Abstract
Human exposures to environmental toxicants have been associated with etiology of many diseases including inflammation, cancer, and cardiovascular and neurodegenerative disorders. To counteract the detrimental effect of environmental insults, mammalian cells have evolved a hierarchy of sophisticated sensing and signaling mechanisms to turn on or off endogenous antioxidant responses accordingly. One of the major cellular antioxidant responses is the induction of antioxidative and carcinogen-detoxification enzymes through the cytoplasmic oxidative stress system (Nrf2-Keap1) activated by a variety of natural and synthetic chemopreventive agents. Under normal conditions, Keap1 anchors the Nrf2 transcription factor within the cytoplasm targeting it for ubiquitination and proteasomal degradation to maintain low levels of Nrf2 that mediate the constitutive expression of Nrf2 downstream genes. When cells are exposed to chemopreventive agents and oxidative stress, a signal involving phosphorylation and/or redox modification of critical cysteine residues in Keap1 inhibits the enzymatic activity of the Keap1–Cul3–Rbx1 E3 ubiquitin ligase complex, resulting in decreased Nrf2 ubiquitination and degradation. As a consequence, free Nrf2 translocates into the nucleus and in combination with other transcription factors (e.g., sMaf, ATF4, JunD, PMF-1) transactivates the antioxidant response elements (AREs)/electrophile response elements (EpREs) of many cytoprotective genes, as well as Nrf2 itself. Upon recovery of cellular redox homeostasis, Keap1 travels into the nucleus to dissociate Nrf2 from the ARE. Subsequently, the Nrf2–Keap1 complex is exported out of the nucleus by the nuclear export sequence (NES) in Keap1. Once in the cytoplasm, the Nrf2–Keap1 complex associates with the Cul3-Rbx1 core ubiquitin machinery, resulting in degradation of Nrf2 and termination of the Nrf2/ARE signaling pathway. The discovery of multiple nuclear localization signals (NLSs) and nuclear export signals (NESs) in Nrf2 also suggests that the nucleocytoplasm translocation of transcription factors is the consequence of a dynamic equilibrium of multivalent NLSs and NESs. On the other hand, Keap1 may provide an additional regulation of the quantity of Nrf2 both in basal and inducible conditions. This chapter summarizes the current body of knowledge regarding the molecular mechanisms through which ARE inducers (chemopreventive agents) regulate the coordinated transcriptional induction of genes encoding phase II and antioxidant enzymes as well as other defensive proteins, via the nuclear factor-erythroid 2 (NF-E2-p45)-related factor 2(Nrf2)/(ARE) signaling pathway.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Klaunig JE, Kamendulis LM (2004) The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 44:239–267
Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247
Osburn WO, Kensler TW (2008) Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res 659:31–39
Nguyen T, Sherrat PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43:233–260
Giudice A, Montella M (2006) Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. Bioessays 28(2):169–181
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. J Biol Chem 278:8135–8145
Hayes JD, McLellan LI (1999) Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic Res 31(4):273–300
Talalay P, Dinkova-Kostova AT, Holtzclaw WD (2003) Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv Enzyme Regul 43:121–134
Li J, Lee JM, Johnson JA (2002) Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells. J Biol Chem 277:388–394
Kelly VP, Ellis EM, Manson MM, Chanas SA, Moffet GJ et al (2000) Chemoprevention 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
Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767
Surh YJ (1999) Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 428:305–327
Anonymous (1999) Prevention of cancer in the next millenium: report of the chemoprevention working group to the American association for cancer research. Cancer Res 59:4743–4758
Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3:768–780
Wattenberg LW (1985) Chemoprevention of cancer. Cancer Res 45:1–8
Wilkinson J 4th, Clapper ML (1997) Detoxification enzymes and chemoprevention. Proc Soc Exp Biol Med 216:192–200
Prochaska HJ, Talalay P (1988) Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res 48:4776–4782
Talalay P (1989) Mechanisms of induction of enzymes that protect against chemical carcinogenesis. Adv Enzyme Regul 28:237–250
Conney AH (2003) Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the seventh DeWitt S. Goodman lecture. Cancer Res 63:7005–7031
Ramos-Gomez M, Kwak MK, Dolan PM, Itoh k, Yamamoto M et al (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A 98:3410–3415
Wolf CR (2001) Chemoprevention: increased potential to bear fruit. Proc Natl Acad Sci U S A 98:2941–2943
Sheweita SA, Tilmisany AK (2003) Cancer and phase II drug-metabolizing enzymes. Curr Drug Metab 4:45–58
Talalay P, Fahey JW, Holtzclaw WD, Prestera T, Zhang Y (1995) Chemoprotection against cancer by phase 2 enzyme induction. Toxicol Lett 82–83:173–179
Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K et al (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86
Xue F, Cooley L (1993) Kelch encodes a component of intercellular bridges in Drosophila egg chambers. Cell 72:681–693
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 U S A 98:3404–3409
Huang HC, Nguyen T, Pickett CB (2000) Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor. Proc Natl Acad Sci U S A 97:12475–12480
Lin W, Shen G, Yuan X, Jain MR, Yu S, Zhang A, Chen JD (2006) Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co-regulators. J Biochem Mol Biol 39(3):304–310
Motohashi H, O’Connors 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 294:1–12
Ikeda H, Nishi S, Sakai M (2004) Transcription factor Nrf2/Mafk regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Biochem J 380:515–521
Sankaranarayanan K, Jaiswal AK (2004) Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase 1 gene. J Biol Chem 279:50810–50817
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(2):364–368
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(52):39776–39784
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 U S A 104(49):19589–19594
Cammas F, Oulad-Abdelghani M, Vonesch JL, Huss-Garcia Y, Chambon P, Losson R (2002) Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction. J Cell Sci 115(Pt 17):3439–3448
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(5):689–700
Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG et al (2006) Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 3:e420
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(2):313–322
Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR (1998) Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. Proc Natl Acad Sci U S A 95(9):5275–5280
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(2):135–145
Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, Kleeberger SR (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 26(2):175–182
Long DJ 2nd, Waikel RL, Wang XJ, Perlaky L, Roop DR, Jaiswal AK (2000) NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis. Cancer Res 60(21):5913–5915
Miyata M, Kudo G, Lee YH, Yang TJ, Gelboin HV, Fernandez-Salguero P, Kimura S, Gonzalez FJ (1999) Targeted disruption of the microsomal epoxide hydrolase gene. Microsomal epoxide hydrolase is required for the carcinogenic activity of 7, 12-dimethylbenz[a]anthracene. J Biol Chem 274(34):23963–23968
Marzec JM, Christie JD, ReddyJedlicka AE, Vuong H, Lanken PN, Aplenc R, Yamamoto T, Yamamoto M, Cho HY, Kleeberger SR (2007) Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J 21(9):2237–2246
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 beta-globin locus control region. Proc Natl Acad Sci U S A 91(21):9926–9930
Zhang J, Hosoya T, Maruyama A, Nishikawa K, Maher JM, Ohta T, Motohashi H, Fukamizu A, Shibahara S, Itoh K, Yamamoto M (2007) Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes. Biochem J 404(3):459–466
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 6:857–868
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(24):10895–10906
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(30):31556–31567
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(34):24756–24768
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(8):2887–2900
Eggler AL, Gay KA, Mesecar AD (2008) Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2. Mol Nutr Food Res 52(Suppl 1):S84–S94
Tong KI, Kobayashi A, Katsuoka F, Yamamoto M (2006) Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism. Biol Chem 387:1311–1320
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(31):28430–28438
Li W, Yu SW, Kong AN (2006) Nrf2 possesses a redox-sensitive nuclear exporting signal in the Neh5 transactivation domain. J Biol Chem 281(37):27251–27263
Jain AK, Bloom DA, Jaiswal AK (2005) Nuclear import and export signals in control of Nrf2. J Biol Chem 280(32):29158–29168
Jain AK, Jaiswal AK (2006) Phosphorylation of tyrosine 568 controls nuclear export of Nrf2. J Biol Chem 281(17):12132–12142
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(18):6139–6150
Theodore M, Kawai Y, Yang J, Kleshchenko Y, Reddy SP, Villalta F, Arinze IJ (2008) Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2. J Biol Chem 283(14):8984–8994
Macara IG (2001) Transport into and out of the nucleus. Microbiol Mol Biol Rev 65(4):570–594
Pemberton LF, Paschal BM (2005) Mechanisms of receptor-mediated nuclear import and nuclear export. Traffic 6(3):187–198
Köhler M, Ansieau S, Prehn S, Leutz A, Haller H, Hartmann E (1997) Cloning of two novel human importin-alpha subunits and analysis of the expression pattern of the importin-alpha protein family. FEBS Lett 417(1):104–108
Köhler M, Speck C, Christiansen M, Bischoff FR, Prehn S, Haller H, Görlich D, Hartmann E (1999) Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import. Mol Cell Biol 19(11):7782–7791
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(22):8137–8151
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(24):10941–10953
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(19):8477–8486
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(3):1089–1099
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(11):4501–4513
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(37):32485–32492
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(10):1163–1178
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(18):6334–6349
Lo SC, Hannink M (2008) PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res 314(8):1789–1803
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 U S A 99(18):11908–11913
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 278:21592–21600
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(16):7130–7139
He X, Chen MG, Lin GX, Ma Q (2006) Arsenic induces NAD(P)H-quinone oxidoreductase I by disrupting the Nrf2 × Keap1 × Cul3 complex and recruiting Nrf2 x Maf to the antioxidant response element enhance. J Biol Chem 281(33):23620–23631
Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479
Ohta T, Michel JJ, Schottelius AJ, Xiong Y (1999) ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell 3(4):535–541
Deshaies RJ (1999) SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol 15:435–467
Goldenberg SJ, Cascio TC, Shumway SD, Garbutt KC, Liu J, Xiong Y, Zheng N (2004) Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases. Cell 119(4):517–528
Cope GA, Deshaies RJ (2003) COP9 signalosome: a multifunctional regulator of SCF and other cullin-based ubiquitin ligases. Cell 114(6):663–671
Min KW, Kwon MJ, Park HS, Park Y, Yoon SK, Yoon JB (2005) CAND1 enhances deneddylation of CUL1 by COP9 signalosome. Biochem Biophys Res Commun 334(3):867–874
Petroski MD, Deshaies RJ (2005) Function and regulation of cullin-RING ubiquitin ligase. Nat Rev Mol Cell Biol 6(1):9–20
Amir RE, Iwai K, Ciechanover A (2002) The NEDD8 pathway is essential for SCF (beta -TrCP)-mediated ubiquitination and processing of the NF-kappa B precursor p105. J Biol Chem 277(26):23253–23259
Kawakami T, Chiba T, Suzuki T, Iwai K, Yamanaka K, Minato N, Suzuki H, Shimbara N, Hidaka Y, Osaka F, Omata M, Tanaka K (2001) NEDD8 recruits E2-ubiquitin to SCF E3 ligase. EMBO J 20(15):4003–4012
Gan-Erdene T, Nagamalleswari K, Yin L, Wu K, Pan ZQ, Wilkinson KD (2003) Identification and characterization of DEN1, a deneddylase of the ULP family. J Biol Chem 278(31):28892–28900
Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Shevchenko A, Deshaies RJ (2001) Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science 292(5520):1382–1385
Cope GA, Suh GS, Aravind L, Schwarz SE, Zipursky SL, Koonin EV, Deshaies R (2002) Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science 298(5593):608–611
Zhang J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke-Andersen K, Wei N, Sun H, Kobayashi R, Zhang H (2002) CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol Cell 10(6):1519–1526
Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (2003) TIP120A associates with cullins and modulates ubiquitin ligase activity. J Biol Chem 278(18):15905–15910
Lo SC, Hannink M (2006) CAND1-mediated substrate adaptor recycling is required for efficient repression of Nrf2 by Keap1. Mol Cell Biol 26(4):1235–1244
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 U S A 101(7):2040–2045
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(15):3605–3617
Fabbro M, Henderson BR (2003) Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp Cell Res 282(2):59–69
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(21):14841–14851
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 U S A 102(29):10070–10075
Luo Y, Eggler AL, Liu D, Liu G, Mesecar AD, van Breemen RB (2007) Sites of alkylation of human Keap1 by natural chemoprevention agents. J Am Soc Mass Spectrom 18(12):2226–2232
Eggler AL, Luo Y, van Breemen RB, Mesecar AD (2007) Identification of the highly reactive cysteine 151 in the chemopreventive agent-sensor Keap1 protein is method-dependent. Chem Res Toxicol 20(12):1878–1884
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(4):2529–2537
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(34):30091–30099
Hong F, Sekhar KR, Freeman ML, Liebler DC (2005) Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation. J Biol Chem 280(36):31768–31775
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(1):298–309
Tanigawa S, Fujii M, Hou DX (2007) Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 42(11):1690–1703
Clerk A, Sugden PH (2001) Untangling the Web: specific signaling from PKC isoforms to MAPK cascades. Circ Res 89(10):847–849
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(12):1797–1806
Apopa PL, He X, Ma Q (2008) Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells. J Biochem Mol Toxicol 22(1):63–76
Numazawa S, Ishikawa M, Yoshida A, Tanaka S, Yoshida T (2003) Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress. Am J Physiol Cell Physiol 285(2):C334–C342
Li B, Ishii T, Tan CP, Soh JW, Goff SP (2002) Pathways of induction of peroxiredoxin I expression in osteoblasts: roles of p38 mitogen-activated protein kinase and protein kinase C. J Biol Chem 277(14):12418–12422
Li B, Wang X, Rasheed N, Hu Y, Boast S, Ishii T, Nakayama K, Nakayama KI, Goff SP (2004) Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C delta. Genes Dev 18(15):1824–1837
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(45):42769–42774
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(45):44675–44682
Keum YS, Yu S, Chang PP, Yuan X, Kim JH, Xu C, Han J, Agarwal A, Kong AN (2006) Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells. Cancer Res 66(17):8804–8813
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(20):7198–7209
Zipper LM, Mulcahy RT (2003) Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells. Toxicol Sci 73(1):124–134
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(36):27694–27702
Kang KW, Ryu JH, Kim SG (2000) The essential role of phosphatidylinositol 3-kinase and of p38 mitogen-activated protein kinase activation in the antioxidant response element-mediated rGSTA2 induction by decreased glutathione in H4IIE hepatoma cell. Mol Pharmacol 58(5):1017–1025
Martin D, Rojo AI, Salinas M, Diaz R, Gallardo G, Alam J, De Galarreta CM, Cuadrado A (2004) 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(10):8919–8929
Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J (2005) Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 83(2):313–328
Nakaso K, Yano H, Fukuhara Y, Takeshima T, Wada-Isoe K, Nakashima K (2003) PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett 546:181–184
Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65(4):391–426
Jain AK, Jaiswal AK (2007) GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem 282(22):16502–16510
Jaiswal AK (2004) Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 36(10):1199–1207
Lee TD, Yang H, Whang J, Lu SC (2005) Cloning and characterization of the human glutathione synthetase 5′-flanking region. Biochem J 390(Pt 2):521–528
Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88
Bloom D, Dhakshinamoorthy S, Jaiswal AK (2002) Site-directed mutagenesis of cysteine to serine in the DNA binding region of Nrf2 decreases its capacity to upregulate antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 21(14):2191–2200
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(3):238–245
Acknowledgments
THE authors would like to specially thank Dr. Alessandra Trocino, Lybrarians of the National Cancer Institute, Naples, for providing them excellent bibliographic services and assistance.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Giudice, A., Arra, C., Turco, M.C. (2010). Review of Molecular Mechanisms Involved in the Activation of the Nrf2-ARE Signaling Pathway by Chemopreventive Agents. In: Higgins, P. (eds) Transcription Factors. Methods in Molecular Biology, vol 647. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-738-9_3
Download citation
DOI: https://doi.org/10.1007/978-1-60761-738-9_3
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60761-737-2
Online ISBN: 978-1-60761-738-9
eBook Packages: Springer Protocols