Transcription Factor Nrf2 Coordinately Regulates a Group of Oxidative Stress-inducible Genes in Macrophages*

By T. Ishii, K. Itoh, Satoru Takahashi, Hideyo Sato, T. Yanagawa, Y. Katoh, S. Bannai, Masayuki Yamamoto. Journal of Biological Chemistry, 2000

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Electrophiles and reactive oxygen species have been implicated in the pathogenesis of many diseases. Transcription factor Nrf2 was recently identified as a general regulator of one defense mechanism against such havoc. Nrf2 regulates the inducible expression of a group of detoxication enzymes, such as glutathione S-transferase and NAD(P)H:quinone oxidoreductase, via antioxidant response elements. Using peritoneal macrophages from Nrf2-deficient mice, we show here that Nrf2 also controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system xc −) activity. The response to electrophilic and reactive oxygen species-producing agents was profoundly impaired in Nrf2-deficient cells. The lack of induction of system xc − activity resulted in the minimum level of intracellular glutathione, and Nrf2-deficient cells were more sensitive to toxic electrophiles. Several stress agents induced the DNA binding activity of Nrf2 in the nucleus without increasing its mRNA level. Thus Nrf2 regulates a wide-ranging metabolic response to oxidative stress.

Subfields: Health, Toxicology and Mutagenesis, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8b2182e58c1470507d7d6c2cfa2d873a389e3064

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Citations in the corpus

Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease (2002, background): “For instance, oxidative stress, by a mainly undefined pathway, induces the expression of genes including heme oxygenase (Ishii et al., 2000), whereas DNA damage, with nuclear sensors, leads to the activation of effectors such as DNA repair enzymes (Herceg and Wang, 2001).”
A Noncanonical Mechanism of Nrf2 Activation by Autophagy Deficiency: Direct Interaction between Keap1 and p62 (2010, background): “It regulates the antioxidant response by activating a battery of genes bearing an antioxidant response element (ARE), including antioxidant enzymes, phase II detoxifying enzymes, xenobiotic transporters, and other stress response proteins (1, 4, 5, 9, 11, 15, 17).”
Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. (2002, positive): “Previous studies using biochemical and Northern blot analyses in wild-type and nrf2-deficient mice have demonstrated that Nrf2 controls the constitutive expression of antioxidative enzymes such as the light regulatory subunit of -glutamylcysteine synthetase, heme oxygenase 1, and peroxiredoxin MSP23”
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease (2015, neutral): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript complete knockout of Txnrd1 is embryonic lethal [28].”
The Roles of NRF2 in Modulating Cellular Iron Homeostasis (2017, background): “Both GPX4 and SLC7A11 are bona fide NRF2 target genes (50,118,133), as are the glutathione synthesis genes γ-glutamylcysteine synthetase (GCS) (153), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC) (73), so NRF2 activation was expected to pro”
The Cystine/Glutamate Antiporter System xc − in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities (2013, positive): “However, the induction of system xc - either by in vitro culture for 12 h or stimulation by LPS was diminished but not abolished, indicating that Nrf2-independent pathways are also involved (101).”
Oxidative stress response and Nrf2 signaling in aging. (2015, positive): “The Nrf2-associated antioxidant enzymes include the two subunits of glutamate-cysteine ligase (GCL) [48], which catalyze the first and committed step in de novo glutathione (GSH) biosynthesis, all three members of superoxide dismutase [49] family [50, 51], catalase [50], glucose-6-phosphate dehydrog”
The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 (2010, background): “The lower p62 level in Atg7 Nrf2 -DKO mouse livers might be attributable, at least in part, to the loss of Nrf2 regulation for p62 gene transcriptio”
High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. (2001, background): “The molecular mechanism of Nrf2 activation by reactive electrophiles has partially been clarified (Ishii et al., 2000; Itoh et al., 1999).”