Antioxidant Responsive Element

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Jeffrey A Johnson - One of the best experts on this subject based on the ideXlab platform.

  • Nrf2, a multi-organ protector?
    The FASEB Journal, 2005
    Co-Authors: Jiang Li, Delinda A Johnson, Thor D. Stein, Andrew D. Kraft, Marcus J. Calkins, Rebekah J. Jakel, Jeffrey A Johnson
    Abstract:

    NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that binds to the promoter sequence “Antioxidant Responsive Element (ARE)” leading to coordinated up-regulation of ARE-driven detoxification and Antioxidant genes. Since the expression of a wide array of Antioxidant and detoxification genes are positively regulated by the ARE sequence, Nrf2 may serve as a master regulator of the ARE-driven cellular defense system against oxidative stress. In support of this, numerous studies have shown that Nrf2 protects many cell types and organ systems from a broad spectrum of toxic insults and disease pathogenesis. This Nrf2-conferred, multi-organ protection phenomenon raises an interesting question about how a single protein can protect many different organs from various toxic insults. A possible molecular mechanism explaining this phenomenon is that Nrf2 protects many different cell types by coordinately up-regulating classic ARE-driven genes as well as cell type-specific target genes that a...

  • Dissecting tBHQ induced ARE-driven gene expression through long and short oligonucleotide arrays
    Physiological Genomics, 2004
    Co-Authors: Jiang Li, Maria L. Spletter, Jeffrey A Johnson
    Abstract:

    This paper compares the gene expression profiles identified by short (Affymetrix U95AV2) or long (Agilent Hu1A) oligonucleotide arrays on a model for upregulation of a cluster of Antioxidant Responsive Element-driven genes by treatment with tert -butylhydroquinone. MAS 5.0, dCHIP, and RMA were applied to normalize the Affymetrix data, and Lowess regression was considered for Agilent data. SAM was used to identify the differential gene expression. A set of biological markers and housekeeping genes were chosen to evaluate the performance of multiple normalization approaches. Both arrays illustrated a definite set of overlapping genes between the data sets regardless of data mining tools used. However, unique gene expression profiles based on the platform used were also revealed and confirmed by quantitative RT-PCR. Further analysis of the data revealed by alternative approaches suggested that alternative splicing, multiple vs. single probe(s) measurement, and use or nonuse of mismatch probes may account for the discrepant data. Therefore, these two microarray technologies offer relatively reliable data. Integration of the gene expression profiles from different array platforms may not only help for cross-validation but also provide a more complete view of the transcriptional scenario.

  • Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia
    Proceedings of the National Academy of Sciences of the United States of America, 2004
    Co-Authors: Kaimin Chan, Jeffrey A Johnson
    Abstract:

    A basic leucine zipper transcription factor, NF-E2-related factor 2 (Nrf2), plays a critical role in the cellular defense mechanism by mediating a coordinate up-regulation of Antioxidant Responsive Element-driven detoxification and Antioxidant genes. Here, we report that targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia due to increased sequestration of damaged erythrocytes. Splenomegaly and spleen toxicity in Nrf2-/- mice raised a possibility of hemolytic anemia and splenic extramedullary hematopoiesis in Nrf2-/- mice. In support of this, hematology analysis revealed that Nrf2-/- mice suffer from anemia with abnormal red cell morphologies (i.e., Howell-Jolly bodies, acantocytes, and schistocytes). In addition, Nrf2-/- erythrocytes were more sensitive to H2O2-induced hemolysis, and erythrocyte-bound IgG levels were markedly increased in Nrf2-/- mice compared with Nrf2+/+ mice. Because IgG bound to erythrocytes in the presence of oxidative damage in erythrocytes (regardless of Nrf2 genotype), these data support that Nrf2-/- erythrocytes have higher levels of damage compared with Nrf2+/+ cells. Finally, Nrf2-/- mice showed increased levels of erythrocyte-bound IgG compared with Nrf2+/+ mice after H2O2 injection in vivo, suggesting that the decreased glutathione and increased H2O2 render the Nrf2-/- mice more susceptible to toxicity. Taken together, these observations indicate that a chronic increase in oxidative stress due to decreased Antioxidant capacity sensitizes erythrocytes and causes hemolytic anemia in Nrf2-/- mice, suggesting a pivotal role of Nrf2-Antioxidant Responsive Element pathway in the cellular Antioxidant defense system.

  • An important role of Nrf2-ARE pathway in the cellular defense mechanism.
    Journal of Biochemistry and Molecular Biology, 2004
    Co-Authors: Jeffrey A Johnson
    Abstract:

    Abstract The Antioxidant Responsive Element (ARE) is a cis-acting regulatory Element of genes encoding phase II detoxification enzymes and Antioxidant proteins, such as NAD(P)H: quinone oxidoreductase 1, glutathione S-transferases, and glutamate-cysteine ligase. Interestingly, it has been reported that Nrf2 (NF-E2-related factor 2) regulates a wide array of ARE-driven genes in various cell types. Nrf2 is a basic leucine zipper transcription factor, which was originally identified as a binding protein of locus control region of beta-globin gene. The DNA binding sequence of Nrf2 and ARE sequence are very similar, and many studies demonstrated that Nrf2 binds to the ARE sites leading to up-regulation of downstream genes. The function of Nrf2 and its downstream target genes suggests that the Nrf2-ARE pathway is important in the cellular Antioxidant defense system. In support of this, many studies showed a critical role of Nrf2 in cellular protection and anti-carcinogenicity, implying that the Nrf2-ARE pathway may serve as a therapeutic target for neurodegenerative diseases and cancers, in which oxidative stress is closely implicated.

  • Antioxidant Responsive Element activation by quinones Antioxidant Responsive Element target genes role of pi3 kinase in activation
    Methods in Enzymology, 2004
    Co-Authors: Jiang Li, Delinda A Johnson, Jeffrey A Johnson
    Abstract:

    Publisher Summary The transcriptional activation of the phase II detoxification enzymes and/or Antioxidant genes by redox-cycling chemicals has been traced to a cis-acting Element called the Antioxidant Responsive Element (ARE) or the electrophile response Element (EpRE) that regulates either or both constitutive and inducible gene expression. ARE sequences are detected in the promoter region of genes, including rat and mouse glutathione S-transferases (GSTs)-Ya, rat GST-P, rat and human NQO1, murine heme oxygenase-1 (HO1), murine ferritin heavy chain, as well as the α-glutamylcysteine ligase catalytic (GCLC) and regulatory (GCLR) subunits. Antioxidant Responsive Element activation elicits a potential chemoprotective response, and the identification of the ARE-targeting genes is an initial step in the explanation of the molecular mechanism of this chemoprotective response. Microarray analysis reveals a cluster of phase 2 detoxification enzymes and some Antioxidant genes that are coordinately upregulated through Nrf2-dependent ARE activation and are responsible for tert-butylhydroquinone (tBHQ) protective effect against oxidative damage in the multiple culture systems. Detailed information is expected in the future to explain how quinone compounds like tBHQ encourage Nrf2 nuclear translocation and subsequent ARE activation through a PI3-kinase pathway.

C. B. Pickett - One of the best experts on this subject based on the ideXlab platform.

  • transcriptional regulation of the rat nad p h quinone reductase gene characterization of a dna protein interaction at the Antioxidant Responsive Element and induction by 12 o tetradecanoylphorbol 13 acetate
    Journal of Biological Chemistry, 1993
    Co-Authors: L. V. Favreau, C. B. Pickett
    Abstract:

    Abstract We have previously identified a novel xenobiotic Responsive Element, which has been termed the Antioxidant Responsive Element (ARE), in the 5'-flanking region of the rat quinone reductase gene (Favreau, L. V., and Pickett, C. B. (1991) J. Biol. Chem. 266, 4556-4561). This Element is responsible for basal level expression of the gene as well as transcriptional activation by phenolic Antioxidants and metabolizable planar aromatic compounds. In this communication, we demonstrate that hydrogen peroxide can act as an inducer through the ARE sequence, a phenomenon recently demonstrated for the glutathione S-transferase Ya subunit gene (Rushmore, T. H., Morton, M. R., and Pickett, C. B. (1991) J. Biol. Chem. 266, 11632-11639). To further characterize the quinone reductase ARE, we demonstrate by DNase I footprinting that in crude Hep G2 nuclear extracts a trans-acting factor exists which interacts with a region of DNA found within the 31-nucleotide ARE sequence. Furthermore, electrophoretic mobility shift assays demonstrate the presence of a specific DNA-protein complex which can be competed only by double-stranded oligonucleotides containing the ARE sequences from the quinone reductase and glutathione S-transferase Ya subunit genes. Methylation interference and protection assays indicate that several guanine residues found in the sequence GTGACTTGGC are involved in the binding of the nuclear factor(s) to the DNA. Although electrophoretic mobility shift assays indicate that the rat quinone reductase ARE does not contain a high affinity recognition site for in vitro translated c-Jun and c-Fos, 12-O-tetradecanoylphorbol 13-acetate can act as an inducer through the ARE sequence in Hep G2 cells.

  • regulation of rat glutathione s transferase ya subunit gene expression dna protein interaction at the Antioxidant Responsive Element
    Journal of Biological Chemistry, 1992
    Co-Authors: T Nguyen, C. B. Pickett
    Abstract:

    Abstract We have characterized the interaction of the Antioxidant Responsive Element (ARE) in the 5'-flanking region of the rat glutathione S-transferase Ya subunit gene with its trans-acting factor. The ARE core sequence, 5'-ggTGACaaaGC-3', previously identified as the cis-acting Element required for activation of the Ya subunit gene by planar aromatic compounds and phenolic Antioxidants, is shown to be the high affinity recognition motif for a trans-acting factor(s) as determined by gel mobility shift assays as well as methylation interference and protection studies. The DNA-protein interaction appears to occur in the major groove and involves the GpG dinucleotide preceding and the G residue within the TGAC tetramer on the coding strand of the core sequence. In addition, DNase I protection analysis maps an extended region 5' from the core recognition motif, which was shown previously to be essential for basal activity of the ARE. The trans-acting factor is present in nuclear extracts from untreated and tert-butylhydroquinone-treated cells as determined by photochemical cross-linking experiments. The cross-linked protein appears to be a heterodimer with subunit molecular weights of approximately 28,000 and approximately 45,000.

  • characterization of the Antioxidant Responsive Element are a xenobiotic Responsive Element controlling expression of the rat glutathione s transferase ya subunit gene by phenolic Antioxidants
    FASEB Journal (Federation of American Societies for Experimental Biology); (United States), 1991
    Co-Authors: T H Rushmore, C. B. Pickett
    Abstract:

    The Antioxidant Responsive Element (ARE) is responsible for part of the basal level expression of the Ya subunit gene and for the induction by phenolic Antioxidants and metabolites of planar aromatic hydrocarbons (PAH), such as {beta}-naphthoflavone ({beta}-NF). As an initial step in the characterization of the mechanism(s) by which phenolic Antioxidants and metabolites of PAH activate transcription via the ARE, the authors prepared 5{prime} and 3{prime}-deletions and point mutants of the 41 bp ARE, transfected them into HepG2 cells and monitored the basal and {beta}-NF inducible activities. Deletion analysis permitted separation of the basal and {beta}-NF inducible components of the ARE. The minimum sequence required for {beta}-NF inducible expression was PuGTGACAAAGCAPu, nucleotides {minus}697 to {minus}687. Point mutations at nucleotides {minus}696, {minus}695, {minus}694, {minus}693, {minus}689 or {minus}688 abolished the {beta}-NF inducible expression. Mutations at the other positions had little or no effect on {beta}-NF inducible expression. Gel shift assays suggest that at least 2 proteins bind to regions within the ARE shown to be important for basal and {beta}-NF inducible expression.

  • Transcriptional regulation of the rat NAD(P)H:quinone reductase gene: Identification of regulatory Elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic Antioxidants
    Journal of Biological Chemistry, 1991
    Co-Authors: L. V. Favreau, C. B. Pickett
    Abstract:

    We have identified two regions in the 5'-flanking sequence of the rat quinone reductase gene that contain xenobiotic Responsive Elements. The DNA sequence of the first region spans nucleotides -393 to -352 of the 5'-flanking region and shares sequence identity with the xenobiotic Responsive Element (XRE) described for the cytochrome P-450 CYPIA1 gene. The DNA sequence of the second region spans nucleotides -434 to -404 of the 5'-flanking region of the quinone reductase structural gene. When a synthetic oligonucleotide corresponding to nucleotides -434 to -404 was inserted in front of a heterologous promoter linked to the chloramphenicol acetyltransferase structural gene, an increase in basal level expression as well as Responsiveness to beta-naphthoflavone and t-butylhydroquinone, but not 2,3,7,8-tetrachlorodibenzo-p-dioxin, was observed. The sequence, -434 to -404, did not have any sequence identity with the XRE but shared a large degree of identity with the Antioxidant Responsive Element recently described for the rat glutathione S-transferase Ya subunit gene (Rushmore, T. H., King, R. G., Paulson, K. E., and Pickett, C. B. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 3826-3830; Rushmore, T. H., and Pickett, C. B. (1990) J. Biol. Chem. 265, 14648-14653). These results indicate that the Antioxidant Responsive Element can be distinguished functionally from the classical XRE and is also involved in the regulation of the quinone reductase gene by planar aromatic compounds and phenolic Antioxidants.

Janean M Hanson - One of the best experts on this subject based on the ideXlab platform.

  • nrf2 not the estrogen receptor mediates catechol estrogen induced activation of the Antioxidant Responsive Element
    Biochimica et Biophysica Acta, 2003
    Co-Authors: Peter C Anderson, Janette K Padgitt, Janean M Hanson, Christopher M Waters, Jeffrey A Johnson
    Abstract:

    Abstract The Antioxidant Responsive Element (ARE) plays an important role in the gene expression of phase II detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), and NF-E2-related factor2 (Nrf2) is the transcription factor for the ARE-driven genes. Interestingly, estrogen receptor (ER) was reported to increase NQO1 gene expression through the ARE. In this study, we investigated the role of ER and Nrf2 in ARE activation using IMR-32 cells and mouse primary astrocytes. Among tested estrogen-related compounds, only catechol estrogens (i.e. 4-hydroxyestradiol) activated the ARE. Since 4-hydroxyestradiol-induced ARE activation was not inhibited by either 17β-estradiol or tamoxifen, and overexpression of ER-α decreased 4-hydroxyestradiol-induced ARE activation, ARE activation by catechol estrogen was independent of ER. Nrf2, however, was very important in the 4-hydroxyestradiol-induced ARE activation. 4-Hydroxyestradiol did not activate the ARE in Nrf2 knockout (−/−) primary astrocytes, but did activate the ARE when Nrf2 was transfected into Nrf2−/− astrocytes. In addition, dominant negative Nrf2 completely blocked 4-hydroxyestradiol-induced ARE activation in Nrf2+/+ astrocytes, and only 4-hydroxyestradiol induced Nrf2 nuclear translocation in IMR-32 cells. A selective phosphatidylinositol 3-kinase (PI3-kinase) inhibitor (LY294002) blocked 4-hydroxyestradiol-induced Nrf2 nuclear translocation and NQO1 activity induction in IMR-32 cells. Taken together, these observations suggest that 4-hydroxyestradiol activates the ARE by a PI3-kinase-Nrf2 dependent mechanism, not involving ER.

  • Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the Antioxidant Responsive Element.
    Biochimica et biophysica acta, 2003
    Co-Authors: Peter C Anderson, Janette K Padgitt, Janean M Hanson, Christopher M Waters, Jeffrey A Johnson
    Abstract:

    The Antioxidant Responsive Element (ARE) plays an important role in the gene expression of phase II detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), and NF-E2-related factor2 (Nrf2) is the transcription factor for the ARE-driven genes. Interestingly, estrogen receptor (ER) was reported to increase NQO1 gene expression through the ARE. In this study, we investigated the role of ER and Nrf2 in ARE activation using IMR-32 cells and mouse primary astrocytes. Among tested estrogen-related compounds, only catechol estrogens (i.e. 4-hydroxyestradiol) activated the ARE. Since 4-hydroxyestradiol-induced ARE activation was not inhibited by either 17beta-estradiol or tamoxifen, and overexpression of ER-alpha decreased 4-hydroxyestradiol-induced ARE activation, ARE activation by catechol estrogen was independent of ER. Nrf2, however, was very important in the 4-hydroxyestradiol-induced ARE activation. 4-Hydroxyestradiol did not activate the ARE in Nrf2 knockout (-/-) primary astrocytes, but did activate the ARE when Nrf2 was transfected into Nrf2-/- astrocytes. In addition, dominant negative Nrf2 completely blocked 4-hydroxyestradiol-induced ARE activation in Nrf2+/+ astrocytes, and only 4-hydroxyestradiol induced Nrf2 nuclear translocation in IMR-32 cells. A selective phosphatidylinositol 3-kinase (PI3-kinase) inhibitor (LY294002) blocked 4-hydroxyestradiol-induced Nrf2 nuclear translocation and NQO1 activity induction in IMR-32 cells. Taken together, these observations suggest that 4-hydroxyestradiol activates the ARE by a PI3-kinase-Nrf2 dependent mechanism, not involving ER.

  • phosphatidylinositol 3 kinase not extracellular signal regulated kinase regulates activation of the Antioxidant Responsive Element in imr 32 human neuroblastoma cells
    Journal of Biological Chemistry, 2001
    Co-Authors: Janean M Hanson, Jeffrey A Johnson
    Abstract:

    Abstract The Antioxidant-Responsive Element (ARE) plays an important role in the induction of phase II detoxifying enzymes including NADPH:quinone oxidoreductase (NQO1). We report herein that activation of the human NQO1-ARE (hNQO1-ARE) bytert-butylhydroquinone (tBHQ) is mediated by phosphatidylinositol 3-kinase (PI3-kinase), not extracellular signal-regulated kinase (Erk1/2), in IMR-32 human neuroblastoma cells. Treatment with tBHQ significantly increased NQO1 protein without activation of Erk1/2. In addition, PD 98059 (a selective mitogen-activated kinase/Erk kinase inhibitor) did not inhibit hNQO1-ARE-luciferase expression or NQO1 protein induction by tBHQ. Pretreatment with LY 294002 (a selective PI3-kinase inhibitor), however, inhibited both hNQO1-ARE-luciferase expression and endogenous NQO1 protein induction. In support of a role for PI3-kinase in ARE activation we show that: 1) transfection of IMR-32 cells with constitutively active PI3-kinase selectively activated the ARE in a dose-dependent manner that was completely inhibited by treatment with LY 294002; 2) pretreatment of cells with the PI3-kinase inhibitors, LY 294002 and wortmannin, significantly decreased NF-E2-related factor 2 (Nrf2) nuclear translocation induced by tBHQ; and 3) ARE activation by constitutively active PI3-kinase was blocked completely by dominant negative Nrf2. Taken together, these data clearly show that ARE activation by tBHQ depends on PI3-kinase, which lies upstream of Nrf2.

  • nrf2 dependent activation of the Antioxidant Responsive Element by tert butylhydroquinone is independent of oxidative stress in imr 32 human neuroblastoma cells
    Biochemical and Biophysical Research Communications, 2001
    Co-Authors: Jeffrey D Moehlenkamp, Janean M Hanson, Jeffrey A Johnson
    Abstract:

    Abstract The Antioxidant Responsive Element (ARE) is a cis-acting regulatory Element located in the 5′-flanking region of several genes encoding phase II detoxification enzymes, including NAD(P)H:quinone oxidoreductase (NQO1). We report here that activation of the NQO1 ARE by tert-butylhydroquinone (tBHQ) is dependent on Nrf2 and not oxidative stress in IMR-32 human neuroblastoma cells. Overexpression of wild-type Nrf2 activated ARE in a dose-dependent manner, and ARE activation by tBHQ or diethyl maleate (DEM) was inhibited by dominant/negative Nrf2 not by dominant/negative c-Jun. According to our observation, the palindromic sequence (5′ to the core) and the GC box in the ARE core sequence are essential for maximal inducibility by tBHQ or DEM. Overexpression of Nrf2 selectively activated wild-type ARE up to 24 h. In addition, a dramatic nuclear translocation of Nrf2 by tBHQ supports a role for Nrf2 in ARE activation. Although oxidative stress is hypothesized to be a major driving force for ARE activation, pretreatment of Antioxidant or Antioxidant enzyme did not block tBHQ-mediated ARE activation. In contrast, ARE activation by DEM was inhibited by Antioxidants or catalase. These results suggest that ARE activation signals from tBHQ and DEM converge at Nrf2 transcription factor through independent mechanisms.

Zhiyue Wang - One of the best experts on this subject based on the ideXlab platform.

Eun Young Park - One of the best experts on this subject based on the ideXlab platform.

  • The transcriptional activation of the human copper/zinc superoxide dismutase gene by 2,3,7,8-tetrachlorodibenzo-p-dioxin through two different regulator sites, the Antioxidant Responsive Element and xenobiotic Responsive Element.
    Molecular and cellular biochemistry, 2020
    Co-Authors: Eun Young Park
    Abstract:

    Cu/Zn superoxide dismutase (SOD1) catalyzes the dismutation of superoxide radicals produced during biological oxidations and environmental stress. The most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces SOD1 in human liver cells. Deletion analyses showed that the promoter region between -400 and -239 was responsible for the induction, in which two different characteristic regulatory Elements, the Antioxidant Responsive Element (ARE) and xenobiotic Responsive Element (XRE), are located. When the cells transfected with the plasmid containing those two cis-Elements, the transactivation of SOD1 promoter was about 4-fold by TCDD, whereas mutation either on the ARE or XRE elevated the promoter activity by about 2-fold. Functional analyses of these two Elements by deletion, mutation in the natural context, heterologous promoter assay, and gel mobility shift assay supported the notion that the activation of the SOD1 promoter was induced by TCDD through these two regulatory Elements ARE and XRE. These results alongside our previous data indicate that the induction of SOD1 in response to TCDD is mediated by either Nrf2 protein or Ah receptor protein through ARE and XRE, respectively. These results also imply that the SOD1 can be induced by dioxin either in combination with or independently of these two regulatory Elements to effectively defend cells from oxidative stress.

  • the transcriptional activation of the human copper zinc superoxide dismutase gene by 2 3 7 8 tetrachlorodibenzo p dioxin through two different regulator sites the Antioxidant Responsive Element and xenobiotic Responsive Element
    Molecular and Cellular Biochemistry, 2002
    Co-Authors: Eun Young Park
    Abstract:

    Cu/Zn superoxide dismutase (SOD1) catalyzes the dismutation of superoxide radicals produced during biological oxidations and environmental stress. The most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces SOD1 in human liver cells. Deletion analyses showed that the promoter region between −400 and −239 was responsible for the induction, in which two different characteristic regulatory Elements, the Antioxidant Responsive Element (ARE) and xenobiotic Responsive Element (XRE), are located. When the cells transfected with the plasmid containing those two cis-Elements, the transactivation of SOD1 promoter was about 4-fold by TCDD, whereas mutation either on the ARE or XRE elevated the promoter activity by about 2-fold. Functional analyses of these two Elements by deletion, mutation in the natural context, heterologous promoter assay, and gel mobility shift assay supported the notion that the activation of the SOD1 promoter was induced by TCDD through these two regulatory Elements ARE and XRE. These results alongside our previous data indicate that the induction of SOD1 in response to TCDD is mediated by either Nrf2 protein or Ah receptor protein through ARE and XRE, respectively. These results also imply that the SOD1 can be induced by dioxin either in combination with or independently of these two regulatory Elements to effectively defend cells from oxidative stress.