Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Xue, M; Rabbani, N; Momiji, H; Imbasi, P; Anwar, MM; Kitteringham, N; Park, BK; Souma, T; Moriguchi, T; Yamamoto, M; Thornalley, PJ

Published Date

  • April 1, 2012

Published In

Volume / Issue

  • 443 / 1

Start / End Page

  • 213 - 222

PubMed ID

  • 22188542

Pubmed Central ID

  • 22188542

Electronic International Standard Serial Number (EISSN)

  • 1470-8728

Digital Object Identifier (DOI)

  • 10.1042/BJ20111648


  • eng

Conference Location

  • England