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Archives of Toxicology

, Volume 85, Issue 4, pp 241–272 | Cite as

The cytoprotective role of the Keap1–Nrf2 pathway

  • Liam Baird
  • Albena T. Dinkova-Kostova
Review Article

Abstract

An elaborate network of highly inducible proteins protects aerobic cells against the cumulative damaging effects of reactive oxygen intermediates and toxic electrophiles, which are the major causes of neoplastic and chronic degenerative diseases. These cytoprotective proteins share common transcriptional regulation, through the Keap1–Nrf2 pathway, which can be activated by various exogenous and endogenous small molecules (inducers). Inducers chemically react with critical cysteine residues of the sensor protein Keap1, leading to stabilisation and nuclear translocation of transcription factor Nrf2, and ultimately to coordinate enhanced expression of genes coding for cytoprotective proteins. In addition, inducers inhibit pro-inflammatory responses, and there is a linear correlation spanning more than six orders of magnitude of concentrations between inducer and anti-inflammatory activity. Genetic deletion of transcription factor Nrf2 renders cells and animals much more sensitive to the damaging effects of electrophiles, oxidants and inflammatory agents in comparison with their wild-type counterparts. Conversely, activation of the Keap1–Nrf2 pathway allows survival and adaptation under various conditions of stress and has protective effects in many animal models. Cross-talks with other signalling pathways broadens the role of the Keap1–Nrf2 pathway in determining the fate of the cell, impacting fundamental biological processes such as proliferation, apoptosis, angiogenesis and metastasis.

Keywords

Keap1 Nrf2 Cytoprotective enzymes Phase 2 inducer 

Notes

Acknowledgments

We are very grateful to Lulu Baird for artwork and the Medical Research Council, Research Councils UK, Cancer Research UK (C20953/A10270), the Royal Society, Tenovus Scotland and the Anonymous Trust for financial support.

References

  1. Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9:400–414PubMedCrossRefGoogle Scholar
  2. Ahn YH, Hwang Y, Liu H, Wang XJ, Zhang Y, Stephenson KK, Boronina TN, Cole RN, Dinkova-Kostova AT, Talalay P, Cole PA (2010) Electrophilic tuning of the chemoprotective natural product sulforaphane. Proc Natl Acad Sci USA 107:9590–9595PubMedCrossRefGoogle Scholar
  3. Akao M, Kuroda K (1990) Inhibitory effect of fumaric acid on hepatocarcinogenesis by thioacetamide in mice. Chem Pharm Bull (Tokyo) 38:2012–2014Google Scholar
  4. Alam J, Wicks C, Stewart D, Gong P, Touchard C, Otterbein S, Choi AM, Burow ME, Tou J (2000) Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. J Biol Chem 275:27694–27702PubMedGoogle Scholar
  5. An JH, Blackwell TK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17:1882–1893PubMedCrossRefGoogle Scholar
  6. Ansell PJ, Lo SC, Newton LG, Espinosa-Nicholas C, Zhang DD, Liu JH, Hannink M, Lubahn DB (2005) Repression of cancer protective genes by 17beta-estradiol: ligand-dependent interaction between human Nrf2 and estrogen receptor alpha. Mol Cell Endocrinol 243:27–34PubMedCrossRefGoogle Scholar
  7. Aoki Y, Sato H, Nishimura N, Takahashi S, Itoh K, Yamamoto M (2001) Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust. Toxicol Appl Pharmacol 173:154–160PubMedCrossRefGoogle Scholar
  8. Asher G, Lotem J, Cohen B, Sachs L, Shaul Y (2001) Regulation of p53 stability, p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci USA 98:1188–1193PubMedCrossRefGoogle Scholar
  9. Asher G, Lotem J, Sachs L, Kahana C, Shaul Y (2002) Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. Proc Natl Acad Sci USA 99:13125–13130PubMedCrossRefGoogle Scholar
  10. Bae I, Fan S, Meng Q, Rih JK, Kim HJ, Kang HJ, Xu J, Goldberg ID, Jaiswal AK, Rosen EM (2004) BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res 64:7893–7909PubMedCrossRefGoogle Scholar
  11. Baeuerle PA, Baltimore D (1988) IκB: a specific inhibitor of the NF-κB transcription factor. Science 242:540–546PubMedCrossRefGoogle Scholar
  12. Bakin AV, Stourman NV, Sekhar KR, Rinehart C, Yan X, Meredith MJ, Arteaga CL, Freeman ML (2005) Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase II detoxifying proteins. Free Radic Biol Med 38:375–387PubMedCrossRefGoogle Scholar
  13. Bannai S, Ishii T (1982) Transport of cystine and cysteine and cell growth in cultured human diploid fibroblasts: effect of glutamate and homocysteate. J Cell Physiol 112:265–272PubMedCrossRefGoogle Scholar
  14. Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M (2004) Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 428:190–193PubMedCrossRefGoogle Scholar
  15. Bensasson RV, Zoete V, Dinkova-Kostova AT, Talalay P (2008) Two-step mechanism of induction of the gene expression of a prototypic cancer-protective enzyme by diphenols. Chem Res Toxicol 21:805–812PubMedCrossRefGoogle Scholar
  16. Benson AM, Batzinger RP, Ou SY, Bueding E, Cha YN, Talalay P (1978) Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites of benzo(a)pyrene by dietary antioxidants. Cancer Res 38:4486–4495PubMedGoogle Scholar
  17. Benson AM, Cha YN, Bueding E, Heine HS, Talalay P (1979) Elevation of extrahepatic glutathione S-transferase and epoxide hydratase activities by 2(3)-tert-butyl-4-hydroxyanisole. Cancer Res 39:2971–2977PubMedGoogle Scholar
  18. Benson AM, Hunkeler MJ, Talalay P (1980) Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. Proc Natl Acad Sci USA 77:5216–5220PubMedCrossRefGoogle Scholar
  19. Beyer TA, Xu W, Teupser D, Auf dem Keller U, Bugnon P, Hildt E, Thiery J, Kan YW, Werner S (2008) Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance. EMBO J 27:212–223PubMedCrossRefGoogle Scholar
  20. Bhattacharya A, Li Y, Wade KL, Paonessa JD, Fahey JW, Zhang Y (2010) Allyl Isothiocyanate-rich mustard seed powder inhibits bladder cancer growth and muscle invasion. Carcinogenesis (in press)Google Scholar
  21. Biteau B, Labarre J, Toledano MB (2003) ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin. Nature 425:980–984PubMedCrossRefGoogle Scholar
  22. Bloom DA, Jaiswal AK (2003) Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression. J Biol Chem 278:44675–44682PubMedCrossRefGoogle Scholar
  23. Borst P, Evers R, Kool M, Wijnholds J (2000) A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92:1295–1302PubMedCrossRefGoogle Scholar
  24. Brown SL, Sekhar KR, Rachakonda G, Sasi S, Freeman ML (2008) Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res 68:364–368PubMedCrossRefGoogle Scholar
  25. Burczynski ME, Lin HK, Penning TM (1999) Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: implications for the alternative pathway of PAH activation catalysed by human dihydrodiol dehydrogenase. Cancer Res 59:607–614PubMedGoogle Scholar
  26. Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA (2005) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci USA 102:244–249PubMedCrossRefGoogle Scholar
  27. Chambers KF, Bacon JR, Kemsley EK, Mills RD, Ball RY, Mithen RF, Traka MH (2009) Gene expression profile of primary prostate epithelial and stromal cells in response to sulforaphane or iberin exposure. Prostate 69:1411–1421PubMedCrossRefGoogle Scholar
  28. Chan K, Kan YW (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA 96:12731–12736PubMedCrossRefGoogle Scholar
  29. Chanas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, Yamamoto M, Hayes JD (2002) Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem J 365:405–416PubMedCrossRefGoogle Scholar
  30. Chang LC, Gerhäuser C, Song L, Farnsworth NR, Pezzuto JM, Kinghorn AD (1997) Activity-guided isolation of constituents of Tephrosia purpurea with the potential to induce the phase II enzyme, quinone reductase. J Nat Prod 60:869–873PubMedCrossRefGoogle Scholar
  31. Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD (2009) Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell 34:663–673PubMedCrossRefGoogle Scholar
  32. Cho HY, Reddy SP, Debiase A, Yamamoto M, Kleeberger SR (2005) Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radic Biol Med 38:325–343PubMedCrossRefGoogle Scholar
  33. Chung FL, Conaway CC, Rao CV, Reddy BS (2000) Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 21:2287–2291PubMedCrossRefGoogle Scholar
  34. Conaway CC, Wang CX, Pittman B, Yang YM, Schwartz JE, Tian D, McIntee EJ, Hecht SS, Chung FL (2005) 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 65:8548–8557PubMedCrossRefGoogle Scholar
  35. Coulouarn C, Factor VM, Thorgeirsson SS (2008) Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 47:2059–2067PubMedCrossRefGoogle Scholar
  36. Cullinan SB, Diehl JA (2004) PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279:20108–20117PubMedCrossRefGoogle Scholar
  37. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209PubMedCrossRefGoogle Scholar
  38. Cullinan SB, Gordan JD, Jin J, Harper JW, Diehl JA (2004) 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 24:8477–8486PubMedCrossRefGoogle Scholar
  39. Dash PK, Zhao J, Orsi SA, Zhang M, Moore AN (2009) Sulforaphane improves cognitive function administered following traumatic brain injury. Neurosci Lett 460:103–107PubMedCrossRefGoogle Scholar
  40. De Long MJ, Prochaska HJ, Talalay P (1985) Tissue-specific induction patterns of cancer-protective enzymes in mice by tert-butyl-4-hydroxyanisole and related substituted phenols. Cancer Res 45:546–551PubMedGoogle Scholar
  41. Delaunay A, Isnard AD, Toledano MB (2000) H2O2 sensing through oxidation of the Yap1 transcription factor. EMBO J 19:5157–5166PubMedCrossRefGoogle Scholar
  42. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29:117–129PubMedCrossRefGoogle Scholar
  43. Devling TW, Lindsay CD, McLellan LI, McMahon M, Hayes JD (2005) Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype. Proc Natl Acad Sci USA 102:7280–7285PubMedCrossRefGoogle Scholar
  44. Dhakshinamoorthy S, Jain AK, Bloom DA, Jaiswal AK (2005) Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem 280:1900–16891CrossRefGoogle Scholar
  45. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388:548–554PubMedCrossRefGoogle Scholar
  46. Dinkova-Kostova AT, Talalay P (1999) Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes. Carcinogenesis 20:911–914PubMedCrossRefGoogle Scholar
  47. Dinkova-Kostova AT, Talalay P (2010) NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 501:116–123PubMedCrossRefGoogle Scholar
  48. Dinkova-Kostova AT, Abeygunawardana C, Talalay P (1998) Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers. J Med Chem 41:5287–5296PubMedCrossRefGoogle Scholar
  49. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P (2001) 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 98:3404–3409PubMedCrossRefGoogle Scholar
  50. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99:11908–11913PubMedCrossRefGoogle Scholar
  51. Dinkova-Kostova AT, Holtzclaw WD, Wakabayashi N (2005a) Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 44:6889–6899PubMedCrossRefGoogle Scholar
  52. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P (2005b) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102:4584–4589PubMedCrossRefGoogle Scholar
  53. Dinkova-Kostova AT, Jenkins SN, Fahey JW, Ye L, Wehage SL, Liby KT, Stephenson KK, Wade KL, Talalay P (2006) Protection against UV-light-induced skin carcinogenesis in SKH-1 high-risk mice by sulforaphane-containing broccoli sprout extracts. Cancer Lett 240:243–252PubMedCrossRefGoogle Scholar
  54. 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, Talalay P (2008) A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UV-irradiated mice. Biochem Biophys Res Commun 367:859–865PubMedCrossRefGoogle Scholar
  55. Dinkova-Kostova AT, Talalay P, Sharkey J, Zhang Y, Holtzclaw WD, Wang XJ, David E, Schiavoni KH, Finlayson S, Mierke DF, Honda T (2010) An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1. J Biol Chem 285:33747–33755PubMedCrossRefGoogle Scholar
  56. Dumont M, Wille E, Calingasan NY, Tampellini D, Williams C, Gouras GK, Liby K, Sporn M, Nathan C, Flint Beal M, Lin MT (2009) Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer’s disease. J Neurochem 109:502–512PubMedCrossRefGoogle Scholar
  57. Eggler AL, Liu G, Pezzuto JM, van Breemen RB, Mesecar AD (2005) 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 102:10070–10075PubMedCrossRefGoogle Scholar
  58. Eggler AL, Small E, Hannink M, Mesecar AD (2009) Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem J 422:171–180PubMedCrossRefGoogle Scholar
  59. Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59:169–177PubMedCrossRefGoogle Scholar
  60. Esposito F, Cuccovillo F, Russo L, Casella F, Russo T, Cimino F (1998) A new p21waf1/cip1 isoform is an early event of cell response to oxidative stress. Cell Death Differ 5:940–945PubMedCrossRefGoogle Scholar
  61. Fagerholm R, Hofstetter B, Tommiska J, Aaltonen K, Vrtel R, Syrjäkoski K, Kallioniemi A, Kilpivaara O, Mannermaa A, Kosma VM, Uusitupa M, Eskelinen M, Kataja V, Aittomäki K, von Smitten K, Heikkilä P, Lukas J, Holli K, Bartkova J, Blomqvist C, Bartek J, Nevanlinna H (2008) NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 40:844–853PubMedCrossRefGoogle Scholar
  62. Fahey JW, Zhang Y, Talalay P (1997) Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci USA 94:10367–10372PubMedCrossRefGoogle Scholar
  63. Fahey JW, Zalcmann AT, Talalay P (2001) The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56:5–51PubMedCrossRefGoogle Scholar
  64. Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci USA 99:7610–7615PubMedCrossRefGoogle Scholar
  65. Fahey JW, Dinkova-Kostova AT, Stephenson KK, Talalay P (2004) The “Prochaska” microtiter plate bioassay for inducers of NQO1. Methods Enzymol 382:243–258PubMedCrossRefGoogle Scholar
  66. Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M, Russo T, Cimino F (2006) p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 281:39776–39784PubMedCrossRefGoogle Scholar
  67. Fourquet S, Guerois R, Biard D, Toledano MB (2010) Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J Biol Chem 285:8463–8471PubMedCrossRefGoogle Scholar
  68. Frankfurt OS, Lipchina LP, Bunto TV, Emanuel NM (1967) Effect of 4-methyl-2,6-di-tert-butylphenol (Ionol) on induction of liver tumors in rats. Biull Eksp Biol Med USSR 64:86–88Google Scholar
  69. Friling RS, Bensimon A, Tichauer Y, Daniel V (1990) Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Natl Acad Sci USA 87:6258–6262PubMedCrossRefGoogle Scholar
  70. Frohlich DA, McCabe MT, Arnold RS, Day ML (2008) The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis. Oncogene 27:4353–4362PubMedCrossRefGoogle Scholar
  71. Furukawa M, Xiong Y (2005) BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol 25:162–171PubMedCrossRefGoogle Scholar
  72. Furukawa M, He YJ, Borchers C, Xiong Y (2003) Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol 5:1001–1007PubMedCrossRefGoogle Scholar
  73. Galan JM, Peter M (1999) Ubiquitin-dependent degradation of multiple F-box proteins by an autocatalytic mechanism. Proc Natl Acad Sci USA 96:9124–9129PubMedCrossRefGoogle Scholar
  74. Gao L, Wang J, Sekhar KR, Yin H, Yared NF, Schneider SN, Sasi S, Dalton TP, Anderson ME, Chan JY, Morrow JD, Freeman ML (2007) Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J Biol Chem 282:2529–2537PubMedCrossRefGoogle Scholar
  75. Gartel AL, Tyner AL (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1:639–649PubMedGoogle Scholar
  76. Gasper AV, Traka M, Bacon JR, Smith JA, Taylor MA, Hawkey CJ, Barrett DA, Mithen RF (2007) Consuming broccoli does not induce genes associated with xenobiotic metabolism and cell cycle control in human gastric mucosa. J Nutr 137:1718–1724PubMedGoogle Scholar
  77. Geyer R, Wee S, Anderson S, Yates J, Wolf DA (2003) BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases. Mol Cell 12:783–790PubMedCrossRefGoogle Scholar
  78. Gibbs A, Schwartzman J, Deng V, Alumkal J (2009) Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 6. Proc Natl Acad Sci USA 106:16663–16668PubMedCrossRefGoogle Scholar
  79. Gills JJ, Jeffery EH, Matusheski NV, Moon RC, Lantvit DD, Pezzuto JM (2006) Sulforaphane prevents mouse skin tumorigenesis during the stage of promotion. Cancer Lett 236:72–79PubMedCrossRefGoogle Scholar
  80. Gong P, Stewart D, Hu B, Vinson C, Alam J (2002) Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite. Arch Biochem Biophys 405:265–274PubMedCrossRefGoogle Scholar
  81. Gu JQ, Park EJ, Vigo JS, Graham JG, Fong HH, Pezzuto JM, Kinghorn AD (2002) Activity-guided isolation of constituents of Renealmia nicolaioides with the potential to induce the phase II enzyme quinone reductase. J Nat Prod 65:1616–1620PubMedCrossRefGoogle Scholar
  82. Gu JQ, Li W, Kang YH, Su BN, Fong HH, van Breemen RB, Pezzuto JM, Kinghorn AD (2003) Minor withanolides from Physalis philadelphica: structures, quinone reductase induction activities, and liquid chromatography (LC)-MS-MS investigation as artifacts. Chem Pharm Bull (Tokyo) 51:530–539Google Scholar
  83. Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT (2010) ATM activation by oxidative stress. Science 330:517–521PubMedCrossRefGoogle Scholar
  84. Gupta GP, Massagué J (2006) Cancer metastasis: building a framework. Cell 127:679–695PubMedCrossRefGoogle Scholar
  85. Halkier BA, Gershenzon J (2006) Biology and biochemistry of glucosinolates. Annu Rev Plant Biol 57:303–333PubMedCrossRefGoogle Scholar
  86. Hall A, Nelson K, Poole L, Karplus PA (2010) Structure-based insights into the catalytic power and conformational dexterity of peroxiredoxins. Antioxid Redox Signal (in press)Google Scholar
  87. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65:1631–1652PubMedCrossRefGoogle Scholar
  88. Hayashi A, Suzuki H, Itoh K, Yamamoto M, Sugiyama Y (2003) Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem Biophys Res Commun 310:824–829PubMedCrossRefGoogle Scholar
  89. Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88PubMedCrossRefGoogle Scholar
  90. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT (2010) Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 13:1713–1748PubMedCrossRefGoogle Scholar
  91. He X, Ma Q (2009) NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation. Mol Pharmacol 76:1265–1278PubMedCrossRefGoogle Scholar
  92. He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J (2001) Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem 276:20858–20865PubMedCrossRefGoogle Scholar
  93. He X, Chen MG, Lin GX, Ma Q (2006) Arsenic induces NAD(P)H-quinone oxidoreductase I by disrupting the Nrf2 x Keap1 x Cul3 complex and recruiting Nrf2 x Maf to the antioxidant response element enhancer. J Biol Chem 281:23620–23631PubMedCrossRefGoogle Scholar
  94. He X, Lin GX, Chen MG, Zhang JX, Ma Q (2007) Protection against chromium (VI)-induced oxidative stress and apoptosis by Nrf2. Recruiting Nrf2 into the nucleus and disrupting the nuclear Nrf2/Keap1 association. Toxicol Sci 98:298–309PubMedCrossRefGoogle Scholar
  95. He X, Chen MG, Ma Q (2008) Activation of Nrf2 in defense against cadmium-induced oxidative stress. Chem Res Toxicol 21:1375–1383PubMedCrossRefGoogle Scholar
  96. Healy ZR, Lee NH, Gao X, Goldring MB, Talalay P, Kensler TW, Konstantopoulos K (2005) Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis. Proc Natl Acad Sci USA 102:14010–14015PubMedCrossRefGoogle Scholar
  97. Hecht SS, Morse MA, Eklind KI, Chung FL (1991) A/J mouse lung tumorigenesis by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its inhibition by arylalkyl isothiocyanates. Exp Lung Res 17:501–511Google Scholar
  98. Henkel G, Krebs B (2004) Metallothioneins: zinc, cadmium, mercury, and copper thiolates and selenolates mimicking protein active site features–structural aspects and biological implications. Chem Rev 104:801–824PubMedCrossRefGoogle Scholar
  99. Hochmuth CE, Biteau B, Bohmann D, Jasper H (2011) Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8:188–199Google Scholar
  100. Holland R, Fishbein JC (2010) Chemistry of the cysteine sensors in Kelch-like ECH-associated protein 1. Antioxid Redox Signal 13:1749–1761PubMedCrossRefGoogle Scholar
  101. Holmgren A, Lu J (2010) Thioredoxin and thioredoxin reductase: current research with special reference to human disease. Biochem Biophys Res Commun 396:120–124PubMedCrossRefGoogle Scholar
  102. Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N, Itoh K, Yamamoto M (2009) Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15:3423–3432PubMedCrossRefGoogle Scholar
  103. Hong F, Sekhar KR, Freeman ML, Liebler DC (2005) Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation. J Biol Chem 280:31768–31775PubMedCrossRefGoogle Scholar
  104. Hoshino H, Kobayashi A, Yoshida M, Kudo N, Oyake T, Motohashi H, Hayashi N, Yamamoto M, Igarashi K (2000) Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J Biol Chem 275:15370–15376PubMedCrossRefGoogle Scholar
  105. Hu R, Khor TO, Shen G, Jeong WS, Hebbar V, Chen C, Xu C, Reddy B, Chada K, Kong AN (2006) Cancer chemoprevention of intestinal polyposis in ApcMin/+ mice by sulforaphane, a natural product derived from cruciferous vegetable. Carcinogenesis 27:2038–2046PubMedCrossRefGoogle Scholar
  106. Huang LE, Arany Z, Livingston DM, Bunn HF (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 271:32253–32259PubMedCrossRefGoogle Scholar
  107. Huang HC, Nguyen T, Pickett CB (2000) Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci USA 97:12475–12480PubMedCrossRefGoogle Scholar
  108. Huang HC, Nguyen T, Pickett CB (2002) Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem 277:42769–42774PubMedCrossRefGoogle Scholar
  109. Hurst R, Bao Y, Jemth P, Mannervik B, Williamson G (1998) Phospholipid hydroperoxide glutathione peroxidase activity of human glutathione transferases. Biochem J 332:97–100PubMedGoogle Scholar
  110. Iida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, Shimazui T, Akaza H, Yamamoto M (2004) Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res 64:6424–6431PubMedCrossRefGoogle Scholar
  111. Iida K, Itoh K, Maher JM, Kumagai Y, Oyasu R, Mori Y, Shimazui T, Akaza H, Yamamoto M (2007) Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis. Carcinogenesis 28:2398–2403PubMedCrossRefGoogle Scholar
  112. Ikeda Y, Sugawara A, Taniyama Y, Uruno A, Igarashi K, Arima S, Ito S, Takeuchi K (2000) Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor gamma in macrophages via an interaction with NRF2. J Biol Chem 275:33142–33150PubMedCrossRefGoogle Scholar
  113. Innamorato NG, Rojo AI, García-Yagüe AJ, Yamamoto M, de Ceballos ML, Cuadrado A (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181:680–689PubMedGoogle Scholar
  114. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275:16023–16029PubMedCrossRefGoogle Scholar
  115. Itoh K, Igarashi K, Hayashi N, Nishizawa M, Yamamoto M (1995) Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol Cell Biol 15:4184–4193PubMedGoogle Scholar
  116. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322PubMedCrossRefGoogle Scholar
  117. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86PubMedCrossRefGoogle Scholar
  118. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O’Connor T, Yamamoto M (2003) Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8:379–391PubMedCrossRefGoogle Scholar
  119. Iwasaki K, Hailemariam K, Tsuji Y (2007) PIAS3 interacts with ATF1 and regulates the human ferritin H gene through an antioxidant-responsive element. J Biol Chem 282:22335–22343PubMedCrossRefGoogle Scholar
  120. Jain AK, Jaiswal AK (2006) Phosphorylation of tyrosine 568 controls nuclear export of Nrf2. J Biol Chem 281:12132–12142PubMedCrossRefGoogle Scholar
  121. Jain AK, Jaiswal AK (2007) GSK-3β acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem 282:16502–16510PubMedCrossRefGoogle Scholar
  122. Jain AK, Bloom DA, Jaiswal AK (2005) Nuclear import and export signals in control of Nrf2. J Biol Chem 280:29158–29168PubMedCrossRefGoogle Scholar
  123. Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øvervatn A, McMahon M, Hayes JD, Johansen T (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285:22576–22591PubMedCrossRefGoogle Scholar
  124. Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, Zhang DD (2010) High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res 70:5486–5496PubMedCrossRefGoogle Scholar
  125. Jin Y, Penning TM (2007) Aldo-keto reductases and bioactivation/detoxication. Annu Rev Pharmacol Toxicol 47:263–292PubMedCrossRefGoogle Scholar
  126. Johnsen O, Murphy P, Prydz H, Kolsto AB (1998) Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription. Nucleic Acids Res 26:512–520PubMedCrossRefGoogle Scholar
  127. Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG Jr, Elledge SJ, Conaway RC, Harper JW, Conaway JW (1999) Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657–661PubMedCrossRefGoogle Scholar
  128. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K, Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS, Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ, Faham M, Seshagiri S (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466:869–873Google Scholar
  129. Kang JG, Paget MS, Seok YJ, Hahn MY, Bae JB, Hahn JS, Kleanthous C, Buttner MJ, Roe JH (1999) σR, an anti-sigma factor regulated by redox change. EMBO J 18:4292–4298PubMedCrossRefGoogle Scholar
  130. Kang KW, Cho MK, Lee CH, Kim SG (2001) Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells. Mol Pharmacol 59:1147–1156PubMedGoogle Scholar
  131. Kang MI, Kobayashi A, Wakabayashi N, Kim SG, Yamamoto M (2004) Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci USA 101:2046–2051PubMedCrossRefGoogle Scholar
  132. 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, Sandrock AW, O’Neill GN (2008) Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372:1463–1472PubMedCrossRefGoogle Scholar
  133. Karapetian RN, Evstafieva AG, Abaeva IS, Chichkova NV, Filonov GS, Rubtsov YP, Sukhacheva EA, Melnikov SV, Schneider U, Wanker EE, Vartapetian AB (2005) Nuclear oncoprotein prothymosin alpha is a partner of Keap1: implications for expression of oxidative stress-protecting genes. Mol Cell Biol 25:1089–1099PubMedCrossRefGoogle Scholar
  134. Karin M (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270:16483–16486PubMedGoogle Scholar
  135. Karin M, Hunter T (1995) Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr Biol 5:747–757PubMedCrossRefGoogle Scholar
  136. Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (2001) Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6:857–868PubMedCrossRefGoogle Scholar
  137. Katoh Y, Iida K, Kang MI, Kobayashi A, Mizukami M, Tong KI, McMahon M, Hayes JD, Itoh K, Yamamoto M (2005) Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch Biochem Biophys 433:342–350PubMedCrossRefGoogle Scholar
  138. Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M (2005) Genetic evidence that small Maf proteins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol 25:8044–8051PubMedCrossRefGoogle Scholar
  139. Kensler TW, Chen JG, Egner PA, Fahey JW, Jacobson LP, Stephenson KK, Ye L, Coady JL, Wang JB, Wu Y, Sun Y, Zhang QN, Zhang BC, Zhu YR, Qian GS, Carmella SG, Hecht SS, Benning L, Gange SJ, Groopman JD, Talalay P (2005) Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthrene tetraols in a randomized clinical trial in He Zuo township, Qidong, People’s Republic of China. Cancer Epidemiol Biomarkers Prev 14:2605–2613PubMedCrossRefGoogle Scholar
  140. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN (2006) Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 66:11580–11584PubMedCrossRefGoogle Scholar
  141. Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, Cheung WK, Chan JY, Reddy BS, Yang CS, Kong AN (2008) Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res (Phila) 1:187–191CrossRefGoogle Scholar
  142. Ki SH, Cho IJ, Choi DW, Kim SG (2005) Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. Mol Cell Biol 25:4150–4165PubMedCrossRefGoogle Scholar
  143. Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J (2001) 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 276:18399–18406PubMedCrossRefGoogle Scholar
  144. Kim JE, You DJ, Lee C, Ahn C, Seong JY, Hwang JI (2010) Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation. Cell Signal 22:1645–1654PubMedCrossRefGoogle Scholar
  145. Kobayashi M, Itoh K, Suzuki T, Osanai H, Nishikawa K, Katoh Y, Takagi Y, Yamamoto M (2002) Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes Cells 7:807–820PubMedCrossRefGoogle Scholar
  146. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139PubMedCrossRefGoogle Scholar
  147. Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, Yamamoto M (2006) Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 26:221–229PubMedCrossRefGoogle Scholar
  148. Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, Eguchi M, Wada Y, Kumagai Y, Yamamoto M (2009) The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol 29:493–502PubMedCrossRefGoogle Scholar
  149. 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 (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12:213–223PubMedGoogle Scholar
  150. Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa U, Nishizuka Y (1997) Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci USA 94:11233–11237PubMedCrossRefGoogle Scholar
  151. Konishi H, Yamauchi E, Taniguchi H, Yamamoto T, Matsuzaki H, Takemura Y, Ohmae K, Kikkawa U, Nishizuka Y (2001) Phosphorylation sites of protein kinase C delta in H2O2-treated cells and its activation by tyrosine kinase in vitro. Proc Natl Acad Sci USA 98:6587–6592PubMedCrossRefGoogle Scholar
  152. Kuge S, Jones N, Nomoto A (1997) Regulation of yAP-1 nuclear localization in response to oxidative stress. EMBO J 16:1710–1720PubMedCrossRefGoogle Scholar
  153. Kuge S, Arita M, Murayama A, Maeta K, Izawa S, Inoue Y, Nomoto A (2001) Regulation of the yeast Yap1p nuclear export signal is mediated by redox signal-induced reversible disulfide bond formation. Mol Cell Biol 21:6139–6150PubMedCrossRefGoogle Scholar
  154. Kuroda K, Akao M (1989) Inhibitory effect of fumaric acid on 3′-methyl-4-(dimethylamino)azobenzene-induced hepatocarcinogenesis in rats. Chem Pharm Bull (Tokyo) 37:1345–1346Google Scholar
  155. Kuroda K, Kanisawa M, Akao M (1982) Inhibitory effect of fumaric acid on forestomach and lung carcinogenesis by a 5-nitrofuran naphthyridine derivative in mice. J Natl Cancer Inst 69:1317–1320PubMedGoogle Scholar
  156. Kuroda K, Terao K, Akao M (1983) Inhibitory effect of fumaric acid on 3-methyl-4′-(dimethylamino)-azobenzene-induced hepatocarcinogenesis in rats. J Natl Cancer Inst 71:855–857PubMedGoogle Scholar
  157. Kuroda K, Terao K, Akao M (1987) Inhibitory effect of fumaric acid on hepatocarcinogenesis by thioacetamide in rats. J Natl Cancer Inst 79:1047–1051PubMedGoogle Scholar
  158. Kuroiwa Y, Nishikawa A, Kitamura Y, Kanki K, Ishii Y, Umemura T, Hirose M (2006) Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic carcinogenesis in hamsters. Cancer Lett 241:275–280PubMedCrossRefGoogle Scholar
  159. Kwak MK, Itoh K, Yamamoto M, Sutter TR, Kensler TW (2001) Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol Med 7:135–145PubMedGoogle Scholar
  160. Kwak MK, Itoh K, Yamamoto M, Kensler TW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22:2883–2892PubMedCrossRefGoogle Scholar
  161. Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278:8135–8145PubMedCrossRefGoogle Scholar
  162. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, Zhang DD (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30:3275–3285PubMedCrossRefGoogle Scholar
  163. Lee JM, Hanson JM, Chu WA, Johnson JA (2001) Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR-32 human neuroblastoma cells. J Biol Chem 276:20011–20016PubMedCrossRefGoogle Scholar
  164. 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 (2009) KEAP1 E3 ligase-mediated downregulation of NF-κB signaling by targeting IKKβ. Mol Cell 36:131–140PubMedCrossRefGoogle Scholar
  165. Levonen AL, Landar A, Ramachandran A, Ceaser EK, Dickinson DA, Zanoni G, Morrow JD, Darley-Usmar VM (2004) Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem J 378:373–382PubMedCrossRefGoogle Scholar
  166. Levy S, Jaiswal AK, Forman HJ (2009) The role of c-Jun phosphorylation in EpRE activation of phase II genes. Free Radic Biol Med 47:1172–1179PubMedCrossRefGoogle Scholar
  167. Li B, Wang X, Rasheed N, Hu Y, Boast S, Ishii T, Nakayama K, Nakayama KI, Goff SP (2004a) Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C delta. Genes Dev 18:1824–1837PubMedCrossRefGoogle Scholar
  168. Li J, Stein TD, Johnson JA (2004b) Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice. Physiol Genomics 18:261–272PubMedCrossRefGoogle Scholar
  169. Li X, Zhang D, Hannink M, Beamer LJ (2004c) Crystal structure of the Kelch domain of human Keap1. J Biol Chem 279:54750–54758PubMedCrossRefGoogle Scholar
  170. Li Y, Gazdoiu S, Pan ZQ, Fuchs SY (2004d) Stability of homologue of Slimb F-box protein is regulated by availability of its substrate. J Biol Chem 279:11074–11080Google Scholar
  171. Li W, Jain MR, Chen C, Yue X, Hebbar V, Zhou R, Kong AN (2005) Nrf2 possesses a redox-insensitive nuclear export signal overlapping with the leucine zipper motif. J Biol Chem 280:28430–28438PubMedCrossRefGoogle Scholar
  172. Li W, Yu SW, Kong AN (2006) Nrf2 possesses a redox-sensitive nuclear exporting signal in the Neh5 transactivation domain. J Biol Chem 281:27251–27263PubMedCrossRefGoogle Scholar
  173. Li W, Yu S, Liu T, Kim JH, Blank V, Li H, Kong AN (2008) Heterodimerization with small Maf proteins enhances nuclear retention of Nrf2 via masking the NESzip motif. Biochim Biophys Acta 1783:1847–1856PubMedCrossRefGoogle Scholar
  174. Li W, Thakor N, Xu EY, Huang Y, Chen C, Yu R, Holcik M, Kong AN (2010) An internal ribosomal entry site mediates redox-sensitive translation of Nrf2. Nucleic Acids Res 38:778–788PubMedCrossRefGoogle Scholar
  175. Liby K, Honda T, Williams CR, Risingsong R, Royce DB, Suh N, Dinkova-Kostova AT, Stephenson KK, Talalay P, Sundararajan C, Gribble GW, Sporn MB (2007a) Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities. Mol Cancer Ther 6:2113–2119PubMedCrossRefGoogle Scholar
  176. Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, Honda T, Gribble GW, Dmitrovsky E, Sporn TA, Sporn MB (2007b) The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res 67:2414–2419PubMedCrossRefGoogle Scholar
  177. 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, Sporn MB (2008a) A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Res 68:6727–6733PubMedCrossRefGoogle Scholar
  178. Liby K, Black CC, Royce DB, Williams CR, Risingsong R, Yore MM, Liu X, Honda T, Gribble GW, Lamph WW, Sporn TA, Dmitrovsky E, Sporn MB (2008b) The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis. Mol Cancer Ther 7:1251–1257PubMedCrossRefGoogle Scholar
  179. Liby K, Risingsong R, Royce DB, Williams CR, Yore MM, Honda T, Gribble GW, Lamph WW, Vannini N, Sogno I, Albini A, Sporn MB (2008c) Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl Ester and the rexinoid LG100268. Clin Cancer Res 14:4556–4563PubMedCrossRefGoogle Scholar
  180. Liby K, Risingsong R, Royce DB, Williams CR, Ma T, Yore MM, Sporn MB (2009) Triterpenoids CDDO-methyl ester or CDDO-ethyl amide and rexinoids LG100268 or NRX194204 for prevention and treatment of lung cancer in mice. Cancer Prev Res (Phila) 2:1050–1058CrossRefGoogle Scholar
  181. Liby KT, Royce DB, Risingsong R, Williams CR, Maitra A, Hruban RH, Sporn MB (2010) Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. Cancer Prev Res (Phila) (in press)Google Scholar
  182. Lipton SA (2007) Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 8:803–808PubMedCrossRefGoogle Scholar
  183. Liu H, Dinkova-Kostova AT, Talalay P (2008) Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles. Proc Natl Acad Sci USA 105:15926–15931PubMedCrossRefGoogle Scholar
  184. Lo SC, Hannink M (2006a) PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex. J Biol Chem 281:37893–37903PubMedCrossRefGoogle Scholar
  185. Lo SC, Hannink M (2006b) CAND1-mediated substrate adaptor recycling is required for efficient repression of Nrf2 by Keap1. Mol Cell Biol 26:1235–1244PubMedCrossRefGoogle Scholar
  186. Lo SC, Hannink M (2008) PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res 314:1789–1803PubMedCrossRefGoogle Scholar
  187. Lo SC, Li X, Henzl MT, Beamer LJ, Hannink M (2006) Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 25:3605–3617PubMedCrossRefGoogle Scholar
  188. Loignon M, Miao W, Hu L, Bier A, Bismar TA, Scrivens PJ, Mann K, Basik M, Bouchard A, Fiset PO, Batist Z, Batist G (2009) Cul3 overexpression depletes Nrf2 in breast cancer and is associated with sensitivity to carcinogens, to oxidative stress, and to chemotherapy. Mol Cancer Ther 8:2432–2440PubMedCrossRefGoogle Scholar
  189. Lubos E, Loscalzo J, Handy DE (2010) Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal (in press)Google Scholar
  190. MacCallum PR, Jack SC, Egan PA, McDermott BT, Elliott RM, Chan SW (2006) Cap-dependent and hepatitis C virus internal ribosome entry site-mediated translation are modulated by phosphorylation of eIF2alpha under oxidative stress. J Gen Virol 87:3251–3262PubMedCrossRefGoogle Scholar
  191. MacLeod AK, McMahon M, Plummer SM, Higgins LG, Penning TM, Igarashi K, Hayes JD (2009) Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis 30:1571–1580PubMedCrossRefGoogle Scholar
  192. Mahaffey CM, Zhang H, Rinna A, Holland W, Mack PC, Forman HJ (2009) Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma. Free Radic Biol Med 46:1650–1657PubMedCrossRefGoogle Scholar
  193. Maher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, Scheffer GL, Chan JY, Manautou JE, Chen Y, Dalton TP, Yamamoto M, Klaassen CD (2007) Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology 46:1597–1610PubMedCrossRefGoogle Scholar
  194. Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, Shyr C, Wakabayashi N, Kensler TW, Wasserman WW, Biswal S (2010) Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38:5718–5734PubMedCrossRefGoogle Scholar
  195. Mannervik B, Board PG, Hayes JD, Listowsky I, Pearson WR (2005) Nomenclature for mammalian soluble glutathione transferases. Methods Enzymol 401:1–8PubMedCrossRefGoogle Scholar
  196. Marini MG, Chan K, Casula L, Kan YW, Cao A, Moi P (1997) hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2. J Biol Chem 272:16490–16497PubMedCrossRefGoogle Scholar
  197. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275PubMedCrossRefGoogle Scholar
  198. McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD (2001) 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 glutathione biosynthetic enzymes. Cancer Res 61:3299–3307PubMedGoogle Scholar
  199. McMahon M, Itoh K, Yamamoto M, Hayes JD (2003) Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 278:21592–21600PubMedCrossRefGoogle Scholar
  200. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2004) 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 279:31556–31567PubMedCrossRefGoogle Scholar
  201. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2006) 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 281:24756–24768PubMedCrossRefGoogle Scholar
  202. McMahon M, Lamont DJ, Beattie KA, Hayes JD (2010) Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc Natl Acad Sci USA 107:18838–18843PubMedCrossRefGoogle Scholar
  203. Misico RI, Song LL, Veleiro AS, Cirigliano AM, Tettamanzi MC, Burton G, Bonetto GM, Nicotra VE, Silva GL, Gil RR, Oberti JC, Kinghorn AD, Pezzuto JM (2002) Induction of quinone reductase by withanolides. J Nat Prod 65:677–680PubMedCrossRefGoogle Scholar
  204. Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the β-globin locus control region. Proc Natl Acad Sci USA 91:9926–9930PubMedCrossRefGoogle Scholar
  205. Morse MA, Eklind KI, Amin SG, Chung FL (1982) Effect of frequency of isothiocyanate administration on inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenoma formation in A/J mice. Cancer Lett 62:77–81Google Scholar
  206. Morse MA, Amin SG, Hecht SS, Chung FL (1989a) Effects of aromatic isothiocyanates on tumorigenicity, O6-methylguanine formation, and metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung. Cancer Res 49:2894–2897PubMedGoogle Scholar
  207. Morse MA, Wang CX, Stoner GD, Mandal S, Conran PB, Amin SG, Hecht SS, Chung FL (1989b) Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA adduct formation and tumorigenicity in the lung of F344 rats by dietary phenethyl isothiocyanate. Cancer Res 49:549–553PubMedGoogle Scholar
  208. Morse MA, Eklind KI, Hecht SS, Jordan KG, Choi CI, Desai DH, Amin SG, Chung FL (1991) Structure-activity relationships for inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone lung tumorigenesis by arylalkyl isothiocyanates in A/J mice. Cancer Res 51:1846–1850PubMedGoogle Scholar
  209. Motohashi H, O’Connor T, Katsuoka F, Engel JD, Yamamoto M (2002) Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene 294:1–12PubMedCrossRefGoogle Scholar
  210. Mukherjee S, Gangopadhyay H, Das DK (2008) Broccoli: a unique vegetable that protects mammalian hearts through the redox cycling of the thioredoxin superfamily. J Agric Food Chem 56:609–617PubMedCrossRefGoogle Scholar
  211. Mukherjee S, Lekli I, Ray D, Gangopadhyay H, Raychaudhuri U, Das DK (2010) Comparison of the protective effects of steamed and cooked broccolis on ischaemia-reperfusion-induced cardiac injury. Br J Nutr 103:815–823PubMedCrossRefGoogle Scholar
  212. Munday R, Mhawech-Fauceglia P, Munday CM, Paonessa JD, Tang L, Munday JS, Lister C, Wilson P, Fahey JW, Davis W, Zhang Y (2008) Inhibition of urinary bladder carcinogenesis by broccoli sprouts. Cancer Res 68:1593–1600PubMedCrossRefGoogle Scholar
  213. Mustacich D, Powis G (2000) Thioredoxin reductase. Biochem J 346:1–8PubMedCrossRefGoogle Scholar
  214. Muto A, Tashiro S, Tsuchiya H, Kume A, Kanno M, Ito E, Yamamoto M, Igarashi K (2002) Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with promyelocytic leukemia nuclear bodies. J Biol Chem 277:20724–20733PubMedCrossRefGoogle Scholar
  215. Myzak MC, Karplus PA, Chung FL, Dashwood RH (2004) A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res 64:5767–5774PubMedCrossRefGoogle Scholar
  216. Myzak MC, Dashwood WM, Orner GA, Ho E, Dashwood RH (2006) Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice. FASEB J 20:506–508PubMedGoogle Scholar
  217. Nguyen T, Sherratt PJ, Huang HC, Yang CS, Pickett CB (2003) Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem 278:4536–4541PubMedCrossRefGoogle Scholar
  218. Nguyen T, Sherratt PJ, Nioi P, Yang CS, Pickett CB (2005) Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem 280:32485–32492PubMedCrossRefGoogle Scholar
  219. Nioi P, Nguyen T (2007) A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun 362:816–821PubMedCrossRefGoogle Scholar
  220. Nioi P, Nguyen T, Sherratt PJ, Pickett CB (2005) The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 25:10895–10906PubMedCrossRefGoogle Scholar
  221. Niture SK, Jaiswal AK (2009) Prothymosin-α mediates nuclear import of the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2. J Biol Chem 284:13856–13868PubMedCrossRefGoogle Scholar
  222. Niture SK, Jain AK, Jaiswal AK (2009) Antioxidant-induced modification of INrf2 cysteine 151 and PKC-delta-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance. J Cell Sci 122:4452–4464PubMedCrossRefGoogle Scholar
  223. Noyan-Ashraf MH, Wu L, Wang R, Juurlink BH (2006) Dietary approaches to positively influence fetal determinants of adult health. FASEB J 20:371–373PubMedGoogle Scholar
  224. Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, Yamamoto M (2010) 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 107:2842–2847PubMedCrossRefGoogle Scholar
  225. Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, Suzuki T, Kobayashi A, Yokota J, Sakiyama T, Shibata T, Yamamoto M, Hirohashi S (2008) Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res 68:1303–1309PubMedCrossRefGoogle Scholar
  226. Osburn WO, Yates MS, Dolan PD, Chen S, Liby KT, Sporn MB, Taguchi K, Yamamoto M, Kensler TW (2008) Genetic or pharmacologic amplification of Nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci 104:218–227Google Scholar
  227. Padmanabhan B, Scharlock M, Tong KI, Nakamura Y, Kang MI, Kobayashi A, Matsumoto T, Tanaka A, Yamamoto M, Yokoyama S (2005) Purification, crystallization and preliminary X-ray diffraction analysis of the Kelch-like motif region of mouse Keap1. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:153–155PubMedCrossRefGoogle Scholar
  228. Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, Yamamoto M (2006) Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 21:689–700PubMedCrossRefGoogle Scholar
  229. Padmanabhan B, Tong KI, Kobayashi A, Yamamoto M, Yokoyama S (2008) Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1. J Synchrotron Radiat 15:273–276PubMedCrossRefGoogle Scholar
  230. Paget MS, Kang JG, Roe JH, Buttner MJ (1998) σR, an RNA polymerase sigma factor that modulates expression of the thioredoxin system in response to oxidative stress in Streptomyces coelicolor A3(2). EMBO J 17:5776–5782PubMedCrossRefGoogle Scholar
  231. Pause A, Lee S, Worrell RA, Chen DY, Burgess WH, Linehan WM, Klausner RD (1997) The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci USA 94:2156–2161PubMedCrossRefGoogle Scholar
  232. Perkins ND (2004) NF-kappaB: tumor promoter or suppressor? Trends Cell Biol 14:64–69PubMedCrossRefGoogle Scholar
  233. Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G (1998) A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392:190–193PubMedCrossRefGoogle Scholar
  234. Pi J, Bai Y, Reece JM, Williams J, Liu D, Freeman ML, Fahl WE, Shugar D, Liu J, Qu W, Collins S, Waalkes MP (2007) Molecular mechanism of human Nrf2 activation and degradation: role of sequential phosphorylation by protein kinase CK2. Free Radic Biol Med 42:1797–1806PubMedCrossRefGoogle Scholar
  235. Pietsch EC, Chan JY, Torti FM, Torti SV (2003) Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones. J Biol Chem 278:2361–2369PubMedCrossRefGoogle Scholar
  236. Ping Z, Liu W, Kang Z, Cai J, Wang Q, Cheng N, Wang S, Wang S, Zhang JH, Sun X (2010) Sulforaphane protects brains against hypoxic-ischemic injury through induction of Nrf2-dependent phase 2 enzyme. Brain Res 1343:178–185PubMedCrossRefGoogle Scholar
  237. Pintard L, Willis JH, Willems A, Johnson JL, Srayko M, Kurz T, Glaser S, Mains PE, Tyers M, Bowerman B, Peter M (2003) The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 425:311–316PubMedCrossRefGoogle Scholar
  238. Posner GH, Cho CG, Green JV, Zhang Y, Talalay P (1994) Design and synthesis of bifunctional isothiocyanate analogs of sulforaphane: correlation between structure and potency as inducers of anticarcinogenic detoxication enzymes. J Med Chem 37:170–176PubMedCrossRefGoogle Scholar
  239. Powis G, Montfort WR (2001) Properties and biological activities of thioredoxins. Annu Rev Pharmacol Toxicol 41:261–295PubMedCrossRefGoogle Scholar
  240. Prestera T, Talalay P, Alam J, Ahn YI, Lee PJ, Choi AM (1995) Parallel induction of heme oxygenase-1 and chemoprotective phase 2 enzymes by electrophiles and antioxidants: regulation by upstream antioxidant-responsive elements (ARE). Mol Med 1:827–837PubMedGoogle Scholar
  241. Prochaska HJ, Santamaria AB (1988) Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers. Anal Biochem 169:328–336PubMedCrossRefGoogle Scholar
  242. Prochaska HJ, Bregman HS, De Long MJ, Talalay P (1985a) Specificity of induction of cancer protective enzymes by analogues of tert-butyl-4-hydroxyanisole (BHA). Biochem Pharmacol 34:3909–3914PubMedCrossRefGoogle Scholar
  243. Prochaska HJ, De Long MJ, Talalay P (1985b) On the mechanisms of induction of cancer-protective enzymes: a unifying proposal. Proc Natl Acad Sci USA 82:8232–8236PubMedCrossRefGoogle Scholar
  244. Prochaska HJ, Talalay P, Sies H (1987) Direct protective effect of NAD(P)H:quinone reductase against menadione-induced chemiluminescence of postmitochondrial fractions of mouse liver. J Biol Chem 262:1931–1934PubMedGoogle Scholar
  245. Purdom-Dickinson SE, Sheveleva EV, Sun H, Chen QM (2007) Translational control of nrf2 protein in activation of antioxidant response by oxidants. Mol Pharmacol 72:1074–1081PubMedCrossRefGoogle Scholar
  246. Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman ML (2008) Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol 21:705–710PubMedCrossRefGoogle Scholar
  247. Rachakonda G, Sekhar KR, Jowhar D, Samson PC, Wikswo JP, Beauchamp RD, Datta PK, Freeman ML (2010) Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene 29:3703–3714PubMedCrossRefGoogle Scholar
  248. Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD, Cuadrado A (2011) SCF(β-TrCP) promotes Glycogen synthase kinase-3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol (in press)Google Scholar
  249. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98:3410–3415PubMedCrossRefGoogle Scholar
  250. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest 114:1248–1259PubMedGoogle Scholar
  251. Reddy NM, Kleeberger SR, Bream JH, Fallon PG, Kensler TW, Yamamoto M, Reddy SP (2008) Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling. Oncogene 27:5821–5832PubMedCrossRefGoogle Scholar
  252. Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P (2003) The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci USA 100:9244–9249PubMedCrossRefGoogle Scholar
  253. Rhee SG, Jeong W, Chang TS, Woo HA (2007) Sulfiredoxin, the cysteine sulfinic acid reductase specific to 2-Cys peroxiredoxin: its discovery, mechanism of action, and biological significance. Kidney Int Suppl:S3–S8Google Scholar
  254. Robbins DJ, Nybakken KE, Kobayashi R, Sisson JC, Bishop JM, Thérond PP (1997) Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell 90:225–234PubMedCrossRefGoogle Scholar
  255. Robinson DN, Cooley L (1997) Drosophila kelch is an oligomeric ring canal actin organizer. J Cell Biol 138:799–810PubMedCrossRefGoogle Scholar
  256. Ross D, Zhou H (2010) Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity. Chem Biol Interact 184:222–228PubMedCrossRefGoogle Scholar
  257. Rushmore TH, Pickett CB (1990) Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem 265:14648–14653PubMedGoogle Scholar
  258. Rushmore TH, Morton MR, Pickett CB (1991) The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266:11632–11639PubMedGoogle Scholar
  259. Rushworth SA, MacEwan DJ (2008) HO-1 underlies resistance of AML cells to TNF-induced apoptosis. Blood 111:3793–3801PubMedCrossRefGoogle Scholar
  260. Rybin VO, Guo J, Sabri A, Elouardighi H, Schaefer E, Steinberg SF (2004) Stimulus-specific differences in protein kinase C delta localization and activation mechanisms in cardiomyocytes. J Biol Chem 279:19350–19361PubMedCrossRefGoogle Scholar
  261. Ryter SW, Choi AM (2010) Heme oxygenase-1/carbon monoxide: novel therapeutic strategies in critical care medicine. Curr Drug Targets 11:1485–1494PubMedGoogle Scholar
  262. Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281:14841–14851PubMedCrossRefGoogle Scholar
  263. Sankaranarayanan K, Jaiswal AK (2004) Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. J Biol Chem 279:50810–50817PubMedCrossRefGoogle Scholar
  264. Sasaki S (1963) Inhibitory effects by α-naphthyl-isothiocyanale on development of hepatoma in rats treated with 3′-methyl-4-dimethyl-aminoazobenzene. J Nara Med Assoc 14:101–115Google Scholar
  265. Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, Rieks M, Hoffmann V, Pöhlau D, Przuntek H (2006) Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 13:604–610PubMedCrossRefGoogle Scholar
  266. Sekhar KR, Soltaninassab SR, Borrelli MJ, Xu ZQ, Meredith MJ, Domann FE, Freeman ML (2000) Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase. Biochem Biophys Res Commun 270:311–317PubMedCrossRefGoogle Scholar
  267. Sekhar KR, Rachakonda G, Freeman ML (2010) Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicol Appl Pharmacol 244:21–26PubMedCrossRefGoogle Scholar
  268. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedCrossRefGoogle Scholar
  269. Shapiro TA, Fahey JW, Dinkova-Kostova AT, Holtzclaw WD, Stephenson KK, Wade KL, Ye L, Talalay P (2006) Safety, tolerance, and metabolism of broccoli sprout glucosinolates and isothiocyanates: a clinical phase I study. Nutr. Cancer 55:53–62Google Scholar
  270. Shen G, Khor TO, Hu R, Yu S, Nair S, Ho CT, Reddy BS, Huang MT, Newmark HL, Kong AN (2007) Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse. Cancer Res 67:9937–9944PubMedCrossRefGoogle Scholar
  271. Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (2008a) Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA 105:13568–13573PubMedCrossRefGoogle Scholar
  272. Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, Hirohashi S (2008b) Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 135:1358–1368 1368.e1-4PubMedCrossRefGoogle Scholar
  273. Shibata T, Saito S, Kokubu A, Suzuki T, Yamamoto M, Hirohashi S (2010) Global downstream pathway analysis reveals a dependence of oncogenic NF-E2-related factor 2 mutation on the mTOR growth signaling pathway. Cancer Res 70:9095–9105PubMedCrossRefGoogle Scholar
  274. Sidransky H, Ito N, Verney E (1966) Influence of a-naphthyl-isothiocyanate on liver tumorigenesis in rats ingesting ethionine and N-2-fluorenylacetamide. J Natl Cancer Inst 37:677–686PubMedGoogle Scholar
  275. Siebenlist U, Franzoso G, Brown K (1994) Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 10:405–455PubMedCrossRefGoogle Scholar
  276. Siegel D, Gustafson DL, Dehn DL, Han JY, Boonchoong P, Berliner LJ, Ross D (2004) NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol 65:1238–1247PubMedCrossRefGoogle Scholar
  277. Siglin JC, Barch DH, Stoner GD (1995) Effects of dietary phenethyl isothiocyanate, ellagic acid, sulindac and calcium on the induction and progression of N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. Carcinogenesis 16:1101–1106PubMedCrossRefGoogle Scholar
  278. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S (2006) Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 3:e420PubMedCrossRefGoogle Scholar
  279. Singh A, Ling G, Suhasini AN, Zhang P, Yamamoto M, Navas-Acien A, Cosgrove G, Tuder RM, Kensler TW, Watson WH, Biswal S (2009) Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs. Free Radic Biol Med 46:376–386PubMedCrossRefGoogle Scholar
  280. Sisson JC, Ho KS, Suyama K, Scott MP (1997) Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 90:235–245PubMedCrossRefGoogle Scholar
  281. Sjöblom 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 (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274PubMedCrossRefGoogle Scholar
  282. Smith MT, Wang Y, Skibola CF, Slater DJ, Lo Nigro L, Nowell PC, Lange BJ, Felix CA (2002) Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children. Blood 100:4590–4593PubMedCrossRefGoogle Scholar
  283. Snyder GH, Cennerazzo MJ, Karalis AJ, Field D (1981) Electrostatic influence of local cysteine environments on disulfide exchange kinetics. Biochemistry 20:6509–6519PubMedCrossRefGoogle Scholar
  284. Spencer SR, Xue LA, Klenz EM, Talalay P (1991) The potency of inducers of NAD(P)H:(quinone-acceptor) oxidoreductase parallels their efficiency as substrates for glutathione transferases. Structural and electronic correlations. Biochem J 273:711–717PubMedGoogle Scholar
  285. Stack C, Ho D, Wille E, Calingasan NY, Williams C, Liby K, Sporn M, Dumont M, Beal MF (2010) Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radic Biol Med 49:147–158PubMedCrossRefGoogle Scholar
  286. Stacy DR, Ely K, Massion PP, Yarbrough WG, Hallahan DE, Sekhar KR, Freeman ML (2006) Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas. Head Neck 28:813–818PubMedCrossRefGoogle Scholar
  287. Stanley EL, Hume R, Coughtrie MW (2005) Expression profiling of human fetal cytosolic sulfotransferases involved in steroid and thyroid hormone metabolism and in detoxification. Mol Cell Endocrinol 240:32–42PubMedCrossRefGoogle Scholar
  288. Stewart D, Killeen E, Naquin R, Alam S, Alam J (2003) Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J Biol Chem 278:2396–2402PubMedCrossRefGoogle Scholar
  289. Stoner GD, Adams C, Kresty LA, Amin SG, Desai D, Hecht SS, Murphy SE, Morse MA (1998) Inhibition of N′-nitrosonornicotine-induced esophageal tumorigenesis by 3-phenylpropyl isothiocyanate. Carcinogenesis 19:2139–2143PubMedCrossRefGoogle Scholar
  290. Su BN, Park EJ, Nikolic D, Santarsiero BD, Mesecar AD, Vigo JS, Graham JG, Cabieses F, van Breemen RB, Fong HH, Farnsworth NR, Pezzuto JM, Kinghorn AD (2003) Activity-guided isolation of novel norwithanolides from depreasubtriflora with potential cancer chemopreventive activity. J Org Chem 68:2350–2361Google Scholar
  291. Sun Z, Zhang S, Chan JY, Zhang DD (2007) Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol 27:6334–6349PubMedCrossRefGoogle Scholar
  292. Sun Z, Huang Z, Zhang DD (2009) Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS One 4:e6588PubMedCrossRefGoogle Scholar
  293. Surh YJ, Chun KS (2007) Cancer chemopreventive effects of curcumin. Adv Exp Med Biol 595:149–172PubMedCrossRefGoogle Scholar
  294. Sykiotis GP, Bohmann D (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell 14:76–85PubMedCrossRefGoogle Scholar
  295. Taguchi K, Maher JM, Suzuki T, Kawatani Y, Motohashi H, Yamamoto M (2010) Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol Cell Biol 30:3016–3026PubMedCrossRefGoogle Scholar
  296. Talalay P, De Long MJ, Prochaska HJ (1988) Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci USA 85:8261–8265PubMedCrossRefGoogle Scholar
  297. Talalay P, Fahey JW, Healy ZR, Wehage SL, Benedict AL, Min C, Dinkova-Kostova AT (2007) Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci USA 104:17500–17505PubMedCrossRefGoogle Scholar
  298. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196–5203PubMedGoogle Scholar
  299. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M (2006) Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 26:2887–2900PubMedCrossRefGoogle Scholar
  300. Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M (2007) Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol 27:7511–7521PubMedCrossRefGoogle Scholar
  301. Traka M, Gasper AV, Melchini A, Bacon JR, Needs PW, Frost V, Chantry A, Jones AM, Ortori CA, Barrett DA, Ball RY, Mills RD, Mithen RF (2008) Broccoli consumption interacts with GSTM1 to perturb oncogenic signalling pathways in the prostate. PLoS One 3:e2568PubMedCrossRefGoogle Scholar
  302. Tsuji Y (2005) JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress. Oncogene 24:7567–7578PubMedCrossRefGoogle Scholar
  303. Velichkova M, Hasson T (2005) Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol Cell Biol 25:4501–4513PubMedCrossRefGoogle Scholar
  304. Venugopal R, Jaiswal AK (1996) Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci USA 93:14960–14965PubMedCrossRefGoogle Scholar
  305. Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, Imakado S, Kotsuji T, Otsuka F, Roop DR, Harada T, Engel JD, Yamamoto M (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35:238–245PubMedCrossRefGoogle Scholar
  306. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P (2004) 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 101:2040–2045PubMedCrossRefGoogle Scholar
  307. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW (2010a) When NRF2 talks, who’s listening? Antioxid Redox Signal 13:1649–1663PubMedCrossRefGoogle Scholar
  308. Wakabayashi N, Shin S, Slocum SL, Agoston ES, Wakabayashi J, Kwak MK, Misra V, Biswal S, Yamamoto M, Kensler TW (2010b) Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci Signal 3:ra52Google Scholar
  309. Wang XJ, Hayes JD, Wolf CR (2006) 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 66:10983–10994PubMedCrossRefGoogle Scholar
  310. Wang XJ, Hayes JD, Henderson CJ, Wolf CR (2007) Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci USA 104:19589–19594PubMedCrossRefGoogle Scholar
  311. Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (2008a) Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1–C151: enhanced Keap1-Cul3 interaction. Toxicol Appl Pharmacol 230:383–389PubMedCrossRefGoogle Scholar
  312. Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, Wong PK, Zhang DD (2008b) Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29:1235–1243PubMedCrossRefGoogle Scholar
  313. Wang XJ, Hayes JD, Higgins LG, Wolf CR, Dinkova-Kostova AT (2010) Activation of the NRF2 signaling pathway by copper-mediated redox cycling of para- and ortho-hydroquinones. Chem Biol 17:75–85PubMedCrossRefGoogle Scholar
  314. Wasserman WW, Fahl WE (1997) Comprehensive analysis of proteins which interact with the antioxidant responsive element: correlation of ARE-BP-1 with the chemoprotective induction response. Arch Biochem Biophys 344:387–396PubMedCrossRefGoogle Scholar
  315. Watai Y, Kobayashi A, Nagase H, Mizukami M, McEvoy J, Singer JD, Itoh K, Yamamoto M (2007) Subcellular localization and cytoplasmic complex status of endogenous Keap1. Genes Cells 12:1163–1178PubMedCrossRefGoogle Scholar
  316. Wattenberg LW (1977) Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst 58:395–398PubMedGoogle Scholar
  317. Wattenberg LW (1981) Inhibition of carcinogen-induced neoplasia by sodium cyanate, tert-butyl isocyanate, and benzyl isothiocyanate administered subsequent to carcinogen exposure. Cancer Res 41:2991–2994PubMedGoogle Scholar
  318. Wattenberg LW (1983) Inhibition of neoplasia by minor dietary constituents. Cancer Res 43:2448s–2453sPubMedGoogle Scholar
  319. Wattenberg LW (1985) Chemoprevention of cancer. Cancer Res 45:1–8PubMedCrossRefGoogle Scholar
  320. Wattenberg LW (1987) Inhibitory effects of benzyl isothiocyanate administered shortly before diethylnitrosamine or benzo[a]pyrene on pulmonary and forestomach neoplasia in A/J mice. Carcinogenesis 8:1971–1973PubMedCrossRefGoogle Scholar
  321. Wattenberg LW, Jerina DM, Lam LK, Yagi H (1979) Neoplastic effects of oral administration of (+/−)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and their inhibition by butylated hydroxyanisole. J Natl Cancer Inst 62:1103–1106Google Scholar
  322. Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr (2004) Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428:194–198PubMedCrossRefGoogle Scholar
  323. Welsh SJ, Bellamy WT, Briehl MM, Powis G (2002) The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 62:5089–5095PubMedGoogle Scholar
  324. Wild AC, Moinova HR, Mulcahy RT (1999) Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 274:33627–33636PubMedCrossRefGoogle Scholar
  325. Woo HA, Jeong W, Chang TS, Park KJ, Park SJ, Yang JS, Rhee SG (2005) Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-cys peroxiredoxins. J Biol Chem 280:3125–3128PubMedCrossRefGoogle Scholar
  326. Wu L, Noyan-Ashraf MH, Facci M, Wang R, Paterson PG, Ferrie A, Juurlink BH (2004) Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system. Proc Natl Acad Sci USA 101:7094–7099PubMedCrossRefGoogle Scholar
  327. Xu L, Wei Y, Reboul J, Vaglio P, Shin TH, Vidal M, Elledge SJ, Harper JW (2003) BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 425:316–321PubMedCrossRefGoogle Scholar
  328. Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, Conney AH, Kong AN (2006) 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 66:8293–8296PubMedCrossRefGoogle Scholar
  329. Xue F, Cooley L (1993) kelch encodes a component of intercellular bridges in Drosophila egg chambers. Cell 72:681–693PubMedCrossRefGoogle Scholar
  330. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 28:2758–2770PubMedCrossRefGoogle Scholar
  331. Yan C, Lee LH, Davis LI (1998) Crm1p mediates regulated nuclear export of a yeast AP-1-like transcription factor. EMBO J 17:7416–7429PubMedCrossRefGoogle Scholar
  332. Yanaka A, Fahey JW, Fukumoto A, Nakayama M, Inoue S, Zhang S, Tauchi M, Suzuki H, Hyodo I, Yamamoto M (2009) Dietary sulforaphane-rich broccoli sprouts reduce colonization and attenuate gastritis in Helicobacter pylori-infected mice and humans. Cancer Prev Res (Phila) 2:353–360CrossRefGoogle Scholar
  333. Yang L, Calingasan NY, Thomas B, Chaturvedi RK, Kiaei M, Wille EJ, Liby KT, Williams C, Royce D, Risingsong R, Musiek ES, Morrow JD, Sporn M, Beal MF (2009) Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription. PLoS One 4:e5757PubMedCrossRefGoogle Scholar
  334. Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben-Neriah Y (1998) Identification of the receptor component of the IκBα-ubiquitin ligase. Nature 396:590–594PubMedCrossRefGoogle Scholar
  335. Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddigari S, Sutter TR, Baumgartner KJ, Roebuck BD, Liby KT, Yore MM, Honda T, Gribble GW, Sporn MB, Kensler TW (2006) Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-, 12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole. Cancer Res 66:2488–2494PubMedCrossRefGoogle Scholar
  336. 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 (2009) Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30:1024–1031PubMedCrossRefGoogle Scholar
  337. Ye L, Zhang Y (2001) Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes. Carcinogenesis 22:1987–1992PubMedCrossRefGoogle Scholar
  338. Yu R, Lei W, Mandlekar S, Weber MJ, Der CJ, Wu J, Kong AN (1999) Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J Biol Chem 274:27545–27552PubMedCrossRefGoogle Scholar
  339. Yu R, Mandlekar S, Lei W, Fahl WE, Tan TH, Kong AN (2000) p38 mitogen-activated protein kinase negatively regulates the induction of phase II drug-metabolizing enzymes that detoxify carcinogens. J Biol Chem 275:2322–2327PubMedCrossRefGoogle Scholar
  340. Zhang Y (2000) Role of glutathione in the accumulation of anticarcinogenic isothiocyanates and their glutathione conjugates by murine hepatoma cells. Carcinogenesis 21:1175–1182PubMedCrossRefGoogle Scholar
  341. Zhang Y (2001) Molecular mechanism of rapid cellular accumulation of anticarcinogenic isothiocyanates. Carcinogenesis 22:425–431Google Scholar
  342. Zhang Y, Callaway EC (2002) High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J 364:301–307PubMedGoogle Scholar
  343. Zhang DD, Hannink M (2003) 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 23:8137–8151PubMedCrossRefGoogle Scholar
  344. Zhang Y, Talalay P (1998) Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes. Cancer Res 58:4632–4639PubMedGoogle Scholar
  345. Zhang Y, Talalay P, Cho CG, Posner GH (1992) A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci USA 89:2399–2403PubMedCrossRefGoogle Scholar
  346. Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P (1994) Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 91:3147–3150PubMedCrossRefGoogle Scholar
  347. Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24:10941–10953PubMedCrossRefGoogle Scholar
  348. Zhang DD, Lo SC, Sun Z, Habib GM, Lieberman MW, Hannink M (2005) Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem 280:30091–30099PubMedCrossRefGoogle Scholar
  349. Zhang J, Ohta T, Maruyama A, Hosoya T, Nishikawa K, Maher JM, Shibahara S, Itoh K, Yamamoto M (2006) BRG1 interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress. Mol Cell Biol 26:7942–7952PubMedCrossRefGoogle Scholar
  350. Zhao J, Moore AN, Clifton GL, Dash PK (2005) Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. J Neurosci Res 82:499–506PubMedCrossRefGoogle Scholar
  351. Zhao J, Kobori N, Aronowski J, Dash PK (2006) Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neurosci Lett 393:108–112PubMedCrossRefGoogle Scholar
  352. Zhao J, Moore AN, Redell JB, Dash PK (2007a) Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 27:10240–10248PubMedCrossRefGoogle Scholar
  353. Zhao X, Sun G, Zhang J, Strong R, Dash PK, Kan YW, Grotta JC, Aronowski J (2007b) Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 38:3280–3286PubMedCrossRefGoogle Scholar
  354. Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP (2002) Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 416:703–709PubMedCrossRefGoogle Scholar
  355. Zhou P, Howley PM (1998) Ubiquitination and degradation of the substrate recognition subunits of SCF ubiquitin-protein ligases. Mol Cell 2:571–580PubMedCrossRefGoogle Scholar
  356. Zhou W, Edelman GM, Mauro VP (2001) Transcript leader regions of two Saccharomyces cerevisiae mRNAs contain internal ribosome entry sites that function in living cells. Proc Natl Acad Sci USA 98:1531–1536PubMedCrossRefGoogle Scholar
  357. Zhou W, Lo SC, Liu JH, Hannink M, Lubahn DB (2007) ERRbeta: a potent inhibitor of Nrf2 transcriptional activity. Mol Cell Endocrinol 278:52–62PubMedCrossRefGoogle Scholar
  358. Zipper LM, Mulcahy RT (2002) The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem 277:36544–36552PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Biomedical Research InstituteUniversity of DundeeDundeeScotland, UK
  2. 2.The Department of Pharmacology and Molecular SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Biomedical Research Institute, Level 5Ninewells Hospital and Medical SchoolDundeeUK

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