Showing papers on "Antioxidant Response Elements published in 2006"
TL;DR: The results contribute to clarify the cross-talk between the survival signal elicited by PI3K/Akt and the antioxidant phase II cell response, and introduce GSK-3β as the key mediator of this regulation mechanism.
457 citations
TL;DR: The current understanding of the Nrf2/ARE pathway as a potential molecular target for cancer chemoprevention is discussed, as well as the feasibility of screening natural compounds for activation of this pathway and as potential cancer preventive agents for human use are discussed.
Abstract: One of the most prominent strategies of cancer chemoprevention might be protecting cells or tissues against various carcinogens and carcinogenic metabolites derived from exogenous or endogenous sources. This protection could be achieved through the induction of phase 2 detoxifying enzymes and antioxidant enzymes such as glutathione S-transferase, NAD(P)H quinone oxidoreductase 1, and heme oxygenase-1, a process that is mediated mainly by the antioxidant response elements (ARE) within the promoter regions of these genes. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap 'n' collar (CNC) family of basic regionleucine zipper transcription factors, plays a key role in ARE-mediated gene expression. Under normal condition, Nrf2 is sequestered in the cytoplasm by an actin-binding protein, Kelch-like ECH associating protein 1 (Keap1), and upon exposure of cells to inducers such as oxidative stress and certain chemopreventive agents, Nrf2 dissociates from Keap1, translocates to the nucleus, b...
348 citations
TL;DR: Results suggest that Nrf1 is normally targeted to the endoplasmic reticulum membrane and that endoplasmsic Reticulum stress may play a role in modulating NRF1 function as a transcriptional activator.
152 citations
TL;DR: The association of decreased cancer risk with intake of cruciferous vegetables and selenium is stronger than that reported for fruits and vegetables in general and depends on adequate seenium supply, which explains the synergism of Nrf2 activators and Selenium.
Abstract: The association of decreased cancer risk with intake of cruciferous vegetables and selenium is stronger than that reported for fruits and vegetables in general. An active constituent in cruciferae is sulforaphane. Chemopreventive effects of both, sulforaphane and selenium have been attributed to an antioxidant action which certainly is too simplicistic. Sulforaphane induces via activation of the Nrf2/Keap1 system phase 2 enzymes that protect against carcinogens and oxidants. Induced enzymes comprise the selenoproteins thioredoxin reductase-1 (TrxR1) and gastrointestinal glutathione peroxidase (GI-GPx, GPx2), which contain antioxidant response elements (ARE) in their promoter regions. Translational realisation of the enhanced transcripts depends on adequate selenium supply, which explains the synergism of Nrf2 activators and selenium. Regarding tumorigenesis the role of TrxR1 is ambiguous: it is essential for fast tumor cell growth but also diminishes vascularisation of tumors. The anticarcinogenic role of...
77 citations
TL;DR: Elevated GST activities in the livers of Gstz1–/– mice suggest that GSTZ1-1 deficiency may alter the metabolism of some drugs and xenobiotics, and supports the conclusion that under normal dietary conditions, the accumulation of electrophilic intermediates such as maleylacetoacetate and MA results in a high level of oxidative stress.
Abstract: Glutathione S-transferase (GST) zeta (GSTZ1-1) plays a significant role in the catabolism of phenylalanine and tyrosine, and a deficiency of GSTZ1-1 results in the accumulation of maleylacetoacetate and its derivatives maleylacetone (MA) and succinylacetone. Induction of GST subunits was detected in the liver of Gstz1–/– mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins. The greatest induction was observed in members of the mu class. Induction of NAD(P)H:quinone oxidoreductase 1 and the catalytic and modifier subunits of glutamate-cysteine ligase was also observed. Many of the enzymes that are induced in Gstz1–/– mice are regulated by antioxidant response elements that respond to oxidative stress via the Keap1/Nrf2 pathway. It is significant that diminished glutathione concentrations were also observed in the liver of Gstz1–/– mice, which supports the conclusion that under normal dietary conditions, the accumulation of electrophilic intermediates such as maleylacetoacetate and MA results in a high level of oxidative stress. Elevated GST activities in the livers of Gstz1–/– mice suggest that GSTZ1-1 deficiency may alter the metabolism of some drugs and xenobiotics. Gstz1–/– mice given acetaminophen demonstrated increased hepatotoxicity compared with wild-type mice. This toxicity may be attributed to the increased GST activity or the decreased hepatic concentrations of glutathione, or both. Patients with acquired deficiency of GSTZ1-1 caused by therapeutic exposure to dichloroacetic acid for the clinical treatment of lactic acidosis may be at increased risk of drug- and chemical-induced toxicity.
73 citations
TL;DR: The results combined demonstrated that Nrf2 associates with JunD, binds to ARE at nucleotide -1433, and regulates human NQO2 gene expression and induction in response to antioxidants.
52 citations
TL;DR: The findings suggest that a natural protective mechanism in B cells from oxidant pollutants such as diesel particles is the expression of phase II enzymes through induction of antioxidant response elements and support the approach of overexpression of these enzymes as a potential future chemopreventative strategy.
Abstract: Oxidant pollutants such as diesel exhaust particles (DEPs) can initiate and exacerbate airway allergic responses through enhanced IgE production These effects are especially pronounced in individuals in whom phase II antioxidant enzyme responses are impaired We confirmed that DEPs and DEP extracts (DEPX) can act directly on B lymphocytes and showed that DEPX could enhance IgH e germline transcription in a B cell line and in PBMCs We therefore studied the regulation in B cells of NAD(P)H: quinone oxidoreductase (NQO1) as a typical model phase II enzyme and its role in modulating DEPX-enhanced IgE responses DEPX increased NQO1 mRNA expression in a dose-dependent manner NQO1 protein induction by DEPX was confirmed by Western blot DEPs induced activity of the antioxidant response element located in the NQO1 gene promoter Induction of both NQO1 mRNA and protein expression could be blocked by coculture with an antioxidant and partly repressed by inhibitors of PI3K and p38 MAPK, but not by inhibitors of MAPK/ERK kinase (MEK/ERK) or protein kinase C The ability of DEPX to enhance IgE production was blocked by the induction of phase II enzymes, including NQO1 in B cells by the chemical sulforaphane These findings suggest that a natural protective mechanism in B cells from oxidant pollutants such as diesel particles is the expression of phase II enzymes through induction of antioxidant response elements and support the approach of overexpression of these enzymes as a potential future chemopreventative strategy
41 citations
TL;DR: The results suggest that constitutively expressed PRDX5 gene plays an important role in protecting the genome against oxidation and may also be involved in the control of transcription of noncoding DNA.
Abstract: Peroxiredoxins belong to a family of antioxidant proteins that neutralize reactive oxygen species. One member of this family, peroxiredoxin I (PRDX1), suppresses DNA oxidation. Peroxiredoxin V (PRDX5) has been cloned as a transcriptional corepressor, as a peroxisomal/mitochondrial antioxidant protein, and as an inhibitor of p53-dependent apoptosis. Promoters of mammalian PRDX5 genes contain clusters of antioxidant response elements, which can bind the transcription factor NRF2. However, we found that expression of the human PRDX5 gene in situ was not stimulated by the oxidative agent menadione. Silencing of the NRF2 gene in the absence of oxidative stress by specific siRNA did not decrease PRDX5 protein concentration. We also constructed clones of human lung epithelial cells A549 with siRNA-mediated knockdown of the PRDX5 gene. This led to a significant increase in 8-oxoguanine formation in cell DNA. In the PRDX5 knockdown clone, an increase in transcripts containing sequences of alpha-satellite and satellite III DNAs was also detected, suggesting that this protein may be required for silencing of heterochromatin. Together, these results suggest that constitutively expressed PRDX5 gene plays an important role in protecting the genome against oxidation and may also be involved in the control of transcription of noncoding DNA.
39 citations
TL;DR: Treatment of cultured human hepatoma (HepG2) cells with green tea extract resulted in dramatically increased expression of at least 15 genes that are present on a commercial human drug metabolism gene array, which may help to explain the previously observed increased cytotoxicity of green tea catechins on this cell line.
18 citations
TL;DR: Fe (cellular iron), O (dioxygen, antioxidant inducers, hydrogen peroxide), and P (protein phosphorylation) signals combine to regulate DNA activity (transcription/mRNA synthesis) for antioxidant/Phase II response proteins and Ferritin regulation links the two groups of genetic controls via DNA and mRNA structures.
9 citations
01 Jan 2006
TL;DR: In this article, the authors investigated whether Nrf1 activity is regulated similarly to Nrf2 by Keap1-mediated compartmentalization in the cell and found that deletion of this domain resulted in a predominantly nuclear localization of NRF1 that significantly increased the activation of reporter gene expression.
Abstract: Expression of antioxidant and phase 2 xenobiotic metabolizing enzyme genes is regulated through cis-acting sequences known as antioxidant response elements. Transcriptional activation through the antioxidant response elements involves members of the CNC (Cap ‘n’ Collar) family of basic leucine zipper proteins including Nrf1 and Nrf2. Nrf2 activity is regulated by Keap1-mediated compartmentalization in the cell. Given the structural similarities between Nrf1 and Nrf2, we sought to investigate whether Nrf1 activity is regulated similarly to Nrf2. Nrf1 also resides normally in the cytoplasm of cells. Cytoplasmic localization however, is independent of Keap1. Colocalization analysis using green fluorescent protein-tagged Nrf1 and subcellular fractionation of endogenous Nrf1 and fusion proteins indicate that Nrf1 is primarily a membranebound protein localized in the endoplasmic reticulum. Membrane targeting is mediated by the N terminus of the Nrf1 protein that contains a predicted transmembrane domain, and deletion of this domain resulted in a predominantly nuclear localization of Nrf1 that significantly increased the activation of reporter gene expression. Treatment with tunicamycin, an endoplasmic reticulum stress inducer, caused an accumulation of a smaller form of Nrf1 that correlated with detection of Nrf1 in the nucleus by biochemical fractionation and immunofluorescent analysis. These results suggest that Nrf1 is normally targeted to the endoplasmic reticulum membrane and that endoplasmic reticulum stress may play a role in modulating Nrf1 function as a transcriptional activator.