Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chicken beta-globin enhancer is critical for the tissue- and developmental stage-specific expression of the beta-globin genes. This enhancer contains two indispensable cis elements, one containing two GATA sites and the other containing an NF-E2 site. To identify the putative transcription factor acting through the NF-E2 motif in the chicken beta-globin enhancer, we screened chicken cDNA libraries with a mouse p45 NF-E2 cDNA probe and isolated cDNA clones which encode a protein of 582 amino acid residues. This protein contains a region that includes the basic region-leucine zipper domain which is well conserved among members of the CNC family proteins (Cap 'n' collar, p45 NF-E2, LCR-F1, Nrf1, and Nrf2). Hence, we named this protein ECH (erythroid cell-derived protein with CNC homology). ECH is expressed abundantly in cultured erythroid cells undergoing terminal differentiation, peripheral erythrocytes, and some nonhematopoietic tissues. Since most of the cDNA clones obtained from the chicken erythrocyte cDNA library encoded ECH, ECH is likely the predominant CNC family protein present in avian peripheral erythrocytes. Like p45 NF-E2, ECH can heterodimerize with any of the small Maf family proteins and bind the NF-E2 site as a heterodimer in vitro. In a transfection assay, ECH transactivates transcription depending on the presence of NF-E2 sites on the reporter gene plasmid. These results indicate that ECH is likely a key regulator of avian erythropoiesis.
Mol Cell Biol 1995 Aug
PMID:Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. 762 13

A strong role for reactive oxygen species (ROS) has been proposed in the pathogenesis of a number of lung diseases. Hyperoxia (> 95% oxygen) generates ROS and extensive lung damage, and has been used as a model of oxidant injury. However, the precise mechanisms of hyperoxia-induced toxicity have not been completely clarified. This study was designed to identify hyperoxia susceptibility genes in C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. The quantitative phenotypes used for this analysis were pulmonary inflammatory cell influx, epithelial cell sloughing, and hyperpermeability. Genome-wide linkage analyses of intercross (F2) and recombinant inbred cohorts identified significant and suggestive quantitative trait loci on chromosomes 2 (hyperoxia susceptibility locus 1 [Hsl1]) and 3 (Hsl2), respectively. Comparative mapping of Hsl1 identified a strong candidate gene, Nfe2l2 (nuclear factor, erythroid derived 2, like 2 or Nrf2) that encodes a transcription factor NRF2 which regulates antioxidant and phase 2 gene expression. Strain-specific variation in lung Nrf2 messenger RNA expression and a T --> C substitution in the B6 Nrf2 promoter that cosegregated with susceptibility phenotypes in F2 animals supported Nrf2 as a candidate gene. Results from this study have important implications for understanding the mechanisms through which oxidants mediate the pathogenesis of lung disease.
Am J Respir Cell Mol Biol 2002 Jan
PMID:Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. 1175 Dec 2

NRF2 is a transcription factor important in the protection against carcinogenesis and oxidative stress through antioxidant response element (ARE)-mediated transcriptional activation of several phase 2 detoxifying and antioxidant enzymes. This study was designed to determine the role of NRF2 in the pathogenesis of hyperoxic lung injury by comparing pulmonary responses to 95-98% oxygen between mice with site-directed mutation of the gene for NRF2 (Nrf2-/-) and wild-type mice (Nrf2+/+). Pulmonary hyperpermeability, macrophage inflammation, and epithelial injury in Nrf2-/- mice were 7.6-fold, 47%, and 43% greater, respectively, compared with Nrf2+/+ mice after 72 h hyperoxia exposure. Hyperoxia markedly elevated the expression of NRF2 mRNA and DNA-binding activity of NRF2 in the lungs of Nrf2+/+ mice. mRNA expression for ARE- responsive lung antioxidant and phase 2 enzymes was evaluated in both genotypes of mice to identify potential downstream molecular mechanisms of NRF2 in hyperoxic lung responses. Hyperoxia-induced mRNA levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione-S-transferase (GST)-Ya and -Yc subunits, UDP glycosyl transferase (UGT), glutathione peroxidase-2 (GPx2), and heme oxygenase-1 (HO-1) were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice. Consistent with differential mRNA expression, NQO1 and total GST activities were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice after hyperoxia. Results demonstrated that NRF2 has a significant protective role against pulmonary hyperoxic injury in mice, possibly through transcriptional activation of lung antioxidant defense enzymes.
Am J Respir Cell Mol Biol 2002 Feb
PMID:Role of NRF2 in protection against hyperoxic lung injury in mice. 1180 63

Induction of phase 2 enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, is an important mechanism for protection against carcinogenesis. The transcription factor Nrf2, which binds to the antioxidant response element (ARE) found in the upstream regulatory region of many phase 2 genes, is essential for the induction of these enzymes. We have investigated the effect of the potent enzyme inducer and anticarcinogen 3H-1,2-dithiole-3-thione (D3T) on the fate of Nrf2 in murine keratinocytes. Both total and nuclear Nrf2 levels increased rapidly and persistently after treatment with D3T but could be blocked by cotreatment with cycloheximide. Nrf2 mRNA levels increased approximately 2-fold 6 h after D3T treatment. To examine the transcriptional activation of Nrf2 by D3T, the proximal region (1 kb) of the nrf2 promoter was isolated. Deletion and mutagenesis analyses demonstrated that nrf2 promoter-luciferase reporter activity was enhanced by treatment with D3T and that ARE-like sequences were required for this activation. Gel shift assays with nuclear extracts from PE cells indicated that common factors bind to typical AREs and the ARE-like sequences of the nrf2 promoter. Direct binding of Nrf2 to its own promoter was demonstrated by chromatin immunoprecipitation assay. Overexpression of Nrf2 increased the activity of the nrf2 promoter-luciferase reporter, while expression of mutant Nrf2 protein repressed activity. Thus, Nrf2 appears to autoregulate its own expression through an ARE-like element located in the proximal region of its promoter, leading to persistent nuclear accumulation of Nrf2 and protracted induction of phase 2 genes in response to chemopreventive agents.
Mol Cell Biol 2002 May
PMID:Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. 1194 Jun 47

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.
Mol Cell Biochem 2002 Nov
PMID: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. 1248 71

The utility of oltipraz as a cancer chemopreventive agent is thought to depend on the induction of enzymes involved in phase 2 xenobiotic detoxification. Although studies of some enzymes induced by oltipraz implicate a novel transcriptional activating pathway involving Nrf2 and antioxidant-response elements (AREs), the mechanism of phenol UGT induction has remained unclear. Previous work showed that UGT1A6 is transcribed from two promoters, P1 and P2, that are both induced by oltipraz in rat liver. The effect also occurs in rat hepatocytes treated with oltipraz (concentrations >3 microM). To investigate the mechanism, luciferase reporter plasmids under the control of P1 [p(-1078/+27)1A6P1-luc] or P2 [p(-1354/+65)1A6P2-luc] were transfected into rat hepatocytes and tested for inducibility. P1, but not P2, showed responsiveness to oltipraz (2- to 5-fold increase) and 3-methylcholanthrene (10- to 30-fold increase). Because P1 contained no visible AREs, the role of a xenobiotic response element (XRE) centered between bases -134 and -129 was evaluated. Mutation of the XRE core reduced the effects of both oltipraz and 3-methylcholanthrene on the P1 reporter. The 1A6 XRE conferred oltipraz responsiveness on the simian virus 40 promoter of pGL3-Promoter. Comparative effects of oltipraz and 3-methylcholanthrene on transfected cytochrome P4501A1 reporters support the general but relatively weak XRE-stimulating activity of oltipraz. The involvement of the aryl hydrocarbon receptor (AHR) and aryl hydrocarbon nuclear translocator (ARNT) in mediating the effects of oltipraz on the XRE is supported by electrophoretic mobility supershift data and AHR/ARNT overexpression studies. These data raise questions about the contribution of AHR and other secondary induction pathways in the mechanism of oltipraz.
Mol Pharmacol 2003 Jan
PMID:Mechanism of rat UDP-glucuronosyltransferase 1A6 induction by oltipraz: evidence for a contribution of the Aryl hydrocarbon receptor pathway. 1248 44

The erythroid-specific enhancer within hypersensitivity site 2 (HS2) of the human beta-globin locus control region is required for high level globin gene expression. We used an oligonucleotide of the NF-E2 tandem repeat, within HS2, as recognition site probe to screen a K562 cDNA library for interacting transcription factors. A 2.3 kb full length cDNA encoding the b-zip transcription factor MafF was isolated. MafF can form both homodimers and high affinity heterodimers with Nrf1, Nrf2 and Nf-E2, three members of the CNC-bZip family. Despite obvious structural similarities with the other small Maf proteins, MafF differs in its tissue distribution and its inability to repress transcription when overexpressed as homodimer. In fact, in different cell lines and on different promoters (gamma-globin, beta-globin and glutamylcysteine synthetase genes) the MafF homodimers do not appreciably affect transcription of target promoters, whereas MafF/CNC member heterodimers act as weak transcriptional activators. Even though MafF was cloned using probes derived from the globin LCR, it is in the context of the GCSl promoter and in combination with Jun that MafF shows a rather distinct and specific regulatory role. These observations suggest that a complex network of small Maf and CNC-AP1 protein interactions might be involved in regulating transcription in diverse tissues or developmental stages.
Blood Cells Mol Dis
PMID:Cloning MafF by recognition site screening with the NFE2 tandem repeat of HS2: analysis of its role in globin and GCSl genes regulation. 1249 Feb 81

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme, the expression of which is highly sensitive to induction by pro-oxidant stimuli including the substrate heme and reactive oxygen species. Conceptually, the perception that HO-1 plays a key role in response to oxidative damage is paralleled by evidence showing high expression of HO-1 in a variety of cell systems challenged with nitric oxide (NO) or NO-derivatives, thus revealing a potential biological function for HO-1 against nitrosative stress. In this study, we report that exposure of cardiac cells to hemin (5-20 microM) in combination with compounds that liberate nitroxyl (HNO/NO-) or release NO significantly potentiates HO-1 mRNA and protein expression leading to a remarkable increase in heme oxygenase activity under both normoxic and hypoxic conditions. The amplification of the heme oxygenase pathway appears to involve a direct interaction between heme and the NO groups, as the ability of both NO(-)- and NO-releasing agents to induce HO-1 is totally lost by their pre-incubation for 1 hr in complete medium prior to cell treatment but is highly preserved by addition of hemin during the preincubation step. In addition, we show that the redox-sensitive transcription factor Nrf2 is highly expressed in the nuclear fraction of cells exposed to the NO- generator and that this effect is totally abolished by the presence of N-acetyl-L-cysteine. Interestingly, the expression of Nrf2 is gradually intensified by treating cells with a combination of the NO- releaser and increasing concentrations of hemin. Thus, a strict parallelism exists between the extent of HO-1 induction and expression of Nrf2 elicited by the heme-NO interaction. We propose that modification of the iron protoporphyrin centers by NO groups to modulate HO-1 expression might be regarded as a molecular switch to maximize heme oxygenase enzymatic activity and consequently mitigate the redox imbalance imposed by oxidative and nitrosative stress.
Cell Mol Biol (Noisy-le-grand) 2002 Dec
PMID:Interaction of heme with nitroxyl or nitric oxide amplifies heme oxygenase-1 induction: involvement of the transcription factor Nrf2. 1269 47

Diesel exhaust particles (DEP) induce a proinflammatory response in human bronchial epithelial cells (16HBE) characterized by the release of proinflammatory cytokines after activation of transduction pathways involving MAPK and the transcription factor NF-kappaB. Because cellular effects induced by DEP are prevented by antioxidants, they could be mediated by reactive oxygen species (ROS). Using fluorescent probes, we detected ROS production in bronchial and nasal epithelial cells exposed to native DEP, organic extracts of DEP (OE-DEP), or several polyaromatic hydrocarbons. Carbon black particles mimicking the inorganic part of DEP did not increase ROS production. DEP and OE-DEP also induced the expression of genes for phase I [cytochrome P-450 1A1 (CYP1A1)] and phase II [NADPH quinone oxidoreductase-1 (NQO-1)] xenobiotic metabolization enzymes, suggesting that DEP-adsorbed organic compounds become bioavailable, activate transcription, and are metabolized since the CYP1A1 enzymatic activity is increased. Because NQO-1 gene induction is reduced by antioxidants, it could be related to the ROS generated by DEP, most likely through the activation of the stress-sensitive Nrf2 transcription factor. Indeed, DEP induced the translocation of Nrf2 to the nucleus and increased protein nuclear binding to the antioxidant responsive element. In conclusion, we show that DEP-organic compounds generate an oxidative stress, activate the Nrf2 transcription factor, and increase the expression of genes for phase I and II metabolization enzymes.
Am J Physiol Lung Cell Mol Physiol 2003 Sep
PMID:Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. 1273 81

Activation of PERK following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) promotes translation inhibition and cell cycle arrest. PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription factor as a novel PERK substrate. In unstressed cells, Nrf2 is maintained in the cytoplasm via association with Keap1. PERK-dependent phosphorylation triggers dissociation of Nrf2/Keap1 complexes and inhibits reassociation of Nrf2/Keap1 complexes in vitro. Activation of PERK via agents that trigger the unfolded protein response is both necessary and sufficient for dissociation of cytoplasmic Nrf2/Keap1 and subsequent Nrf2 nuclear import. Finally, we demonstrate that cells harboring a targeted deletion of Nrf2 exhibit increased cell death relative to wild-type counterparts following exposure to ER stress. Our data demonstrate that Nrf2 is a critical effector of PERK-mediated cell survival.
Mol Cell Biol 2003 Oct
PMID:Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. 1451 90


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