title: Hepatic response to oxidative injury in long-lived Ames dwarf mice.
abstract: Multiple stress resistance pathways were evaluated in the liver of Ames dwarf mice before and after exposure to the oxidative toxin diquat, seeking clues to the exceptional longevity conferred by this mutation. Before diquat treatment, Ames dwarf mice, compared with nonmutant littermate controls, had 2- to 6-fold higher levels of expression of mRNAs for immediate early genes and 2- to 5-fold higher levels of mRNAs for genes dependent on the transcription factor Nrf2. Diquat led to a 2-fold increase in phosphorylation of the stress kinase ERK in control (but not Ames dwarf) mice and to a 50% increase in phosphorylation of the kinase JNK2 in Ames dwarf (but not control) mice. Diquat induction of Nrf2 protein was higher in dwarf mice than in controls. Of 6 Nrf2-responsive genes evaluated, 4 (HMOX, NQO-1, MT-1, and MT-2) remained 2- to 10-fold lower in control than in dwarf liver after diquat, and the other 2 (GCLM and TXNRD) reached levels already seen in dwarf liver at baseline. Thus, livers of Ames dwarf mice differ systematically from controls in multiple stress resistance pathways before and after exposure to diquat, suggesting mechanisms for stress resistance and extended longevity in Ames dwarf mice.
authors.affiliation: Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109-0940, USA.
authors.forename: Liou Y
authors.initials: LY
authors.lastname: Sun
authors.forename: Alex F
authors.initials: AF
authors.lastname: Bokov
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004178:Diquat / Q000633:toxicity*; D004393:Dwarfism, Pituitary / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000235:genetics; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D006540:Herbicides / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054481:Thioredoxin Reductase 1 / Q000235:genetics
chemical_list: D006540:Herbicides; D008565:Membrane Proteins; C491054:Mt2 protein, mouse; D051267:NF-E2-Related Factor 2; D021122:Protein Subunits; C525355:metallothionein-1, mouse; D008668:Metallothionein; D004178:Diquat; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D005721:Glutamate-Cysteine Ligase
references.citation: Tumour Biol. 2002 Mar-Apr;23(2):93-102
references.pmid: 12065847
references.citation: J Nutr. 2001 Mar;131(3):918S-923S
references.pmid: 11238786
references.citation: J Nutr. 1993 Feb;123(2):269-74
references.pmid: 8429371
references.citation: Cell Death Differ. 2006 Aug;13(8):1351-9
references.pmid: 16763616
references.citation: J Clin Invest. 2008 Oct;118(10):3378-89
references.pmid: 18776938
references.citation: Annu Rev Genet. 2009;43:335-67
references.pmid: 19691428
references.citation: Aging (Albany NY). 2009 Jul 31;1(9):784-802
references.pmid: 20157567
references.citation: Arthritis Rheum. 2006 Sep;54(9):2745-56
references.pmid: 16947383
references.citation: Free Radic Biol Med. 2009 Nov 1;47(9):1304-9
references.pmid: 19666107
references.citation: Annu Rev Plant Biol. 2002;53:159-82
references.pmid: 12221971
references.citation: Nat Genet. 1996 May;13(1):25-34
references.pmid: 8673100
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8905-9
references.pmid: 8415630
references.citation: Free Radic Biol Med. 2009 Jul 1;47(1):1-12
references.pmid: 19362144
references.citation: Science. 1998 Oct 30;282(5390):943-6
references.pmid: 9794765
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:89-116
references.pmid: 16968214
references.citation: J Gerontol A Biol Sci Med Sci. 2003 Apr;58(4):291-6
references.pmid: 12663691
references.citation: Am J Physiol Endocrinol Metab. 2005 Jul;289(1):E23-9
references.pmid: 15701676
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2325-30
references.pmid: 18287083
references.citation: N Engl J Med. 1997 Oct 2;337(14):986-94
references.pmid: 9309105
references.citation: Nature. 1996 Nov 7;384(6604):33
references.pmid: 8900272
references.citation: Free Radic Biol Med. 2004 Oct 15;37(8):1152-9
references.pmid: 15451055
references.citation: J Gerontol A Biol Sci Med Sci. 2009 Feb;64(2):179-82
references.pmid: 19225033
references.citation: J Heart Valve Dis. 2009 Nov;18(6):653-61
references.pmid: 20099714
references.citation: FASEB J. 2008 Apr;22(4):954-65
references.pmid: 18039929
references.citation: J Cell Physiol. 2002 Dec;193(3):287-92
references.pmid: 12384981
references.citation: J Gerontol A Biol Sci Med Sci. 2008 Mar;63(3):219-31
references.pmid: 18375871
references.citation: Endocrinology. 2005 Sep;146(9):3718-23
references.pmid: 15919742
references.citation: Aging Cell. 2006 Feb;5(1):89-96
references.pmid: 16441847
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6736-41
references.pmid: 11371619
references.citation: Cell. 1988 Apr 8;53(1):37-43
references.pmid: 3127059
references.citation: Exp Gerontol. 2004 May;39(5):735-44
references.pmid: 15130668
references.citation: Brain Res. 2001 Feb 16;892(1):70-7
references.pmid: 11172750
references.citation: Mol Carcinog. 2010 May;49(5):464-75
references.pmid: 20175127
references.citation: Nat Rev Cancer. 2003 Oct;3(10):768-80
references.pmid: 14570043
references.citation: Biochim Biophys Acta. 1973 Sep 26;314(3):372-81
references.pmid: 4751237
references.citation: J Gerontol A Biol Sci Med Sci. 2006 Jun;61(6):557-61
references.pmid: 16799136
references.citation: Aging Cell. 2005 Jun;4(3):119-25
references.pmid: 15924568
references.citation: Cell Metab. 2008 Jul;8(1):38-48
references.pmid: 18590691
references.citation: Science. 1999 Aug 27;285(5432):1390-3
references.pmid: 10464095
references.citation: Vitam Horm. 2008;78:63-84
references.pmid: 18374190
references.citation: Blood. 1996 Jul 15;88(2):386-401
references.pmid: 8695785
references.citation: FASEB J. 2003 Aug;17(11):1565-6
references.pmid: 12824282
references.citation: J Gerontol A Biol Sci Med Sci. 2009 Aug;64(8):819-27
references.pmid: 19414510
references.citation: Free Radic Biol Med. 2008 Sep 1;45(5):562-9
references.pmid: 18549826
references.citation: Nature. 2001 Mar 1;410(6824):37-40
references.pmid: 11242034
references.citation: Free Radic Biol Med. 2009 Dec 15;47(12):1753-61
references.pmid: 19786089
references.citation: Exp Gerontol. 2003 Sep;38(9):997-1008
references.pmid: 12954487
references.citation: Mech Ageing Dev. 2006 Aug;127(8):687-94
references.pmid: 16713617
references.citation: Endocrinology. 2000 Jul;141(7):2608-13
references.pmid: 10875265
references.citation: Mol Cell Biol. 2001 Feb;21(4):1249-59
references.pmid: 11158311
references.citation: J Biol Chem. 2009 May 15;284(20):13291-5
references.pmid: 19182219
references.citation: Nature. 2007 May 31;447(7144):545-9
references.pmid: 17538612
references.citation: Mol Cell Biol. 2010 Feb;30(3):871-84
references.pmid: 19933842
references.citation: Horm Behav. 2001 Jun;39(4):277-84
references.pmid: 11374913
references.citation: Cell Death Differ. 2004 Apr;11(4):381-9
references.pmid: 14685163
references.citation: J Cell Physiol. 2009 Feb;218(2):294-303
references.pmid: 18844239
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:293-322
references.pmid: 17009925
references.citation: Dev Cell. 2008 Jan;14(1):76-85
references.pmid: 18194654
references.citation: Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):385-94
references.pmid: 15706085
references.citation: J Toxicol Clin Toxicol. 2000;38(2):123-8
references.pmid: 10778908
references.citation: J Cell Physiol. 2008 Dec;217(3):652-66
references.pmid: 18651635
references.citation: Free Radic Biol Med. 1999 Mar;26(5-6):495-500
references.pmid: 10218637
references.citation: Cell. 2008 Mar 21;132(6):1025-38
references.pmid: 18358814
references.citation: Endocrinology. 2006 Nov;147(11):5480-90
references.pmid: 16935839
references.citation: Autophagy. 2008 Jul;4(5):600-6
references.pmid: 18497563
references.citation: J Clin Invest. 2003 Jul;112(2):197-208
references.pmid: 12843127
references.citation: Aging Cell. 2004 Dec;3(6):423-41
references.pmid: 15569359