-31775, 2005.
122. Hu R, Hebbar V, Kim BR, Chen C, Winnik B, Buckley B, Soteropoulos P, Tolias P, Hart RP, and Kong AN. In vivo pharmacokinetics and regulation of gene expression pro-files by isothiocyanate sulforaphane in the rat. J Pharmacol Exp Ther 310: 263-271, 2004.
123. Hu R, Khor TO, Shen G, Jeong WS, Hebbar V, Chen C, Xu C, Reddy B, Chada K, and Kong AN. Cancer chemopre-vention of intestinal polyposis in ApcMin/+ mice by sul-foraphane, a natural product derived from cruciferous vegetable. Carcinogenesis 27: 2038-2046, 2006.
124. Hu R, Xu C Shen G, Jain MR, Khor TO, Gopalkrishnan A, Lin W, Reddy B, Chan JY, and Kong AN. Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Cancer Lett 243: 170-192, 2006.
125. Hu R, Xu C Shen G, Jain MR, Khor TO, Gopalkrishnan A, Lin W, Reddy B, Chan JY, and Kong AN. Identification of Nrf2-regulated genes induced by chemopreventive iso-thiocyanate PEITC by oligonucleotide microarray. Life Sci 79: 1944-1955, 2006.
126. Huang MT, Ho CT, Wang ZY, Ferraro T, Lou YR, Stauber K, Ma W, Georgiadis C, Laskin JD, and Conney AH Inhibition of skin tumorigenesis by rosemary and its constituents car-nosol and ursolic acid. Cancer Res 54: 701-708, 1994.
127. Huang Y, Zhou Y, Fan Y, and Zhou D. Celastrol inhibits the growth of human glioma xenografts in nude mice through suppressing VEGFR expression. Cancer Lett 264: 101-106, 2008.
128. Ichimura Y, Kumanomidou T, Sou YS, Mizushima T, Ezaki J, Ueno T, Kominami E, Yamane T, Tanaka K, and Komatsu M. Structural basis for sorting mechanism of p62 in selec-tive autophagy. J Biol Chem 283: 22847-22857, 2008.
129. Idris AI, Libouban H, Nyangoga H, Landao-Bassonga E, Chappard D, and Ralston SH. Pharmacologic inhibitors of I?B kinase suppress growth and migration of mammary carcinosarcoma cells in vitro and prevent osteolytic bone metastasis in vivo. Mol Cancer Ther 8: 2339-2347, 2009.
130. Iida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, Shimazui T, Akaza H, and Yamamoto M. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res 64: 6424-6431, 2004.
131. Iida K, Itoh K, Maher JM, Kumagai Y, Oyasu R, Mori Y, Shimazui T, Akaza H, and Yamamoto M. Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis. Carcinogenesis 28: 2398-2403, 2007.
132. Ikeda H, Omoteyama K, Yoshida K, Nishi S, and Sakai M. CCAAT enhancer-binding protein a suppresses the rat placental glutathione S-transferase gene in normal liver. J Biol Chem 281: 6734-6741, 2006.
133. Ikeda Y, Sugawara A, Taniyama Y, Uruno A, Igarashi K, Arima S, Ito S, and Takeuchi K. Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor γ in macrophages via an interaction with NRF2. J Biol Chem 275: 33142-33150, 2000.
134. Ilic Z, Crawford D, Egner PA, and Sell S. Glutathione S-transferase A3 knockout mice are sensitive to acute cyto-toxic and genotoxic effects of aflatoxin B1. Toxicol Appl Pharmacol 242: 241-246, 2010.
135. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, and Yamamoto M. Transcription factor Nrf2 co-ordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275: 16023-16029, 2000.
136. Itoh K, Igarashi K, Hayashi N, Nishizawa M, and Yama-moto M. Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor hetero-dimerizing with the small Maf family proteins. Mol Cell Biol 15: 4184-4193, 1995.
137. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, and Nabeshima Y. An Nrf2/small Maf heterodimer medi-ates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236: 313-322, 1997.
138. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, and Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through bind-ing to the amino-terminal Neh2 domain. Genes Dev 13: 76-86, 1999.
139. Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Overvatn A, McMahon M, Hayes JD, and Johansen T. p62/SQSTM1 creates a positive feedback loop by interacting with KEAP1 to induce NRF2-mediated transcription of its own gene. J Biol Chem 285: 22576-22591, 2010.
140. Jaiswal AK. Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin. Biochem-istry 30: 10647-10653, 1991.
141. Jhee EC, Ho LL, Tsuji K, Gopalan P, and Lotlikar PD. Effect of butylated hydroxyanisole pretreatment on aflatoxin B1-DNA binding and aflatoxin B1-glutathione conjugation in isolated hepatocytes from rats. Cancer Res 49: 1357-1360, 1989.
142. Johnson WW, Ueng YF, Widersten M, Mannervik B, Hayes JD, Sherratt PJ, Ketterer B, and Guengerich FP. Conjugation of highly reactive aflatoxin B1 exo-8,9-epoxide catalyzed by rat and human glutathione transferases: Estimation of ki-netic parameters. Biochemistry 36: 3056-3060, 1997.
143. Jowsey IR, Jiang Q, Itoh K, Yamamoto M, and Hayes JD. Expression of the aflatoxin B1-8,9-epoxide-metabolizing murine glutathione S-transferase A3 subunit is regulated by the Nrf2 transcription factor through an antioxidant response element. Mol Pharmacol 64: 1018-1028, 2003.
144. Judah DJ, Hayes JD, Yang JC, Lian LY, Roberts GC, Farmer PB, Lamb JH, and Neal GE. A novel aldehyde reductase with activity towards a metabolite of aflatoxin B1 is ex-pressed in rat liver during carcinogenesis and following the administration of an antioxidant. Biochem J 292:13-18,1993.
145. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, San-drock AW, and O'Neill GN; BG-12 Phase IIb Study In-vestigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: A multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372: 1463-1472, 2008.
146. Karapetian RN, Evstafieva AG, Abaeva IS, Chichkova NV, Filonov GS, Rubtsov YP, Sukhacheva EA, Melnikov SV, Schneider U, Wanker EE, and Vartapetian AB. Nuclear oncoprotein prothymosin is a partner of Keap1: Implica-tions for expression of oxidative stress-protecting genes. Mol Cell Biol 25: 1089-1099, 2005.
147. Kataoka K, Noda M, and Nishizawa M. Maf nuclear on-coprotein recognizes sequences related to an AP-1 site and forms heterodimers with both Fos and Jun. Mol Cell Biol 14: 700-712, 1994.
148. Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, and Yamamoto M. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6: 857-868, 2001.
149. Katsuoka F, Motohashi H, Engel JD, and Yamamoto M. Nrf2 transcriptionally activates the mafG gene through an antioxidant response element. J Biol Chem 280: 4483-4490, 2005.
150. Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, and Yamamoto M. Genetic evidence that small maf pro-teins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol 25: 8044-8051,2005.
151. Kelleher MO, McMahon M, Eggleston IM, Dixon MJ, Taguchi K, Yamamoto M, and Hayes JD. 1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford re-sistance against the genotoxic a,b-unsaturated aldehyde acrolein. Carcinogenesis 30: 1754-1762, 2009.
152. Kelly VP, Ellis EM, Manson MM, Chanas SA, Moffat GJ, McLeod R, Judah DJ, Neal GE, and Hayes JD. Chemopre-vention of aflatoxin B1 hepatocarcinogenesis by coumarin, a natural benzopyrone that is a potent inducer of aflatoxin B1-aldehyde reductase, the glutathione S-transferase A5 and P1 subunits, and NAD(P)H:quinone oxidoreductase in rat liver. Cancer Res 60: 957-969, 2000.
153. Kelner MJ, Bagnell RD, Montoya MA, Estes LA, Forsberg L, Morgenstern R. Structural organization of the microsomal glutathione S-transferase gene (MGST1) on chromosome 12p13.1-13.2. Identification of the correct promoter region and demonstration of transcriptional regulation in response to oxidative stress. J Biol Chem 275: 13000-13006, 2000.
154. Kensler TW, Egner PA, Trush MA, Bueding E, and Groopman JD. Modification of aflatoxin B1 binding to DNA in vivo in rats fed phenolic antioxidants, ethoxyquin and a dithiothione. Carcinogenesis 6: 759-763, 1985.
155. Kensler TW, Egner PA, Dolan PM, Groopman JD, and Roebuck BD. Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4- methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones. Cancer Res 47: 4271-4277, 1987.
156. Kensler TW, Groopman JD, Sutter TR, Curphey TJ, and Roebuck BD. Development of cancer chemopreventive agents: Oltipraz as a paradigm. Chem Res Toxicol 12: 113-126, 1999.
157. Kensler TW, Wakabayashi N, and Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47: 89-116,2007.
158. Kensler TW and Wakabayashi N. Nrf2: Friend or foe for chemoprevention? Carcinogenesis 31: 90-99, 2010.
159. Kerppola TK and Curran T. A conserved region adjacent to the basic domain is required for recognition of an extended DNA binding site by Maf/Nrl family proteins. Oncogene 9: 3149-3158, 1994.
160. Keyse SM and Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci USA 86: 99-103, 1989.
161. Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, Cheung WA, Chan JY, Reddy BS, Yang CS, and Kong AN. Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res 1:187-191,2008.
162. Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, and Yodoi J. Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. J Biol Chem 276: 18399-18406, 2001.
163. Kim YJ, Ahn JY, Liang P, Ip C, Zhang Y, and Park YM. Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Cancer Res 67: 546-554, 2007.
164. Kimura M, Yamamoto T, Zhang J, Itoh K, Kyo M, Kamiya T, Aburatani H, Katsuoka F, Kurokawa H, Tanaka T, Mo-tohashi H, and Yamamoto M. Molecular basis distin-guishing the DNA binding profile of Nrf2-Maf heterodimer from that of Maf homodimer. J Biol Chem 282: 33681-33690, 2007.
165. th Ed); McGraw-Hill, pp. 329-379.
166. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, and Yamamoto M. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24: 7130-7139, 2004.
167. Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, and Yamamoto M. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 26: 221-219, 2006.
168. Kohn KW, Aladjem MI, Weinstein JN, and Pommier Y. Molecular interaction maps of bioregulatory networks: A general rubric for systems biology. Mol Biol Cell 17: 1-13, 2006.
169. 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, and Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12: 213-223, 2010.
170. Kuroda K, Kanisawa M, and Akao M. Inhibitory effect of fumaric acid on forestomach and lung carcinogenesis by a 5-nitrofuran naphthyridine derivative in mice. J Natl Cancer Inst 69: 1317-1320, 1982.
171. Kuroda K, Terao K, and Akao M. Inhibitory effect of fu-maric acid on 3-methyl-4'-(dimethylamino)-azobenzene-induced hepatocarcinogenesis in rats. J Natl Cancer Inst 71: 855-857, 1983.
172. Kuroda K and Akao M. Inhibitory effect of fumaric acid on 3'-methyl-4-(dimethylamino)azobenzene-induced hepato-carcinogenesis in rats. Chem Pharm Bull (Tokyo) 37: 1345-1346, 1989.
173. Kuroiwa Y, Nishikawa A, Kitamura Y, Kanki K, Ishii Y, Umemura T, and Hirose M. Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic carcinogenesis in hamsters. Cancer Lett 241: 275-280, 2006.
174. Kurokawa H, Motohashi H, Sueno S, Kimura M, Takagawa H, Kanno Y, Yamamoto M, and Tanaka T. Structural basis of alternative DNA recognition by Maf transcription fac-tors. Mol Cell Biol 29: 6232-6244, 2009.
175. Kwak MK, Egner PA, Dolan PM, Ramos-Gomez M, Groopman JD, Itoh K, Yamamoto M, and Kensler TW. Role of phase 2 enzyme induction in chemoprotection by di-thiolethiones. Mutat Res 480-481: 305-315, 2001.
176. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, and Kensler TW. Antioxidants enhance mammalian pro-teasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23: 8786-8794, 2003.
177. Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yama-moto M, and Kensler TW. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278: 8135-8145, 2003.
178. Kyung KH, Fleming HP, Young CT, and Haney CA (1995) 1-Cyano-2,3- epithiopropane as the primary sinigrin hy-drolysis product of fresh cabbage. J Food Sci 60: 157-159, 1995.
179. Lao CD, Ruffin MT 4th, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, and Brenner DE. Dose escalation of a curcuminoid formulation. BMC Com-plement Altern Med 6: 10, 2006.
180. 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, and Hung MC. KEAP1 E3 ligase-mediated downregulation of NF-κB signaling by targeting IKK/Iκ. Mol Cell 36: 131-140, 2009.
181. Levonen AL, Landar A, Ramachandran A, Ceaser EK, Dickinson DA, Zanoni G, Morrow JD, and Darley-Usmar VM. Cellular mechanisms of redox cell signalling: Role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem J 378: 373-382, 2004.
182. Levy S, Jaiswal AK, and Forman HJ. The role of c-Jun phosphorylation in EpRE activation of phase II genes. Free Radic Biol Med 47: 1172-1179, 2009.
183. Li J, Lee JM, and Johnson JA. Microarray analysis reveals an antioxidant responsive element-driven gene set in-volved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells. J Biol Chem 277: 388-394, 2002.
184. Li W, Thakor N, Xu EY, Huang Y, Chen C, Yu R, Holcik M, and Kong AN. An internal ribosomal entry site mediates redox-sensitive translation of Nrf2. Nucleic Acids Res 38: 778-788, 2010.
185. Li X, Zhang D, Hannink M, and Beamer LJ. Crystal struc-ture of the Kelch domain of human Keap1. J Biol Chem 279: 54750-54758, 2004.
186. Li YJ, Takizawa H, Azuma A, Kohyama T, Yamauchi Y, Takahashi S, Yamamoto M, Kawada T, Kudoh S, and Su-gawara I. Disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Clin Immunol 128: 366-373, 2008.
187. Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, Gribble GW, Hill-Kapturczak N, Agarwal A, and Sporn MB. The syn-thetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE sig-naling. Cancer Res 65: 4789-4798, 2005.
188. Liby K, Honda T, Williams CR, Risingsong R, Royce DB, Suh N, Dinkova-Kostova AT, Stephenson KK, Talalay P, Sundararajan C, Gribble GW, and Sporn MB. Novel semi-synthetic analogues of betulinic acid with diverse cyto-protective, antiproliferative, and proapoptotic activities. Mol Cancer Ther 6: 2113-2119, 2007.
189. Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, Honda T, Gribble GW, Dmitrovsky E, Sporn TA, and Sporn MB. The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res 67: 2414-2419, 2007.
190. Liby K, Black CC, Royce DB, Williams CR, Risingsong R, Yore MM, Liu X, Honda T, Gribble GW, Lamph WW, Sporn TA, Dmitrovsky E, and Sporn MB. The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis. Mol Cancer Ther 7: 1251-1257, 2008.
191. Liby K, Risingsong R, Royce DB, Williams CR, Yore MM, Honda T, Gribble GW, Lamph WW, Vannini N, Sogno I, Albini A, and Sporn MB. Prevention and treatment of ex-perimental estrogen receptor-negative mammary carcino-genesis by the synthetic triterpenoid CDDO-methyl Ester and the rexinoid LG100268. Clin Cancer Res 14: 4556-4563, 2008.
192. Liby K, Yore MM, Roebuck BD, Baumgartner KJ, Honda T, Sundararajan C, Yoshizawa H, Gribble GW, Williams CR, Risingsong R, Royce DB, Dinkova-Kostova AT, Stephenson KK, Egner PA, Yates MS, Groopman JD, Kensler TW, and Sporn MB. A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Res 68: 6727-6733, 2008.
193. Linseisen J, Rohrmann S, Miller AB, Bueno-de-Mesquita HB, Büchner FL, Vineis P, Agudo A, Gram IT, Janson L, Krogh V, Overvad K, Rasmuson T, Schulz M, Pischon T, Kaaks R, Nieters A, Allen NE, Key TJ, Bingham S, Khaw KT, Amiano P, Barricarte A, Martinez C, Navarro C, Quirós R, Clavel-Chapelon F, Boutron-Ruault MC, Touvier M, Peeters PH, Berglund G, Hallmans G, Lund E, Palli D, Panico S, Tumino R, Tjønneland A, Olsen A, Trichopoulou A, Trichopoulos D, Autier P, Boffetta P, Slimani N, and Riboli E. Fruit and vegetable consumption and lung cancer risk: Updated information from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 121: 1103-1114, 2007. (Pubitemid 47101650)
194. Liu GH, Qu J, and Shen X. NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim Biophys Acta 1783: 713-727, 2008.
195. Liu RM, Hu H, Robison TW, and Forman HJ. Differential enhancement of y-glutamyl transpeptidase and y-gluta-mylcysteine synthetase by tert-butylhydroquinone in rat lung epithelial L2 cells. Am J Respir Cell Mol Biol 14: 186-191, 1996. (Pubitemid 126441392)
196. Liu X, Wang L, Zhao K, Thompson PR, Hwang Y, Mar-morstein R, and Cole PA. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451: 846-850, 2008.
197. Liu Y, Kern JT, Walker JR, Johnson JA, Schultz PG, and Luesch H. A genomic screen for activators of the antioxi-dant response element. Proc Natl Acad Sci USA 104: 5205-5210, 2007.
198. 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 281: 37893-37903, 2006.
199. Lo SC, Li X, Henzl MT, Beamer LJ, and Hannink M. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 25: 3605-3617, 2006.
200. Lou H, Du S, Ji Q, and Stolz A. Induction of AKR1C2 by phase II inducers: Identification of a distal consensus anti-oxidant response element regulated by NRF2. Mol Phar-macol 69: 1662-1672, 2006.
201. Luo Y, Eggler AL, Liu D, Liu G, Mesecar AD, and van Breemen RB. Sites of alkylation of human Keap1 by natural chemoprevention agents. J Am Soc Mass Spectrom 18: 2226-2232, 2007.
202. MacLeod AK, McMahon M, Plummer SM, Higgins LG, Penning TM, Igarashi K, and Hayes JD. Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: Demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, con-trols cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis 30: 1571-1580, 2009.
203. Mahéo K, Morel F, Langouët S, Kramer H, Le Ferrec E, Ketterer B, and Guillouzo A. Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulfor-aphane in primary human and rat hepatocytes. Cancer Res 57: 3649-3652, 1997.
204. Mandel HG, Manson MM, Judah DJ, Simpson JL, Green JA, Forrester LM, Wolf CR, and Neal GE. Metabolic basis for the protective effect of the antioxidant ethoxyquin on af-latoxin B1 hepatocarcinogenesis in the rat. Cancer Res 47: 5218-5223, 1987.
205. Manson MM, Ball HW, Barrett MC, Clark HL, Judah DJ, Williamson G, and Neal GE. Mechanism of action of die-tary chemoprotective agents in rat liver: Induction of phase I and II drug metabolizing enzymes and aflatoxin B1 me-tabolism. Carcinogenesis 18: 1729-1738, 1997.
206. Martin D, Rojo AI, Salinas M, Diaz R, Gallardo G, Alam J, De Galarreta CM, and Cuadrado A. Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J Biol Chem 279: 8919-8929, 2004.
207. Maucher A and von Angerer E. Antitumour activity of coumarin and 7-hydroxycoumarin against 7,12-dimethylbenz[a]anthracene-induced rat mammary carci-nomas. J Cancer Res Clin Oncol 120: 502-504, 1994.
208. McLellan LI and Hayes JD. Differential induction of class alpha glutathione S-transferases in mouse liver by the an-ticarcinogenic antioxidant butylated hydroxyanisole. Pur-ification and characterization of glutathione S-transferase Ya1Ya1. Biochem J 263: 393-402, 1989.
209. 3, in mouse liver. Biochem J 276: 461-469, 1991.
210. McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, and Hayes JD. The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and gluta-thione biosynthetic enzymes. Cancer Res 61: 3299-3307, 2001.
211. McMahon M, Itoh K, Yamamoto M, and Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 278: 21592-21600, 2003.
212. McMahon M, Thomas N, Itoh K, Yamamoto M, and Hayes JD. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J Biol Chem 279: 31556-31567, 2004.
213. McMahon M, Thomas N, Itoh K, Yamamoto M, and Hayes JD. Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: A two-site interaction model for the Nrf2-Keap1 complex. J Biol Chem 281: 24756-24768, 2006.
214. McWalter GK, Higgins LG, McLellan LI, Henderson CJ, Song L, Thornalley PJ, Itoh K, Yamamoto M, and Hayes JD. Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J Nutr 134: 3499S-3506S, 2004.
215. Mignotte V, Wall L, deBoer E, Grosveld F, and Romeo PH. Two tissue-specific factors bind the erythroid promoter of the human porphobilinogen deaminase gene. Nucleic Acids Res 17: 37-54, 1989.
216. Moffat GJ, McLaren AW, and Wolf CR. Involvement of Jun and Fos proteins in regulating transcriptional activation of the human pi class glutathione S-transferase gene in mul-tidrug-resistant MCF7 breast cancer cells. J Biol Chem 269: 16397-16402, 1994.
217. Moinova HR and Mulcahy RT. An electrophile responsive element (EpRE) regulates/ï-naphthoflavone induction of the human y-glutamylcysteine synthetase regulatory sub-unit gene. Constitutive expression is mediated by an adja-cent AP-1 site. J Biol Chem 273: 14683-14689, 1998.
218. Monroe DH and Eaton DL. Effects of modulation of hepatic glutathione on biotransformation and covalent binding of aflatoxin B1 to DNA in the mouse. Toxicol Appl Pharmacol 94: 118-127, 1988.
219. Moran AE, Carothers AM, Weyant MJ, Redston M, and Bertagnolli MM. Carnosol inhibits/ï-catenin tyrosine phosphorylation and prevents adenoma formation in the C57BL/6J/Min/+ (Min/+) mouse. Cancer Res 65: 1097-1104, 2005.
220. Moran JA, Dahl EL, and Mulcahy RT. Differential induc-tion of mafF, mafG and mafK expression by electrophile-response-element activators. Biochem J 361: 371-377, 2002.
221. Morel F, Fardel O, Meyer DJ, Langouet S, Gilmore KS, Meunier B, Tu CP, Kensler TW, Ketterer B, and Guillouzo A. Preferential increase of glutathione S-transferase class α transcripts in cultured human hepatocytes by phenobarbi-tal, 3-methylcholanthrene, and dithiolethiones. Cancer Res 53: 231-234, 1993.
222. Moscat J, Diaz-Meco MT, and Wooten MW. Signal inte-gration and diversification through the p62 scaffold pro-tein. Trends Biochem Sci 32: 95-100, 2007.
223. Moscat J and Diaz-Meco MT. p62 at the crossroads of au-tophagy, apoptosis, and cancer. Cell 137: 1001-1004, 2009.
224. Motohashi H, Katsuoka F, Engel JD, and Yamamoto M. Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Proc Natl Acad Sci USA 101: 6379-6384, 2004.
225. Moy KA, Yuan JM, Chung FL, Van Den Berg D, Wang R, Gao YT, and Yu MC. Urinary total isothiocyanates and colorectal cancer: A prospective study of men in Shanghai, China. Cancer Epidemiol Biomarkers Prev 17: 1354-1359, 2008.
226. Moy KA, Yuan JM, Chung FL, Wang XL, Van Den Berg D, Wang R, Gao YT, and Yu MC. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and gastric cancer risk: A prospective study of men in Shanghai, China. Int J Cancer 125: 2652-2659, 2009.
227. Mulcahy RT, Wartman MA, Bailey HH, and Gipp JJ. Constitutive and/ï-naphthoflavone-induced expression of the human y-glutamylcysteine synthetase heavy subunit gene is regulated by a distal antioxidant response ele-ment/TRE sequence. J Biol Chem 272: 7445-7454, 1997.
228. Munday R, Mhawech-Fauceglia P, Munday CM, Paonessa JD, Tang L, Munday JS, Lister C, Wilson P, Fahey JW, Davis W, and Zhang Y. Inhibition of urinary bladder carcino-genesis by broccoli sprouts. Cancer Res 68: 1593-1600, 2008.
229. Murakami A, Ashida H, and Terao J. Multitargeted cancer prevention by quercetin. Cancer Lett 269: 315-325, 2008.
230. Myzak MC, Dashwood WM, Orner GA, Ho E, and Dash-wood RH. Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice. FASEB J 20: 506-508, 2006.
231. Nair S, Xu C, Shen G, Hebbar V, Gopalakrishnan A, Hu R, Jain MR, Lin W, Keum YS, Liew C, Chan JY, and Kong AN. Pharmacogenomics of phenolic antioxidant butylated hy-droxyanisole (BHA) in the small intestine and liver of Nrf2 knockout and C57BL/6J mice. Pharm Res 23: 2621-2637, 2006.
232. Nakamura Y, Kawakami M, Yoshihiro A, Miyoshi N, Ohigashi H, Kawai K, Osawa T, and Uchida K. Involve-ment of the mitochondrial death pathway in chemopre-ventive benzyl isothiocyanate-induced apoptosis. J Biol Chem 277: 8492-8499, 2002.
233. Ney PA, Sorrentino BP, Lowrey CH, and Nienhuis AW. Inducibility of the HSII enhancer depends on binding of an erythroid specific nuclear protein. Nucleic Acids Res 18: 6011-6017, 1990.
234. Nguyen T, Huang HC, and Pickett CB. Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. J Biol Chem 275: 15466-15473, 2000.
235. Nguyen T, Sherratt PJ, Huang HC, Yang CS, and Pickett CB. Increased protein stability as a mechanism that en-hances Nrf2-mediated transcriptional activation of the an-tioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem 278: 4536-4541, 2003.
236. Nguyen T, Nioi P, and Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284: 13291-13295, 2009.
237. Nian H, Delage B, Ho E, and Dashwood RH. Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organo-sulfur compounds. Environ Mol Mutagen 50: 213-221, 2009.
238. Nieboer C, de Hoop D, van Loenen AC, Langendijk PN, and van Dijk E. Systemic therapy with fumaric acid deri-vates: New possibilities in the treatment of psoriasis. J Am Acad Dermatol 20: 601-608, 1989.
239. Nioi P, McMahon M, Itoh K, Yamamoto M, and Hayes JD. Identification of a novel Nrf2-regulated antioxidant re-sponse element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: Reassessment of the ARE consensus sequence. Biochem J 374: 337-348, 2003.
240. Nioi P and Nguyen T. A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun 362: 816-821, 2007.
241. Nishinaka T and Yabe-Nishimura C. Transcription factor Nrf2 regulates promoter activity of mouse aldose reductase (AKR1B3) gene. J Pharmacol Sci 97: 43-51, 2005.
242. Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, and Yamamoto M. Keap1 is a forked-stem dimmer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci USA 107: 2842-2847, 2010.
243. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler TW, and Yamamoto M. Hepatocyte-specific dele-tion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun 339: 79-88, 2006.
244. Okuda A, Imagawa M, Maeda Y, Sakai M, and Muramatsu M. Structural and functional analysis of an enhancer GPEI having a phorbol 12-O-tetradecanoate 13-acetate respon-sive element-like sequence found in the rat glutathione transferase P gene. J Biol Chem 264: 16919-16926, 1989.
245. Okuda A, Imagawa M, Sakai M, and Muramatsu M. Functional cooperativity between two TPA responsive el-ements in undifferentiated F9 embryonic stem cells. EMBO J 9: 1131-1135, 1990.
246. Osburn WO, Yates MS, Dolan PD, Chen S, Liby KT, Sporn MB, Taguchi K, Yamamoto M, and Kensler TW. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci 104: 218-227, 2008.
247. Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, and Yamamoto M. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 21: 689-700, 2006.
248. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G, and Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate deg-radation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282: 24131-24145, 2007.
249. Pearson WR, Windle JJ, Morrow JF, Benson AM, and Ta-lalay P. Increased synthesis of glutathione S-transferases in response to anticarcinogenic antioxidants. Cloning and measurement of messenger RNA. J Biol Chem 258: 2052-2062, 1983.
250. Pearson WR, Reinhart J, Sisk SC, Anderson KS, and Adler PN. Tissue-specific induction of murine glutathione trans-ferase mRNAs by butylated hydroxyanisole. J Biol Chem 263: 13324-13332, 1988.
251. Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function. Nat Rev Mol Cell Biol 8: 49-62, 2007.
252. Posner GH, Cho CG, Green JV, Zhang Y, and Talalay P. Design and synthesis of bifunctional isothiocyanate analogs of sulforaphane: Correlation between structure and po-tency as inducers of anticarcinogenic detoxication enzymes. J Med Chem 37: 170-176, 1994.
253. Powell CJ, Connelly JC, Jones SM, Grasso P, and Bridges JW. Hepatic responses to the administration of high doses of BHT to the rat: Their relevance to hepatocarcinogenicity. Food Chem Toxicol 24: 1131-1143, 1986.
254. Prestera T and Talalay P. Electrophile and antioxidant regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA 92: 8965-8969, 1995.
255. Prestera T, Talalay P, Alam J, Ahn YI, Lee PJ, and Choi AM. Parallel induction of heme oxygenase-1 and chemoprotec-tive phase 2 enzymes by electrophiles and antioxidants: Regulation by upstream antioxidant-responsive elements (ARE). Mol Med 1: 827-837, 1995.
256. Primiano T, Kensler TW, Kuppusamy P, Zweier JL, and Sutter TR. Induction of hepatic heme oxygenase-1 and ferritin in rats by cancer chemopreventive dithiolethiones. Carcinogenesis 17: 2291-2296, 1996.
257. 4 12-hydroxydehydrogenase: implications for chemoprevention. Carcinogenesis 19: 999-1005, 1998.
258. Prochaska HJ, and Santamaria AB. Direct measurement of NAD(P)H:quinone reductase from cells cultured in micro-titer wells: A screening assay for anticarcinogenic enzyme inducers. Anal Biochem 169: 328-336, 1988.
259. Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, and Freeman ML. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin li-gase CUL3. Chem Res Toxicol 21: 705-710, 2008.
260. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yama-moto M, Talalay P, and Kensler TW. Sensitivity to carci-nogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98: 3410-3415, 2001.
261. Ramos-Gomez M, Dolan PM, Itoh K, Yamamoto M, and Kensler TW. Interactive effects of nrf2 genotype and olti-praz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis 24: 461-467, 2003.
262. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, and Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin In-vest 114: 1248-1259, 2004.
263. Reddy NM, Kleeberger SR, Yamamoto M, Kensler TW, Scollick C, Biswal S, and Reddy SP. Genetic dissection of the Nrf2-dependent redox signaling-regulated transcrip-tional programs of cell proliferation and cytoprotection. Physiol Genomics 32: 74-81, 2007.
264. Reddy NM, Kleeberger SR, Bream JH, Fallon PG, Kensler TW, Yamamoto M, and Reddy SP. Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling. Oncogene 27: 5821-5832, 2008.
265. Reichard JF, Motz GT, and Puga A. Heme oxygenase-1 induction by NRF2 requires inactivation of the transcrip-tional repressor BACH1. Nucleic Acids Res 35: 7074-7086, 2007.
266. Riedl MA, Saxon A, and Diaz-Sanchez D. Oral sulfor-aphane increases Phase II antioxidant enzymes in the hu-man upper airway. Clin Immunol 130: 244-251, 2009.
267. Roebuck BD, Johnson DN, Sutter CH, Egner PA, Scholl PF, Friesen MD, Baumgartner KJ, Ware NM, Bodreddigari S, Groopman JD, Kensler TW, and Sutter TR. Transgenic ex-pression of aflatoxin aldehyde reductase (AKR7A1) mod-ulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat. Toxicol Sci 109: 41-49, 2009.
268. Rundlöf AK, Carlsten M, and Arnér ES. The core promoter of human thioredoxin reductase 1: Cloning, transcriptional activity, and Oct-1, Sp1, and Sp3 binding reveal a house-keeping-type promoter for the AU-rich element-regulated gene. J Biol Chem 276: 30542-30551, 2001.
269. Rushmore TH and Pickett CB. Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Char-acterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem 265: 14648-14653, 1990.
270. Rushmore TH, Morton MR, and Pickett CB. The antioxi-dant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266: 11632-11639, 1991.
271. Salsbury FR Jr, Knutson ST, Poole LB, and Fetrow JS. Functional site profiling and electrostatic analysis of cys-teines modifiable to cysteine sulfenic acid. Protein Sci 17: 299-312, 2008.
272. Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Mae-bara K, Wang H, Tamba M, Itoh K, Yamamoto M, and Bannai S. Electrophile response element-mediated induc-tion of the cystine/glutamate exchange transporter gene expression. J Biol Chem 277: 44765-44771, 2002.
273. duction by butylated hydroxyanisole of specific molecular forms of glutathione S-transferase and UDP-glucuronyl-transferase and inhibition of development of y-glutamyl transpeptidase-positive foci in rat liver. Carcinogenesis 5: 473-477, 1984.
274. Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, Rieks M, Hoffmann V, Pöhlau D, and Przuntek H. Oral fumaric acid esters for the treatment of active multiple sclerosis: An open-label, baseline-controlled pilot study. Eur J Neurol 13: 604-610, 2006.
275. Shapiro TA, Fahey JW, Wade KL, Stephenson KK, and Talalay P. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomarkers Prev 7: 1091-1100, 1998.
276. Shen G, Xu C, Hu R, Jain MR, Nair S, Lin W, Yang CS, Chan JY, and Kong AN. Comparison of (-)-epigalloca-techin-3-gallate elicited liver and small intestine gene ex-pression profiles between C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Pharm Res 22: 1805-1820, 2005.
277. Shen G, Xu C, Hu R, Jain MR, Gopalkrishnan A, Nair S, Huang MT, Chan JY, and Kong AN. Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin. Mol Cancer Ther 5: 39-51, 2006.
278. Shen G, Khor TO, Hu R, Yu S, Nair S, Ho CT, Reddy BS, Huang MT, Newmark HL, and Kong AN. Chemopreven-tion of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse. Cancer Res 67: 9937-9944, 2007.
279. Sherratt PJ, Manson MM, Thomson AM, Hissink EA, Neal GE, van Bladeren PJ, Green T, and Hayes JD. Increased bioactivation of dihaloalkanes in rat liver due to induction of class theta glutathione S-transferase T1-1. Biochem J 335: 619-630, 1998.
280. Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, and Biswal S. RNAi-mediated silencing of nuclear factor erythroid-2-re-lated factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemo-therapy. Cancer Res 68: 7975-7984, 2008.
281. Singh A, Ling G, Suhasini AN, Zhang P, Yamamoto M, Navas-Acien A, Cosgrove G, Tuder RM, Kensler TW, Watson WH, and Biswal S. Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxi-dative stress in lungs. Free Radic Biol Med 46: 376-386, 2009.
282. Singh SV, Herman-Antosiewicz A, Singh AV, Lew KL, Srivastava SK, Kamath R, Brown KD, Zhang L, and Bas-karan R. Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. J Biol Chem 279: 25813-25822, 2004.
283. Singletary K, MacDonald C, and Wallig M. Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Lett 104: 43-48, 1996.
284. Snyder GH, Cennerazzo MJ, Karalis AJ, and Field D. Electrostatic influence of local cysteine environments on disulfide exchange kinetics. Biochemistry 20: 6509-6519, 1981.
285. Soriano FX, Léveillé F, Papadia S, Higgins LG, Varley J, Baxter P, Hayes JD, and Hardingham GE. Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione. J Neurochem 107: 533-543, 2008.
286. Spencer SR, Wilczak CA, and Talalay P. Induction of glu-tathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. Cancer Res 50: 7871-7875, 1990.
287. Spencer SR, Xue LA, Klenz EM, and Talalay P. The potency of inducers of NAD(P)H:(quinone-acceptor) oxidoreduc-tase parallels their efficiency as substrates for glutathione transferases. Structural and electronic correlations. Biochem J 273: 711-717, 1991.
288. Sporn MB, Dunlop NM, Newton DL, and Smith JM. Pre-vention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 35: 1332-1338, 1976.
289. Sporn MB and Suh N. Chemoprevention: An essential ap-proach to controlling cancer. Nat Rev Cancer 2: 537-543, 2002.
290. Stamatoyannopoulos JA, Goodwin A, Joyce T, and Lowrey CH. NF-E2 and GATA binding motifs are required for the formation of DNase I hypersensitive site 4 of the human ß-globin locus control region. EMBO J 14: 106-116, 1995.
291. Steiner C, Peters WH, Gallagher EP, Magee P, Rowland I, and Pool-Zobel BL. Genistein protects human mammary epithelial cells from benzo[a]pyrene-7,8- dihydrodiol-9,10-epoxide and 4-hydroxy-2-nonenal genotoxicity by modu-lating the glutathione/glutathione S-transferase system. Carcinogenesis 28: 738-748, 2007.
292. Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, Tashiro S, Takahashi S, Shibahara S, Alam J, Taketo MM, Yamamoto M, and Igarashi K. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J 21: 5216-5224, 2002.
293. Sun Z, Huang Z, and Zhang DD. Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS One 4: e6588, 2009.
294. Surh YJ and Chun KS. Cancer chemopreventive effects of curcumin. Adv Exp Med Biol 595: 149-172, 2007.
295. Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, and Biswal S. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci USA 106: 250-255, 2009.
296. Sykiotis GP and Bohmann D. Stress-activated cap'n'collar transcription factors in aging and human disease. Sci Signal 3: re3, 2010.
297. Talalay P, De Long MJ, and Prochaska HJ. Identification of a common chemical signal regulating the induction of en-zymes that protect against chemical carcinogenesis. Proc Natl Acad Sci USA 85: 8261-8265, 1988.
298. Tang L, Zirpoli GR, Guru K, Moysich KB, Zhang Y, Am-brosone CB, and McCann SE. Consumption of raw crucif-erous vegetables is inversely associated with bladder cancer risk. Cancer Epidemiol Biomarkers Prev 17: 938-944, 2008.
299. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Ya-mamoto M, and Biswal S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62: 5196-5203, 2002.
300. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, and Yamamoto M. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: Characterization of the two-site molecular recognition model. Mol Cell Biol 26: 2887-2900, 2006.
301. Toledano MB. The guardian recruits cops: The p53-p21 axis delegates prosurvival duties to the Keap1-Nrf2 stress pathway. Mol Cell 34: 637-639, 2009.
302. Traka M, Gasper AV, Smith JA, Hawkey CJ, Bao Y, and Mithen RF. Transcriptome analysis of human colon Caco-2 cells exposed to sulforaphane. J Nutr 135: 1865-1872, 2005.
303. Tseng TH and Lee YJ. Evaluation of natural and synthetic compounds from East Asiatic folk medicinal plants on the mediation of cancer. Anticancer Agents Med Chem 6: 347-365, 2006.
304. Tsuji Y. JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress. Oncogene 24: 7567-7578, 2005.
305. Tsuji Y, Ayaki H, Whitman SP, Morrow CS, Torti SV, and Torti FM. Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress. Mol Cell Biol 20: 5818-5827, 2000.
306. Ulland BM, Weisburger JH, Yamamoto RS, and Weisburger EK. Antioxidants and carcinogenesis: butylated hydro-xytoluene, but not diphenyl-p- phenylenediamine, inhibits cancer induction by N-2-fluorenylacetamide and by N-hydroxy-N-2-fluorenylacetamide in rats. Food Cosmet Toxicol 11: 199-207, 1973.
307. van Duijnhoven FJ, Bueno-De-Mesquita HB, Ferrari P, Je-nab M, Boshuizen HC, Ros MM, Casagrande C, Tjønneland A, Olsen A, Overvad K, Thorlacius-Ussing O, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, Kaaks R, Lin-seisen J, Boeing H, Nöthlings U, Trichopoulou A, Tricho-poulos D, Misirli G, Palli D, Sieri S, Panico S, Tumino R, Vineis P, Peeters PH, van Gils CH, Ocké MC, Lund E, Engeset D, Skeie G, Suárez LR, González CA, Sánchez MJ, Dorronsoro M, Navarro C, Barricarte A, Berglund G, Manjer J, Hallmans G, Palmqvist R, Bingham SA, Khaw KT, Key TJ, Allen NE, Boffetta P, Slimani N, Rinaldi S, Gallo V, Norat T, and Riboli E. Fruit, vegetables, and co-lorectal cancer risk: The European Prospective Investiga-tion into Cancer and Nutrition. Am J Clin Nutr 89: 1441-1452, 2009.
308. Venugopal R and Jaiswal AK. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:qui-none oxidoreductase1 gene. Proc Natl Acad Sci USA 93: 14960-14965, 1996.
309. Venugopal R and Jaiswal AK. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17: 3145-3156, 1998.
310. von Angerer E, Kager M, and Maucher A. Antitumour activity of coumarin in prostate and mammary cancer models. J Cancer Res Clin Oncol 120 Suppl: S14-S16, 1994.
311. Vile GF and Tyrrell RM. Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin. J Biol Chem 268:14678-14681, 1993.
312. Vollrath V, Wielandt AM, Iruretagoyena M, and Chianale J. Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem J 395: 599-609, 2006.
313. Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, Imakado S, Kotsuji T, Otsuka F, Roop DR, Harada T, Engel JD, and Yamamoto M. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35: 238-245, 2003.
314. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, and 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 101: 2040-2045, 2004. (Pubitemid 38229011)
315. Wakabayashi N, Shin SL, Slocum SL, Agoston ES, Waka-bayashi J, Kwak M-K, Misra V, Biswal S, Yamamoto M, and Kensler TW. Regulation of Notch1 signaling by Nrf2: im-plications for tissue regeneration. Sci Signal 3, ra52, 2010.
316. Wang XJ, Hayes JD, and Wolf CR. Generation of a stable antioxidant response element-driven reporter gene cell line and its use to show redox-dependent activation of nrf2 by cancer chemotherapeutic agents. Cancer Res 66: 10983-10994, 2006.
317. Wang XJ, Hayes JD, Henderson CJ, and Wolf CR. Identi-fication of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor α. Proc Natl Acad Sci USA 104: 19589-19594, 2007.
318. Wang XJ, Hayes JD, Higgins LG, Wolf CR, and Dinkova-Kostova AT. Activation of the NRF2 signaling pathway by copper-mediated redox cycling of para-and ortho-hydroquinones. Chem Biol 17: 75-85, 2010.
319. Wasserman WW and Fahl WE. Functional antioxidant re-sponsive elements. Proc Natl Acad Sci USA 94: 5361-5366, 1997.
320. Wattenberg LW. Chemoprophylaxis of carcinogenesis: A review. Cancer Res 26: 1520-1526, 1966.
321. Wattenberg LW. Inhibition of carcinogenic effects of poly-cyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst 58: 395-398, 1977.
322. Wattenberg LW. Inhibition of neoplasia by minor dietary constituents. Cancer Res 43: 2448s-2453s, 1983.
323. Wattenberg LW. Chemoprevention of cancer. Cancer Res 45: 1-8, 1985.
324. Wattenberg LW. Inhibitory effects of benzyl isothiocyanate administered shortly before diethylnitrosamine or ben-zo[a]pyrene on pulmonary and forestomach neoplasia in A/J mice. Carcinogenesis 8: 1971-1973, 1987.
325. Wattenberg LW. Inhibition of carcinogenesis by minor nutrient constituents of the diet. Proc Nutr Soc 49: 173-183, 1990.
326. Wattenberg LW. Prevention\therapy\basic science and the resolution of the cancer problem. Cancer Res 53: 5890-5896, 1993.
327. Wilkinson J 4th, Radjendirane V, Pfeiffer GR, Jaiswal AK, and Clapper ML. Disruption of c-Fos leads to increased expression of NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase. Biochem Biophys Res Commun 253: 855-858, 1998.
328. Williams GM, Tanaka T, and Maeura Y. Dose-related inhi-bition of aflatoxin B1 induced hepatocarcinogenesis by the phenolic antioxidants, butylated hydroxyanisole and butyl-ated hydroxytoluene. Carcinogenesis 7: 1043-1050, 1986.
329. Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N, Diaz-Meco MT, Moscat J. Essential role of seques-tosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J Biol Chem 283: 6783-6789, 2008.
330. Xiao GG, Wang M, Li N, Loo JA, and Nel AE. Use of proteomics to demonstrate a hierarchical oxidative stress response to diesel exhaust particle chemicals in a macro-phage cell line. J Biol Chem 278: 50781-50790, 2003.
331. Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, Conney AH, and Kong AN. Inhibition of 7,12-dimethylbenz[a]anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res 66: 8293-8296, 2006.
332. Yamamoto T, Kyo M, Kamiya T, Tanaka T, Engel JD, Motohashi H, and Yamamoto M. Predictive base substitu-tion rules that determine the binding and transcriptional specificity of Maf recognition elements. Genes Cells 11: 575-591, 2006.
333. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, and Yamamoto M. Physiological significance of reactive cysteine residues of Keap1 in de-termining Nrf2 activity. Mol Cell Biol 28: 2758-2770, 2008.
334. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, and Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280: 5892-5901, 2005.
335. Yang H, Chen D, Cui QC, Yuan X, and Dou QP. Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res 66: 4758-4765, 2006.
336. Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddi-gari S, Sutter TR, Baumgartner KJ, Roebuck BD, Liby KT, Yore MM, Honda T, Gribble GW, Sporn MB, and Kensler TW. Potent protection against aflatoxin-induced tumori-genesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12- dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res 66: 2488-2494, 2006.
337. 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, and Kensler TW. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30: 1024-1031, 2009.
338. Yeh CT and Yen GC. Effect of sulforaphane on me-tallothionein expression and induction of apoptosis in hu-man hepatoma HepG2 cells. Carcinogenesis 26: 2138-2148, 2005.
339. Yeldandi AV, Milano M, Subbarao V, Reddy JK, and Rao MS. Evaluation of liver cell proliferation during ciprofi-brate-induced hepatocarcinogenesis. Cancer Lett 47: 21-27, 1989.
340. Yoshioka K, Deng T, Cavigelli M, and Karin M. Antitumor promotion by phenolic antioxidants: inhibition of AP-1 activity through induction of Fra expression. Proc Natl Acad Sci USA 92: 4972-4976, 1995.
341. Yueh MF and Tukey RH. Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice. J Biol Chem 282: 8749-8758, 2007.
342. Zhang DD, Lo SC, Cross JV, Templeton DJ, and Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24: 10941-10953, 2004.
343. Zhang DD and 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 23: 8137-8151, 2003.
344. Zhang J, Ohta T, Maruyama A, Hosoya T, Nishikawa K, Maher JM, Shibahara S, Itoh K, and Yamamoto M. BRG1 interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress. Mol Cell Biol 26: 7942-7952, 2006.
345. Zhang Y, Talalay P, Cho CG, and Posner GH. A major inducer of anticarcinogenic protective enzymes from broc-coli: Isolation and elucidation of structure. Proc Natl Acad Sci USA 89: 2399-2403, 1992.
346. Zhang Y, Kensler TW, Cho CG, Posner GH, and Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 91: 3147-3150, 1994.
347. Zhang Y, Crouch DH, Yamamoto M, and Hayes JD. Ne-gative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum. Biochem J 399: 373-385, 2006.
348. Zhang Y and Tang L. Discovery and development of sul-foraphane as a cancer chemopreventive phytochemical. Acta Pharmacol Sin 28: 1343-1354, 2007.
349. Zhang Y, Kobayashi A, Yamamoto M, and Hayes JD. The Nrf3 transcription factor is a membrane-bound glycopro-tein targeted to the endoplasmic reticulum through its N-terminal homology box 1 sequence. J Biol Chem 284: 3195-3210, 2009.
350. Zhang Y, Lucocq JM, and Hayes JD. The Nrf1 CNC/bZIP protein is a nuclear envelope-bound transcription factor that is activated by t-butyl hydroquinone but not by en-doplasmic reticulum stressors. BiochemJ418: 293-310, 2009.
351. Zhao B, Seow A, Lee EJ, Poh WT, Teh M, Eng P, Wang YT, Tan WC, Yu MC, and Lee HP. Dietary isothiocyanates, glutathione S-transferase-M1,-T1 polymorphisms and lung cancer risk among Chinese women in Singapore. Cancer Epidemiol Biomarkers Prev 10: 1063-1067, 2001.
352. Zhong JL, Raval C, Edwards GP, and Tyrrell RM. A role for Bach1 and HO-2 in suppression of basal and UVA-induced HO-1 expression in human keratinocytes. Free Radic Biol Med 48: 196-206, 2010.
353. Zhou W, Lo SC, Liu JH, Hannink M, and Lubahn DB. ERR/Iκ: A potent inhibitor of Nrf2 transcriptional activity. Mol Cell Endocrinol 278: 52-62, 2007.
354. Zhou YX and Huang YL. Antiangiogenic effect of celastrol on the growth of human glioma: An in vitro and in vivo study. Chin Med J (Engl) 122: 1666-1673, 2009.
355. Zipper LM and Mulcahy RT. The Keap1 BTB/POZ di-merization function is required to sequester Nrf2 in cyto-plasm. J Biol Chem 277: 36544-36552, 2002.
356. Zlotkin S. A new approach to control of anemia in "at risk" infants and children around the world. 2004 Ryley-Jeffs memorial lecture. Can J Diet Pract Res 65: 136-138, 2004