The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin

Hayes, John D.; Chanas, Simon A.; Henderson, Colin J.; McMahon, Michael; Sun, Chongde; Moffat, Graeme J.; Wolf, C. Roland; Yamamoto, Masayuki

doi:10.1042/bst0280033

Cited by 303 publications

(189 citation statements)

References 19 publications

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“…Direct evidence for this finding is provided by the observed reduced basal expression of GCL and other Phase II detoxification enzymes in Nrf2-null mice (17,(19)(20)(21). These mice also display a marked increased susceptibility to toxicological insult (17,(19)(20)(21).…”

mentioning

confidence: 72%

“…Several lines of evidence [e.g., Nrf2-null mice, Nrf2 overexpression systems, and Nrf2-dominant negative mutants (17,(19)(20)(21)(30)(31)(32)] implicate this transcription factor as a central transcriptional regulator of ARE-containing Phase II detoxication genes. For example, Nrf2-null mice share remarkable similarity to old animals, including loss of constitutive GCL levels and activity and a concomitant decline in GSH (22).…”

Section: Discussionmentioning

confidence: 99%

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Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid

Suh

Shenvi

Dixon

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

698

512

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Glutathione (GSH) significantly declines in the aging rat liver. Because GSH levels are partly a reflection of its synthetic capacity, we measured the levels and activity of ␥-glutamylcysteine ligase (GCL), the rate-controlling enzyme in GSH synthesis. With age, both the catalytic (GCLC) and modulatory (GCLM) subunits of GCL decreased by 47% and 52%, respectively (P < 0.005). Concomitant with lower subunit levels, GCL activity also declined by 53% (P < 0.05). Because nuclear factor erythroid2-related factor 2 (Nrf2) governs basal and inducible GCLC and GCLM expression by means of the antioxidant response element (ARE), we hypothesized that aging results in dysregulation of Nrf2-mediated GCL expression. We observed an Ϸ50% age-related loss in total (P < 0.001) and nuclear (P < 0.0001) Nrf2 levels, which suggests attenuation in Nrf2-dependent gene transcription. By using gel-shift and supershift assays, a marked reduction in Nrf2͞ARE binding in old vs. young rats was noted. To determine whether the constitutive loss of Nrf2 transcriptional activity also affects the inducible nature of Nrf2 nuclear translocation, old rats were treated with (R)-␣-lipoic acid (LA; 40 mg͞kg i.p. up to 48 h), a disulfide compound shown to induce Nrf2 activation in vitro and improve GSH levels in vivo. LA administration increased nuclear Nrf2 levels in old rats after 12 h. LA also induced Nrf2 binding to the ARE, and, consequently, higher GCLC levels and GCL activity were observed 24 h after LA injection. Thus, the age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.

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mentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid

Suh

Shenvi

Dixon

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

698

512

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“…Nrf1 and Nrf2 Regulate a Similar Subset of Antioxidant Genes-Our previous studies and those of others have demonstrated a critical role for Nrf2 in regulating expression of genes encoding antioxidants (33,38,39). For example, Nrf2 has been shown to regulate expression of both the catalytic and regulatory subunits of ␥-glutamylcysteine ligase (Gclc and Gclm) that is involved in glutathione biosynthesis (26,40).…”

Section: Apoptosis In Compound Nrf1ϫ/ϫ Nrf2ϫ/ϫ Fibroblasts Correlatesmentioning

confidence: 99%

Deficiency of the Nrf1 and Nrf2 Transcription Factors Results in Early Embryonic Lethality and Severe Oxidative Stress

Leung

Kwong

Hou

et al. 2003

Journal of Biological Chemistry

291

243

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Nrf1 and Nrf2 are members of the CNC family of bZIP transcription factors that exhibit structural similarities, and they are co-expressed in a wide range of tissues during development. Nrf2 has been shown to be dispensable for growth and development in mice. Nrf2-deficient mice, however, are impaired in oxidative stress defense. We previously showed that loss of Nrf1 function in mice results late gestational embryonic lethality. To determine whether Nrf1 and Nrf2 have overlapping functions during early development and in the oxidative stress response, we generated mice that are deficient in both Nrf1 and Nrf2. In contrast to the late embryonic lethality in Nrf1 mutants, compound Nrf1, Nrf2 mutants die early between embryonic days 9 and 10 and exhibit extensive apoptosis that is not observed in the single mutants. Loss of Nrf1 and Nrf2 leads to marked oxidative stress in cells that is indicated by elevated intracellular reactive oxygen species levels and cell death that is reversed by culturing under reduced oxygen tension or the addition of antioxidants. Compound mutant cells also show increased levels of p53 and induction of Noxa, a death effector p53 target gene, suggesting that cell death is potentially mediated by reactive oxygen species activation of p53. Moreover, we show that expression of genes related to antioxidant defense is severely impaired in compound mutant cells compared with single mutant cells. Together, these findings indicate that the functions of Nrf1 and Nrf2 overlap during early development and to a large extent in regulating antioxidant gene expression in cells.Reactive oxygen species (ROS) 1 are generated during aerobic respiration and normal metabolic processes, and they are also byproducts of metabolism of a wide range of environmental agents (1). High levels of ROS are detrimental to the cell, since they react readily with intracellular molecules, causing cell injury and death (1). Cells are equipped with a variety of defense mechanisms that work in parallel or in sequence to minimize ROS levels. These defenses include enzymes that are involved in ROS metabolism and biotransformation of xenobiotics (2). Examples of these enzymes include superoxide dismutases, glutathione peroxidases, thioredoxins, and heme-oxygenases as well as phase 2 enzymes, such as glutathione S-transferases. In addition to enzymatic defenses, cells are also equipped with molecules such as glutathione, metallothioneins, and ferritins that scavenge ROS and metal ions. Basal and inducible expression of a number of these antioxidant defense genes are mediated in part by a cis-acting DNA element known as the antioxidant response element (3-6). Activation through the antioxidant response element (ARE) appears to be driven by conditions that promote intracellular oxidative stress (5,7,8). A number of different transcription factors including basic leucine zipper proteins, AP-1, have been shown to bind the ARE (3, 9, 10).Recent studies implicate the CNC subfamily of bZIP proteins in mediating ARE function (11). Members o...

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“…A unique cis-acting regulatory sequence, termed the antioxidant response element (ARE), is essential for the constitutive and induced expression of many antioxidant genes involved in the phase II pathway (Friling et al, 1990;Rushmore et al, 1991;Nguyen et al, 2000). Several lines of evidence suggest that NF-E2-related factor 2 (Nrf2) is an important transcription factor responsible for upregulating ARE-mediated gene expression (Itoh et al, 1997(Itoh et al, , 1999Alam et al, 1999;Hayes et al, 2000;Ishii et al, 2000). Studies that use knock-out mice have shown that Nrf2 was part of a transcription factor complex required for regula-tion of the mouse glutathione S-transferase (GST) and NADPH: quinone oxidoreductase (NQO1) genes (Itoh et al, 1997;Hayes et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Several lines of evidence suggest that NF-E2-related factor 2 (Nrf2) is an important transcription factor responsible for upregulating ARE-mediated gene expression (Itoh et al, 1997(Itoh et al, , 1999Alam et al, 1999;Hayes et al, 2000;Ishii et al, 2000). Studies that use knock-out mice have shown that Nrf2 was part of a transcription factor complex required for regula-tion of the mouse glutathione S-transferase (GST) and NADPH: quinone oxidoreductase (NQO1) genes (Itoh et al, 1997;Hayes et al, 2000). In addition, Nrf2/small Maf heterodimers bind to the ARE sequence with high affinity during regulation of the GST and NQO1 genes (Venugopal and Jaiswal, 1996).…”

Section: Introductionmentioning

confidence: 99%

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Johnson²,

et al. 2003

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Astrocytes have a higher antioxidant potential in comparison to neurons. Pathways associated with this selective advantage include the transcriptional regulation of antioxidant enzymes via the action of the Cap'n'Collar transcription factor Nrf2 at the antioxidant response element (ARE). Here we show that Nrf2 overexpression can reengineer neurons to express this glial pathway and enhance antioxidant gene expression. However, Nrf2-mediated protection from oxidative stress is conferred primarily by glia in mixed cultures. The antioxidant properties of Nrf2-overexpressing glia are more pronounced than those of neurons, and a relatively small number of these glia (Ͻ 1% of total cell number added) could protect fully cocultured naive neurons from oxidative glutamate toxicity associated with glutathione (GSH) depletion. Microarray and biochemical analyses indicate a coordinated upregulation of enzymes involved in GSH biosynthesis (xCT cystine antiporter, ␥-glutamylcysteine synthetase, and GSH synthase), use (glutathione S-transferase and glutathione reductase), and export (multidrug resistance protein 1) with Nrf2 overexpression, leading to an increase in both media and intracellular GSH. Selective inhibition of glial GSH synthesis and the supplementation of media GSH indicated that an Nrf2-dependent increase in glial GSH synthesis was both necessary and sufficient for the protection of neurons, respectively. Neuroprotection was not limited to overexpression of Nrf2, because activation of endogenous glial Nrf2 by the small molecule ARE inducer, tert-butylhydroquinone, also protected against oxidative glutamate toxicity.

show abstract

The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin

Cited by 303 publications

References 19 publications

Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid

Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid

Deficiency of the Nrf1 and Nrf2 Transcription Factors Results in Early Embryonic Lethality and Severe Oxidative Stress

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

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