title: Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation.
abstract: Abnormal cellular accumulation of the dicarbonyl metabolite MG (methylglyoxal) occurs on exposure to high glucose concentrations, inflammation, cell aging and senescence. It is associated with increased MG-adduct content of protein and DNA linked to increased DNA strand breaks and mutagenesis, mitochondrial dysfunction and ROS (reactive oxygen species) formation and cell detachment from the extracellular matrix. MG-mediated damage is countered by glutathione-dependent metabolism by Glo1 (glyoxalase 1). It is not known, however, whether Glo1 has stress-responsive up-regulation to counter periods of high MG concentration or dicarbonyl stress. We identified a functional ARE (antioxidant-response element) in the 5'-untranslated region of exon 1 of the mammalian Glo1 gene. Transcription factor Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) binds to this ARE, increasing basal and inducible expression of Glo1. Activators of Nrf2 induced increased Glo1 mRNA, protein and activity. Increased expression of Glo1 decreased cellular and extracellular concentrations of MG, MG-derived protein adducts, mutagenesis and cell detachment. Hepatic, brain, heart, kidney and lung Glo1 mRNA and protein were decreased in Nrf2-/- mice, and urinary excretion of MG protein and nucleotide adducts were increased approximately 2-fold. We conclude that dicarbonyl stress is countered by up-regulation of Glo1 in the Nrf2 stress-responsive system, protecting protein and DNA from increased damage and preserving cell function.
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, UK.
authors.forename: Mingzhan
authors.initials: M
authors.lastname: Xue
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Momiji
authors.forename: Precious
authors.initials: P
authors.lastname: Imbasi
authors.forename: M Maqsud
authors.initials: MM
authors.lastname: Anwar
authors.forename: Neil
authors.initials: N
authors.lastname: Kitteringham
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Souma
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
mesh_terms: D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion; D016384:Consensus Sequence; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011485:Protein Binding; D011765:Pyruvaldehyde / Q000378:metabolism*; D020218:Response Elements; D014158:Transcription, Genetic
chemical_list: D017127:Glycation End Products, Advanced; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011765:Pyruvaldehyde; D049410:Luciferases, Renilla; D007791:Lactoylglutathione Lyase