title: Genetic analysis of cytoprotective functions supported by graded expression of Keap1.
abstract: Keap1 regulates Nrf2 activity in response to xenobiotic and oxidative stresses. Nrf2 is an essential regulator of cytoprotective genes. Keap1-null mice are lethal by weaning age due to malnutrition caused by severe hyperkeratosis of the upper digestive tract. Analysis of Keap1::Nrf2 double mutant mice revealed that currently recognizable phenotypes of Keap1-null mice are all attributable to constitutive activation of Nrf2. We previously reported that hepatocyte-specific Keap1 knockout (Keap1(flox/-)::Albumin-Cre) mice are viable and more resistant to acute toxicity of acetaminophen (APAP). In the current study, we found that the floxed Keap1 allele is hypomorphic and that Keap1 expression was decreased in all examined tissues of Keap1(flox/-) mice. Taking advantage of the hypomorphic phenotype of Keap1(flox/-) mice, we examined the effects of graded reduction of Keap1 expression in adult mice. When challenged with APAP, Keap1(flox/-) mice were more protected from mortality than wild-type and even Keap1(flox/-)::Albumin-Cre mice. In contrast, a decrease in Keap1 levels to less than 50% resulted in increased mortality in a study of 2-year-old mice. These results support our contention that the benefits of Nrf2 activation in acute toxicity are hormetic and that constitutive Nrf2 activation beyond a certain threshold is rather disadvantageous to long-term survival.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Maher
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yukie
authors.initials: Y
authors.lastname: Kawatani
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000187:drug effects / Q000473:pathology; D000483:Alleles; D000818:Animals; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000187:drug effects; D004947:Esophagus / Q000187:drug effects / Q000473:pathology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis; D013997:Time Factors; D023382:Toxicity Tests, Acute; D019076:Transgenes / Q000235:genetics; D014886:Weaning
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D000082:Acetaminophen; C045073:Cre recombinase; D019426:Integrases
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13943-8
references.pmid: 8943040
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3410-5
references.pmid: 11248092
references.citation: Mol Cell Biol. 1993 Jun;13(6):3176-90
references.pmid: 7684490
references.citation: Nat Genet. 2003 Nov;35(3):238-45
references.pmid: 14517554
references.citation: Cancer Res. 2002 Sep 15;62(18):5196-203
references.pmid: 12234984
references.citation: PLoS Med. 2006 Oct;3(10):e420
references.pmid: 17020408
references.citation: Cancer Res. 2006 Dec 15;66(24):11580-4
references.pmid: 17178849
references.citation: Hepatology. 2007 Nov;46(5):1597-610
references.pmid: 17668877
references.citation: Alcohol Clin Exp Res. 2007 Jun;31(6):1053-60
references.pmid: 17428293
references.citation: Curr Top Cell Regul. 2000;36:95-116
references.pmid: 10842748
references.citation: Biol Chem. 2006 Oct-Nov;387(10-11):1311-20
references.pmid: 17081101
references.citation: Toxicol Sci. 2001 Jan;59(1):169-77
references.pmid: 11134556
references.citation: Genes Cells. 2007 Oct;12(10):1163-78
references.pmid: 17903176
references.citation: Arch Biochem Biophys. 2005 Jan 15;433(2):342-50
references.pmid: 15581590
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4611-6
references.pmid: 11287661
references.citation: Mol Pharmacol. 2006 May;69(5):1554-63
references.pmid: 16449384
references.citation: Toxicol Appl Pharmacol. 2001 Jun 15;173(3):154-60
references.pmid: 11437637
references.citation: Chem Res Toxicol. 2005 Dec;18(12):1917-26
references.pmid: 16359182
references.citation: Mol Cell Biol. 2009 Jan;29(2):493-502
references.pmid: 19001094
references.citation: Mol Cell Biol. 2004 Aug;24(16):7130-9
references.pmid: 15282312
references.citation: Nat Cell Biol. 2010 Mar;12(3):213-23
references.pmid: 20173742
references.citation: Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
references.pmid: 9240432
references.citation: Arch Biochem Biophys. 2008 Sep 1;477(1):139-45
references.pmid: 18585365
references.citation: Am J Pathol. 2006 Oct;169(4):1118-28
references.pmid: 17003472
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11908-13
references.pmid: 12193649
references.citation: Carcinogenesis. 2010 Jan;31(1):90-9
references.pmid: 19793802
references.citation: Cancer Res. 2008 Mar 1;68(5):1303-9
references.pmid: 18316592
references.citation: Biochem Biophys Res Commun. 2006 Jan 6;339(1):79-88
references.pmid: 16293230
references.citation: Mol Cell Biol. 2008 Apr;28(8):2758-70
references.pmid: 18268004
references.citation: Mol Cell. 2009 Jun 26;34(6):663-73
references.pmid: 19560419
references.citation: Biochem Biophys Res Commun. 2003 Oct 24;310(3):824-9
references.pmid: 14550278
references.citation: Mol Cell Biol. 2006 May;26(10):3773-84
references.pmid: 16648473
references.citation: Mol Cell Biol. 2007 Oct;27(20):7188-97
references.pmid: 17709388
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7400-5
references.pmid: 9207103
references.citation: Mol Cell. 2006 Mar 3;21(5):689-700
references.pmid: 16507366
references.citation: Biochem Biophys Res Commun. 2006 Dec 29;351(4):883-9
references.pmid: 17097057
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13568-73
references.pmid: 18757741
references.citation: Genes Dev. 1999 Jan 1;13(1):76-86
references.pmid: 9887101
references.citation: J Biol Chem. 2005 Sep 9;280(36):31768-75
references.pmid: 15985429
references.citation: Mol Cell. 2009 Oct 9;36(1):131-40
references.pmid: 19818716
references.citation: J Biol Chem. 2003 Mar 7;278(10):8135-45
references.pmid: 12506115
references.citation: Trends Mol Med. 2004 Nov;10(11):549-57
references.pmid: 15519281
references.citation: J Am Soc Mass Spectrom. 2007 Dec;18(12):2226-32
references.pmid: 17980616
references.citation: Genes Cells. 2005 Dec;10(12):1113-25
references.pmid: 16324149
references.citation: Drug Metab Dispos. 2005 Jul;33(7):956-62
references.pmid: 15833929
references.citation: Sci Signal. 2010 Mar 09;3(112):re3
references.pmid: 20215646