Home LiteratureArticle Details
PMID: 20367496 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

When NRF2 talks, who's listening?

Antioxidants & redox signaling ·Vol. 13 ·No. 11 ·2010-12-01 ·Pages 1649-63

Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW

Abstract

Activation of the KEAP1-NRF2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl-reactive, small-molecule pharmacologic agents, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor to antioxidant response elements in the promoter regions of target genes. However, it is becoming evident that some of the protective effects may be mediated indirectly through cross talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses. This review highlights recent observations on the molecular interactions and their functional consequences between NRF2 and the arylhydrocarbon receptor (AhR), NF-κB, p53, and Notch1 signaling pathways.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Animals Cell Survival Humans Intracellular Signaling Peptides and Proteins/metabolism Kelch-Like ECH-Associated Protein 1 Mice Mice, Knockout NF-E2-Related Factor 2/genetics,metabolism NF-kappa B/genetics,metabolism Neoplasms/metabolism,prevention & control Receptor, Notch1/metabolism Receptors, Aryl Hydrocarbon/genetics,metabolism Response Elements Signal Transduction Transcription Factors/metabolism Tumor Suppressor Protein p53/metabolism
Chemicals
Adaptor Proteins, Signal Transducing Intracellular Signaling Peptides and Proteins KEAP1 protein, human Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 NF-kappa B Receptor, Notch1 Receptors, Aryl Hydrocarbon Transcription Factors Tumor Suppressor Protein p53
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wakabayashi Nobunao
Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pennsylvania 15261, USA.
Slocum Stephen L
Skoko John J
Shin Soona
Kensler Thomas W
References (168)
168 references, click to expand
  1. WAF1, a potential mediator of p53 tumor suppression.
    Cell. 1993 Nov 19;75(4):817-25 PMID: 8242752
  2. A Notch updated.
    J Cell Biol. 2009 Mar 9;184(5):621-9 PMID: 19255248
  3. Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK.
    J Biol Chem. 2000 May 19;275(20):15466-73 PMID: 10747902
  4. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis.
    J Clin Invest. 2006 Apr;116(4):984-95 PMID: 16585964
  5. Role of 15-deoxy delta(12,14) prostaglandin J2 and Nrf2 pathways in protection against acute lung injury.
    Am J Respir Crit Care Med. 2005 Jun 1;171(11):1260-6 PMID: 15750045
  6. 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. 2001 May 25;276(21):18399-406 PMID: 11279008
  7. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase.
    Nature. 2007 Mar 29;446(7135):562-6 PMID: 17392787
  8. The PAS superfamily: sensors of environmental and developmental signals.
    Annu Rev Pharmacol Toxicol. 2000;40:519-61 PMID: 10836146
  9. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway.
    Annu Rev Pharmacol Toxicol. 2007;47:89-116 PMID: 16968214
  10. Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms.
    J Biol Chem. 2001 Aug 24;276(34):32008-15 PMID: 11410599
  11. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.
    J Exp Med. 2005 Jul 4;202(1):47-59 PMID: 15998787
  12. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression.
    Am J Physiol Heart Circ Physiol. 2006 May;290(5):H1862-70 PMID: 16339837
  13. 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. 2001 Mar 13;98(6):3410-5 PMID: 11248092
  14. Altered signalling and gene expression associated with the immune system and the inflammatory response in obesity.
    Br J Nutr. 2007 Oct;98 Suppl 1:S121-6 PMID: 17922949
  15. Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages.
    Biochem Pharmacol. 2000 Dec 1;60(11):1665-76 PMID: 11077049
  16. Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance.
    EMBO J. 2008 Jan 9;27(1):212-23 PMID: 18059474
  17. Regulation of notch1 signaling by nrf2: implications for tissue regeneration.
    Sci Signal. 2010 Jul 13;3(130):ra52 PMID: 20628156
  18. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver.
    FASEB J. 2004 May;18(7):854-6 PMID: 15001560
  19. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway.
    Mol Cell Biol. 2003 Dec;23(23):8786-94 PMID: 14612418
  20. NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet.
    J Pharmacol Exp Ther. 2008 May;325(2):655-64 PMID: 18281592
  21. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.
    Planta Med. 2008 Oct;74(13):1526-39 PMID: 18937164
  22. Gliotoxin reduces the severity of trinitrobenzene sulfonic acid-induced colitis in mice: evidence of the connection between heme oxygenase-1 and the nuclear factor-kappaB pathway in vitro and in vivo.
    Inflamm Bowel Dis. 2006 Jul;12(7):619-29 PMID: 16804400
  23. The Notch-responsive transcription factor Hes-1 attenuates osteocalcin promoter activity in osteoblastic cells.
    J Cell Biochem. 2009 Oct 15;108(3):651-9 PMID: 19670267
  24. Notch signaling in gastrointestinal tract (review).
    Int J Oncol. 2007 Jan;30(1):247-51 PMID: 17143535
  25. I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity.
    EMBO J. 1997 Mar 17;16(6):1413-26 PMID: 9135156
  26. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2.
    Mol Cell Biol. 2004 Aug;24(16):7130-9 PMID: 15282312
  27. Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C.
    J Immunol. 2005 Oct 1;175(7):4408-15 PMID: 16177082
  28. c-Jun NH2-terminal kinase-mediated redox-dependent degradation of IkappaB: role of thioredoxin in NF-kappaB activation.
    J Biol Chem. 2001 Feb 16;276(7):4662-70 PMID: 11063742
  29. Defective function of the proteasome in autoimmunity: involvement of impaired NF-kappaB activation.
    Diabetes Technol Ther. 2000 Autumn;2(3):415-28 PMID: 11467344
  30. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development.
    Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6731-6 PMID: 8692887
  31. IKK mediates ischemia-induced neuronal death.
    Nat Med. 2005 Dec;11(12):1322-9 PMID: 16286924
  32. Redox activation of p21Cip1/WAF1/Sdi1: a multifunctional regulator of cell survival and death.
    Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):108-18 PMID: 15650400
  33. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice.
    Carcinogenesis. 2009 Jun;30(6):1024-31 PMID: 19386581
  34. Notch signaling in osteoblasts.
    Sci Signal. 2008 Apr 29;1(17):pe17 PMID: 18445833
  35. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation.
    Nat Genet. 2003 Nov;35(3):238-45 PMID: 14517554
  36. Transcriptional activation of the human Galphai2 gene promoter through nuclear factor-kappaB and antioxidant response elements.
    J Biol Chem. 2005 Mar 18;280(11):9786-95 PMID: 15640523
  37. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells.
    Cell. 1979 May;17(1):43-52 PMID: 222475
  38. NQO1 and NQO2 regulation of humoral immunity and autoimmunity.
    J Biol Chem. 2006 Oct 13;281(41):30917-24 PMID: 16905546
  39. Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile.
    Life Sci. 2007 Mar 20;80(15):1420-30 PMID: 17320913
  40. I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B.
    Cell. 1995 Feb 24;80(4):573-82 PMID: 7867065
  41. Conservation of the Notch signalling pathway in mammalian neurogenesis.
    Development. 1997 Mar;124(6):1139-48 PMID: 9102301
  42. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.
    Nat Med. 2000 Apr;6(4):422-8 PMID: 10742149
  43. Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling.
    Oncogene. 2008 Oct 2;27(44):5821-32 PMID: 18542053
  44. Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction.
    Biochem J. 2004 Jan 1;377(Pt 1):205-13 PMID: 14510636
  45. 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 U S A. 2005 Sep 27;102(39):14010-5 PMID: 16172382
  46. Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE).
    Drug Metab Rev. 2001 Aug-Nov;33(3-4):255-71 PMID: 11768769
  47. The bHLH gene Hes1 regulates differentiation of multiple cell types.
    Mol Cells. 2000 Feb 29;10(1):1-7 PMID: 10774739
  48. Super-induction of HO-1 in macrophages stimulated with lipopolysaccharide by prior depletion of glutathione decreases iNOS expression and NO production.
    Nitric Oxide. 2005 Mar;12(2):70-9 PMID: 15740980
  49. The transcriptional basis of adipocyte development.
    Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):31-4 PMID: 15936931
  50. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179.
    J Biol Chem. 2006 Nov 24;281(47):35764-9 PMID: 16998237
  51. Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene.
    Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5987-91 PMID: 8016102
  52. p53 in recombination and repair.
    Cell Death Differ. 2006 Jun;13(6):1003-16 PMID: 16543940
  53. Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16505-10 PMID: 19805328
  54. Mutations in NOTCH1 cause aortic valve disease.
    Nature. 2005 Sep 8;437(7056):270-4 PMID: 16025100
  55. Notch1-expressing cells are indispensable for prostatic branching morphogenesis during development and re-growth following castration and androgen replacement.
    J Biol Chem. 2004 Jun 4;279(23):24733-44 PMID: 15028713
  56. Expression of Notch pathway components in fetal and adult mouse small intestine.
    Gene Expr Patterns. 2002 Dec;2(3-4):247-50 PMID: 12617809
  57. Oxidoreductive regulation of nuclear factor kappa B. Involvement of a cellular reducing catalyst thioredoxin.
    J Biol Chem. 1993 May 25;268(15):11380-8 PMID: 8496188
  58. Intracellular assembly of inducible NO synthase is limited by nitric oxide-mediated changes in heme insertion and availability.
    J Biol Chem. 1996 Mar 8;271(10):5414-21 PMID: 8621396
  59. Differential transcriptional activation in vitro by NF-kappa B/Rel proteins.
    J Biol Chem. 1995 Feb 17;270(7):3123-31 PMID: 7852394
  60. HES and HERP families: multiple effectors of the Notch signaling pathway.
    J Cell Physiol. 2003 Mar;194(3):237-55 PMID: 12548545
  61. Activators and target genes of Rel/NF-kappaB transcription factors.
    Oncogene. 1999 Nov 22;18(49):6853-66 PMID: 10602461
  62. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase.
    Proc Natl Acad Sci U S A. 1968 Oct;61(2):748-55 PMID: 4386763
  63. Loss of dioxin-receptor expression accelerates wound healing in vivo by a mechanism involving TGFbeta.
    J Cell Sci. 2009 Jun 1;122(Pt 11):1823-33 PMID: 19435800
  64. Nitric oxide mediates the lipopolysaccharide dependent upregulation of the heme oxygenase-1 gene expression in cultured rat Kupffer cells.
    J Hepatol. 1999 Jan;30(1):61-9 PMID: 9927151
  65. Introducing the "TCDD-inducible AhR-Nrf2 gene battery".
    Toxicol Sci. 2009 Oct;111(2):238-46 PMID: 19474220
  66. NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK.
    Biochim Biophys Acta. 2008 May;1783(5):713-27 PMID: 18241676
  67. Rel/NF-kappa B/I kappa B signal transduction in the generation and treatment of human cancer.
    Cancer Lett. 2002 Jul 8;181(1):1-9 PMID: 12430173
  68. Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway.
    Cancer Res. 2008 Jan 15;68(2):364-8 PMID: 18199529
  69. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands.
    Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13481-6 PMID: 19651607
  70. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models.
    Environ Health Perspect. 1995 Oct;103(10):942-50 PMID: 8529591
  71. Expression of notch receptors and ligands in the adult gut.
    J Histochem Cytochem. 2004 Apr;52(4):509-16 PMID: 15034002
  72. Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response.
    Mol Cell. 2009 Jun 26;34(6):663-73 PMID: 19560419
  73. Arylhydrocarbon receptor (AhR) is involved in negative regulation of adipose differentiation in 3T3-L1 cells: AhR inhibits adipose differentiation independently of dioxin.
    J Cell Sci. 2001 Aug;114(Pt 15):2809-17 PMID: 11683414
  74. 3-Hydroxyanthranilic acid, one of L-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells.
    Atherosclerosis. 2006 Aug;187(2):274-84 PMID: 16246346
  75. 3H-1,2-dithiole-3-thione targets nuclear factor kappaB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats.
    J Pharmacol Exp Ther. 2006 Apr;317(1):61-7 PMID: 16371450
  76. Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes.
    Toxicol Sci. 2009 Nov;112(1):257-72 PMID: 19692669
  77. Iron regulates nitric oxide synthase activity by controlling nuclear transcription.
    J Exp Med. 1994 Sep 1;180(3):969-76 PMID: 7520477
  78. Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor gamma in macrophages via an interaction with NRF2.
    J Biol Chem. 2000 Oct 20;275(42):33142-50 PMID: 10930400
  79. Distinct NF-kappa B/Rel transcription factors are responsible for tissue-specific and inducible gene activation.
    Nature. 1993 Oct 21;365(6448):767-70 PMID: 7692309
  80. Therapeutic approaches for control of transcription factors in allergic disease.
    J Allergy Clin Immunol. 2008 Apr;121(4):803-9; quiz 810-1 PMID: 18395546
  81. Genetic susceptibility and regulation of inflammation in Crohn's disease. Relationship with the innate immune system.
    Rev Esp Enferm Dig. 2002 Jun;94(6):351-60 PMID: 12432592
  82. 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 U S A. 1996 Dec 10;93(25):14960-5 PMID: 8962164
  83. 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. 2002 May;22(9):2883-92 PMID: 11940647
  84. Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis.
    J Cell Sci. 1998 Nov;111 ( Pt 22):3311-22 PMID: 9788873
  85. Small-molecule inhibitors of NF-kappaB for the treatment of inflammatory joint disease.
    Curr Opin Pharmacol. 2002 Jun;2(3):316-21 PMID: 12020477
  86. Lipopolysaccharide-induced expression of NAD(P)H:quinone oxidoreductase 1 and heme oxygenase-1 protects against excessive inflammatory responses in human monocytes.
    J Immunol. 2008 Nov 15;181(10):6730-7 PMID: 18981090
  87. Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1.
    Mol Cell Biol. 2005 Jul;25(14):5933-46 PMID: 15988009
  88. Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.
    J Biol Chem. 2005 May 27;280(21):20340-8 PMID: 15790560
  89. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB.
    Nature. 1997 Aug 7;388(6642):548-54 PMID: 9252186
  90. Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1.
    Am J Pathol. 2004 Apr;164(4):1347-59 PMID: 15039222
  91. Genomewide analysis of aryl hydrocarbon receptor binding targets reveals an extensive array of gene clusters that control morphogenetic and developmental programs.
    Environ Health Perspect. 2009 Jul;117(7):1139-46 PMID: 19654925
  92. Functional analysis of Hes-1 in preadipocytes.
    Mol Endocrinol. 2006 Mar;20(3):698-705 PMID: 16282371
  93. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2).
    Mol Cell Biol. 2004 Jan;24(1):36-45 PMID: 14673141
  94. Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis.
    Carcinogenesis. 2007 Nov;28(11):2398-403 PMID: 17602169
  95. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity.
    Cell. 1996 Mar 22;84(6):853-62 PMID: 8601309
  96. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis.
    Mol Cell Biol. 2007 Oct;27(20):7188-97 PMID: 17709388
  97. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism.
    J Biol Chem. 2003 Jan 10;278(2):703-11 PMID: 12370194
  98. Heme oxygenase-1 inhibits the expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation at serine 276.
    J Immunol. 2007 Dec 1;179(11):7840-51 PMID: 18025230
  99. Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis.
    Br J Cancer. 2008 Dec 16;99(12):2070-82 PMID: 19050705
  100. The aryl hydrocarbon receptor functions as a tumor suppressor of liver carcinogenesis.
    Cancer Res. 2010 Jan 1;70(1):212-20 PMID: 19996281
  101. Atherosclerosis: a cancer of the blood vessels?
    Am J Clin Pathol. 2001 Dec;116 Suppl:S97-107 PMID: 11993705
  102. NF-kappaB, Nrf2, and HO-1 interplay in redox-regulated VCAM-1 expression.
    Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):889-99 PMID: 15998244
  103. Transcription factor NF-kappaB: a sensor for smoke and stress signals.
    Ann N Y Acad Sci. 2005 Nov;1056:218-33 PMID: 16387690
  104. Histone deacetylase 3 binds to and regulates the GCMa transcription factor.
    Nucleic Acids Res. 2006 Mar 09;34(5):1459-69 PMID: 16528103
  105. Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation.
    J Immunol. 2004 Mar 15;172(6):3553-63 PMID: 15004156
  106. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.
    Science. 2001 Aug 31;293(5535):1673-7 PMID: 11533494
  107. ERRbeta: a potent inhibitor of Nrf2 transcriptional activity.
    Mol Cell Endocrinol. 2007 Nov 15;278(1-2):52-62 PMID: 17920186
  108. Nuclear factor E2 p45-related factor 2 negatively regulates chondrogenesis.
    Bone. 2007 Feb;40(2):337-44 PMID: 17029980
  109. Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse.
    Biochem Biophys Res Commun. 2003 Mar 28;303(1):105-11 PMID: 12646173
  110. p53 and Nur77/TR3 - transcription factors that directly target mitochondria for cell death induction.
    Oncogene. 2006 Aug 7;25(34):4725-43 PMID: 16892086
  111. p53 suppresses the Nrf2-dependent transcription of antioxidant response genes.
    J Biol Chem. 2006 Dec 29;281(52):39776-84 PMID: 17077087
  112. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice.
    Nat Med. 2002 Mar;8(3):240-6 PMID: 11875494
  113. Activation of the Nrf2/antioxidant response pathway increases IL-8 expression.
    Eur J Immunol. 2005 Nov;35(11):3258-67 PMID: 16220540
  114. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound.
    Mol Cell Biol. 2002 Aug;22(15):5492-505 PMID: 12101242
  115. Cytoplasmic functions of the tumour suppressor p53.
    Nature. 2009 Apr 30;458(7242):1127-30 PMID: 19407794
  116. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome.
    Blood. 2002 Apr 1;99(7):2369-78 PMID: 11895769
  117. Distinct roles of thioredoxin in the cytoplasm and in the nucleus. A two-step mechanism of redox regulation of transcription factor NF-kappaB.
    J Biol Chem. 1999 Sep 24;274(39):27891-7 PMID: 10488136
  118. Diagnosing and exploiting cancer's addiction to blocks in apoptosis.
    Nat Rev Cancer. 2008 Feb;8(2):121-32 PMID: 18202696
  119. AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions.
    Biochem Pharmacol. 2009 Feb 15;77(4):474-84 PMID: 18838062
  120. Nuclear factor kappaB transactivation is increased but is not involved in the proliferative effects of thioredoxin overexpression in MCF-7 breast cancer cells.
    Cancer Res. 1999 Aug 15;59(16):4090-4 PMID: 10463612
  121. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids.
    Mol Cell Biol. 1996 Aug;16(8):4128-36 PMID: 8754811
  122. Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses.
    J Exp Med. 2009 Aug 31;206(9):2027-35 PMID: 19703987
  123. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.
    Nature. 2000 Jan 6;403(6765):103-8 PMID: 10638762
  124. NF-kappa B subunit-specific regulation of the interleukin-8 promoter.
    Mol Cell Biol. 1993 Oct;13(10):6137-46 PMID: 8413215
  125. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.
    EMBO J. 2001 Jul 2;20(13):3427-36 PMID: 11432830
  126. Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2.
    Biochem Pharmacol. 2007 Jun 15;73(12):1853-62 PMID: 17266942
  127. Interaction of bilirubin and biliverdin with reactive nitrogen species.
    FEBS Lett. 2003 May 22;543(1-3):113-9 PMID: 12753916
  128. Ethanol-induced expression of glutamate-cysteine ligase catalytic subunit gene is mediated by NF-kappaB.
    Toxicol Lett. 2009 Mar 10;185(2):110-5 PMID: 19133322
  129. Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62.
    Nucleic Acids Res. 1992 Aug 11;20(15):3821-30 PMID: 1508666
  130. Constitutive and beta-naphthoflavone-induced expression of the human gamma-glutamylcysteine synthetase heavy subunit gene is regulated by a distal antioxidant response element/TRE sequence.
    J Biol Chem. 1997 Mar 14;272(11):7445-54 PMID: 9054446
  131. Solution structure of human thioredoxin in a mixed disulfide intermediate complex with its target peptide from the transcription factor NF kappa B.
    Structure. 1995 Mar 15;3(3):289-97 PMID: 7788295
  132. Purified human I kappa B can rapidly dissociate the complex of the NF-kappa B transcription factor with its cognate DNA.
    Cell. 1990 Apr 20;61(2):255-65 PMID: 2184941
  133. Multiple functions of Notch signaling in self-renewing organs and cancer.
    FEBS Lett. 2006 May 22;580(12):2860-8 PMID: 16574107
  134. A new p21waf1/cip1 isoform is an early event of cell response to oxidative stress.
    Cell Death Differ. 1998 Nov;5(11):940-5 PMID: 9846180
  135. Genetic dissection of the Nrf2-dependent redox signaling-regulated transcriptional programs of cell proliferation and cytoprotection.
    Physiol Genomics. 2007 Dec 19;32(1):74-81 PMID: 17895394
  136. Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo.
    Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):741-7 PMID: 17255530
  137. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration.
    Hepatology. 2004 Apr;39(4):1056-65 PMID: 15057910
  138. Notch signals control the fate of immature progenitor cells in the intestine.
    Nature. 2005 Jun 16;435(7044):964-8 PMID: 15959516
  139. p53 mutations in human cancers.
    Science. 1991 Jul 5;253(5015):49-53 PMID: 1905840
  140. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells.
    J Biol Chem. 2005 Jul 22;280(29):27244-50 PMID: 15917255
  141. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival.
    J Biol Chem. 2003 Mar 7;278(10):8135-45 PMID: 12506115
  142. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver.
    Cancer Res. 1988 Sep 1;48(17):4776-82 PMID: 3409219
  143. A dominant function of IKK/NF-kappaB signaling in global lipopolysaccharide-induced gene expression.
    J Biol Chem. 2006 Oct 13;281(41):31142-51 PMID: 16914552
  144. p21(WAF1/Cip1): more than a break to the cell cycle?
    Biochim Biophys Acta. 2000 Jul 31;1471(1):M43-56 PMID: 10967424
  145. Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2.
    Free Radic Biol Med. 2005 Jul 15;39(2):227-36 PMID: 15964514
  146. The antioxidant function of the p53 tumor suppressor.
    Nat Med. 2005 Dec;11(12):1306-13 PMID: 16286925
  147. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
    Cell. 1993 Nov 19;75(4):805-16 PMID: 8242751
  148. The chemopreventive agent oltipraz stimulates repair of damaged DNA.
    Cancer Res. 1997 Mar 15;57(6):1050-3 PMID: 9067269
  149. Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling.
    Pulm Pharmacol Ther. 2009 Jun;22(3):221-36 PMID: 19138753
  150. Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease.
    Am J Respir Crit Care Med. 2009 Jan 15;179(2):138-50 PMID: 18931336
  151. Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation.
    J Biol Chem. 2006 Jun 30;281(26):18015-24 PMID: 16613847
  152. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide.
    Eur J Pharmacol. 2009 Oct 12;620(1-3):138-44 PMID: 19698707
  153. Repression of cancer protective genes by 17beta-estradiol: ligand-dependent interaction between human Nrf2 and estrogen receptor alpha.
    Mol Cell Endocrinol. 2005 Nov 24;243(1-2):27-34 PMID: 16198475
  154. Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions.
    J Biol Chem. 1997 Jul 18;272(29):18411-7 PMID: 9218484
  155. TIGAR, a p53-inducible regulator of glycolysis and apoptosis.
    Cell. 2006 Jul 14;126(1):107-20 PMID: 16839880
  156. 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. 2007 Dec 4;104(49):19589-94 PMID: 18048326
  157. H2O2-dependent activation of GCLC-ARE4 reporter occurs by mitogen-activated protein kinase pathways without oxidation of cellular glutathione or thioredoxin-1.
    J Biol Chem. 2004 Feb 13;279(7):5837-45 PMID: 14638694
  158. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer.
    Trends Biochem Sci. 2009 Apr;34(4):176-88 PMID: 19321346
  159. Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors.
    Mutat Res. 2004 Nov 2;555(1-2):149-71 PMID: 15476858
  160. Characterization of Nrf2 activation and heme oxygenase-1 expression in NIH3T3 cells exposed to aqueous extracts of cigarette smoke.
    Free Radic Biol Med. 2005 Dec 1;39(11):1438-48 PMID: 16274879
  161. Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli.
    EMBO J. 1995 Jun 15;14(12):2876-83 PMID: 7796813
  162. p21 is a universal inhibitor of cyclin kinases.
    Nature. 1993 Dec 16;366(6456):701-4 PMID: 8259214
  163. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1.
    Nature. 2000 Jun 22;405(6789):966-70 PMID: 10879540
  164. NF-kappaB in neuronal plasticity and neurodegenerative disorders.
    J Clin Invest. 2001 Feb;107(3):247-54 PMID: 11160145
  165. Influence of Nrf2 genotype on pulmonary NF-kappaB activity and inflammatory response after traumatic brain injury.
    Ann Clin Lab Sci. 2008 Summer;38(3):221-7 PMID: 18715849
  166. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis.
    Mol Cancer Ther. 2002 Jun;1(8):639-49 PMID: 12479224
  167. NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages.
    J Biol Chem. 2006 Sep 8;281(36):26041-50 PMID: 16835236
  168. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene.
    J Biol Chem. 1999 Sep 10;274(37):26071-8 PMID: 10473555
Article Info
Journal
Antioxidants & redox signaling
Abbr.
Antioxid Redox Signal
ISSN
1557-7716
DOI
10.1089/ars.2010.3216
Published
2010-12-01
Epub
2010-00-09
Pages
1649-63
Language
English
Region
United States
NLM ID
100888899
PMCID
PMC2966480
Subset
IM
Grants
NCI NIH HHS · CA39416 · United States
NCI NIH HHS · T32 CA009110 · United States
NCI NIH HHS · R01 CA094076 · United States
NCI NIH HHS · R01 CA039416 · United States
NCI NIH HHS · CA94076 · United States
NIEHS NIH HHS · T32 ES07141 · United States
NIGMS NIH HHS · T32 GM08763 · United States
External Links
PubMed source DOI: 10.1089/ars.2010.3216 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2