Written | 2014-09 | Stavroula D Manolakou, Panos G Ziros, Gerasimos P Sykiotis |
Service of Endocrinology, Diabetology, Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland (SDM, PGZ, GPS); Faculty of Biology, Medicine, University of Lausanne, 1011 Lausanne, Switzerland (GPS) |
Identity |
Alias (NCBI) | NRF2 |
HGNC (Hugo) | NFE2L2 |
HGNC Alias symb | NRF2 |
HGNC Alias name | NF-E2-related factor 2 |
HGNC Previous name | "nuclear factor (erythroid-derived 2)-like 2 | nuclear factor, erythroid 2-like 2" |
LocusID (NCBI) | 4780 |
Atlas_Id | 44284 |
Location | 2q31.2 [Link to chromosome band 2q31] |
Location_base_pair | Starts at 177230309 and ends at 177264727 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping NFE2L2.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
ACTR2 (2p14) / NFE2L2 (2q31.2) | N4BP1 (16q12.1) / NFE2L2 (2q31.2) | NDUFS6 (5p15.33) / NFE2L2 (2q31.2) | |
NFE2L2 (2q31.2) / CSAD (12q13.13) | NFE2L2 (2q31.2) / HNRNPD (4q21.22) | NFE2L2 (2q31.2) / KIF5B (10p11.22) | |
NFE2L2 (2q31.2) / NACA (12q13.3) | NFE2L2 (2q31.2) / NFE2L2 (2q31.2) | NFE2L2 (2q31.2) / PDE11A (2q31.2) | |
NFE2L2 (2q31.2) / RFTN2 (2q33.1) | NFE2L2 (2q31.2) / ZC3H13 (13q14.13) | PAX8 (2q13) / NFE2L2 (2q31.2) | |
PAX8 (2q14.1) / NFE2L2 (2q31.2) | RPL18 (19q13.33) / NFE2L2 (2q31.2) | SPG21 (15q22.31) / NFE2L2 (2q31.2) | |
Note | The transcription factor Nrf2, encoded by the NFE2L2 gene, is the mediator of a cellular antioxidant response. Nrf2 belongs to the cap'n'collar (cnc) family of transcription factors. |
DNA/RNA |
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NFE2L2 gene - transcript variants. NFE2L2 gene located on chromosome 2. Multiple transcript variants (TV) encoding different isoforms have been found for this gene. The transcript variants referenced more often in the literature are NM_006164.4 (TV 1), NM_001145412.2 (TV 2) and NM_001145413.2 (TV 3). | |
Description | The NFE2L2 gene is approximately 34.8 kb in size. The mouse homologue of the NFE2L2 gene is a self- and hetero-inducible gene; its promoter region contains two ARE/EpRE (antioxidant or electrophile response element) sequences at -492 bp and -754 bp, through which it is induced by Nrf2. In addition, its regulatory region contains three XRE (xenobiotic response element) sequences at -712 bp, +755 bp and +850 bp. ARE and XRE sequences are implicated in the inducible upregulation of the genes transcription. A kB2 region for NF-κB binding has been detected at +270 bp; proinflammatory stimuli can induce human NFE2L2 transcription via this element. On the other hand, five CpG sequences in the promoter region of NFE2L2 allow hypermethylation and repression of gene expression (Kwak et al., 2002; Hayes and Dinkova-Kostova, 2014). |
Transcription | NM_006164.4 (TV 1) comprises 5 coding exons and is approximately 2.8 kb in size; this transcript encodes the longest protein isoform. NM_001145412.2 (TV 2) and NM_001145413.2 (TV 3) comprise 4 coding exons each and are approximately 2.7 kb and 2.4 kb in size, respectively. MiRNAs |
Protein |
Note | Name: Nuclear factor erythroid 2-related factor 2. Short: NF-E2-related factor 2, NFE2-related factor 2. Alternatives names: Nuclear factor, erythroid derived 2, like 2, NF-E2 p45-related Factor-2. Nrf2, the nuclear factor erythroid 2 (NF-E2)-related transcription factor 2, was first described in 1994 by Moi et al. by screening for factors that could bind to a NFE2-binding DNA sequence. The human Nrf2 protein NP_006155.2 (encoded by TV 1) is 67.8 kDa in weight and consists of 605 amino acids; NP_001138884.1 (encoded by TV2) is 66.1 kDa in weight and consists of 589 amino acids; and NP_001138885.1 (encoded by TV3) is 65.4 kDa in size and consists of 582 amino acids. Nrf2 has been characterized as a modulator protein and is the core of the Nrf2 antioxidant system/pathway. Other main components of the pathway are Keap1, the negative regulator of Nrf2, and small Maf proteins which serve as cofactors for Nrf2 binding to regulatory DNA sequences of ARE-regulated genes (Moi et al., 1994; Li and Kong, 2009). |
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Structural and functional domains of Nrf2. A. Structural features of the human Nrf2 protein that dictate its activity. The interaction with Keap1 is mediated by the Neh2 (Nrf2 extended homology 2) domain of Nrf2. B. Nuclear localisation signals (NLS) and nuclear export signals (NES) have been detected in the Nrf2 sequence. The NESTA motif is the only one shown to be directly redox-sensitive. C. Specific cysteine residues have been characterised as reactive, meaning that they are sensitive to oxidation. Oxidative stress also activates intracellular kinases such as PKC and Fyn which in turn phosphorylate Nrf2 (on Ser40 and Tyr568, respectively) contributing to Nrf2 activation (Jain et al., 2005; Zhang, 2006). | |
Description | Nrf2 binds to ARE sites of antioxidant genes as a heterodimer. Specifically, Nrf2 heterodimerizes with small Maf proteins (which are themselves devoid of transcription activating domains) to induce the transcription of ARE-regulated genes. Other binding partners include members of the AP-1 transcription factor family like Jun and Fos. In contrast, homodimers or heterodimers of the different small Maf proteins, and heterodimers of Bach proteins with small Maf proteins on AREs, have been characterised as negative regulators of Nrf2 signalling pathway that compete with Nrf2 for binding to AREs. The co-factor CBP/p300 is indispensable for transcription activation by Nrf2 and localizes to ARE-binding sites in association with Nrf2-small Maf heterodimers (Dhakshinamoorthy et al., 2005; Ishikawa et al., 2005; Li et al., 2008; Hirotsu et al., 2012). |
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Crystal structures of the Nrf2-binding domain of Keap1 (Keap1 DC/Kelch domain) in complex with peptides derived from the Keap1-binding domain of Nrf2 (the DLG motif of the mouse Neh2 domain or the ETGE motif of the human Neh2 domain). | |
Expression | Nrf2 is considered to be ubiquitously expressed, as it has been shown to be expressed in various cell types (including lung, liver, kidney, stomach, small intestine, neurons, astrocytes, etc) and it has been considered a multi-organ protector that enhances the cellular resistance to potential harmful insults that occur during cells' normal activities and during environmental exposures. Morevoer, Nrf2 has been found to be overexpressed in various human cancers (Yoo et al., 2012; Lee and Surh, 2005). |
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A. Keap1 binds Nrf2 and inhibits its transcriptional activity. The depicted "hinge-and-latch" model proposes a 2:1 Keap1:Nrf2 molecular stoichiometry. B. At the basal cellular state (low oxidative burden), Nrf2 undergoes Keap1-Cul3-mediated poly-ubiquitination and proteasomal degradation. | |
Localisation | Nrf2 can be detected both in the cytoplasm and in the nucleus; the Keap1-mediated degradation of Nrf2 occurs in the cytoplasm. In addition, one of the proposed models for the Keap1-Nrf2 interaction suggests that a Keap1 dimer can bind one Nrf2 molecule and one PGAM5 molecule. PGAM5 possesses a N-terminal membrane targeting signal, through which the Nrf2-Keap1-PGAM complex is tethered to the cytosolic surface of the outer mitochondrial membrane. As a result, Nrf2 can be also localised in the perimitochondrial region (Sykiotis and Bohmann, 2010). |
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Two mechanistic models for the Nrf2-Keap1 interaction. Adapted from Sykiotis and Bohmann, 2010. | |
Function | The Nrf2/Keap1 pathway is a major mediator of cytoprotective responses to oxidative and electrophilic stress. Nrf2 responds to oxidative stress by inducing the transcriptional upregulation of a broad range of cytoprotective genes whose promoters contain Antioxidant Response Element (ARE) sequences. Specifically, Nrf2 translocates to the nucleus, heterodimerizes with small Maf proteins and binds to ARE sequences to induce gene transcription. When redox balance is restored, Nrf2 activity is repressed via export from the nucleus back into the cytoplasm and degradation via a Cullin - RING ligase 3 - Keap1 complex (CRLkeap1 complex), and by other mechanisms (Zhang, 2006). Oxidative stress and the antioxidant transcriptional response mediated by Nrf2 Activity and regulation of Nrf2 Activation of Nrf2 pathway Repression of Nrf2 signaling |
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Schematic overview of the main steps in the regulation of the Keap1-Nrf2 antioxidant response pathway. Adapted from Sykiotis and Bohmann, 2010. | |
Homology | Nrf2 belongs to a family of basic leucine zipper (bZip) transcription factors called cap'n'collar (cnc) proteins. Cnc proteins are defined by the presence of a conserved 43-amino acid cnc domain located N-terminally to the DNA-binding domain (bZip structure) and are conserved in invertebrates and vertebrates but not present in plants or fungi. The best studied cnc proteins are the C. elegans SKN-1 (Skin family member 1), the D. melanogaster Cnc (isoforms B and C), and four vertebrate counterparts: the p45 NFE2 (nuclear factor erythroid-derived 2) and the NFE2-related factors Nrf1, Nrf2 and Nrf3 ("the Nrfs"). In addition, the related transcription factors Bach1 and Bach2 are characterised by the additional presence of a BTB protein interaction domain (Sykiotis and Bohmann, 2010). Although most Cnc factors are transcriptional activators, Bach1 and Bach2 function mainly (through not exclusively) as transcriptional repressors (figure below). Some of the Cnc proteins have important roles in development; for example, CncB is required for the development of head segments in D. melanogaster. Other family members (including Nrf2) are dispensable for development but rather contribute to the maintenance of cellular homeostasis in response to endogenous or exogenous stressors. In particular, the three Nrfs have broad and partly overlapping expression patterns and function as stress-activated transcription factors (Sykiotis and Bohmann, 2010). |
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Mutations |
Somatic | Somatic mutations of the NFE2L2 gene have been detected in cancers. Mainly missense mutations and in frame insertions/deletions of NFE2L2 localised in the DLG and ETGE motifs of the Neh2 domain cause modifications in Nrf2 protein that lead to impaired interaction of Nrf2 with Keap1, and thereby to constitutive Nrf2 activation. Thus, the Nrf2 pathway is currently believed to have a role not only in cancer prevention via detoxification and maintenance of cellular homeostasis, but also in the cell growth and survival of malignant or premalignant cells. NFE2L2 mutations have been identified in oesophageal squamous cell carcinoma (8/70, 11.4%; 6/32, 18.8%), skin cancer (1/17, 6.3%; 1/22, 4.5%), non-small cell lung carcinoma (NSCLC, 6.9-10.7%), head and neck carcinoma (HN, 13-25%), cervical cancer (1/18, 5.6%) and papillary renal cell carcinoma (2 cases). Interestingly, lung cancer, and particularly non-small cell lung cancer, has been investigated for NFE2L2 mutations in various patient populations, and in all studies the presence of NFE2L2 mutations was positively correlated with smoking history. In addition, it has been observed that the frequency of NFE2L2 gene mutations is higher in lung squamous cell carcinoma than in lung adenocarcinoma (Shibata et al., 2008a; Kim et al., 2010; Solis et al., 2010; Shibata et al., 2011; Hu et al., 2012; Gañán-Gómez et al., 2013; Ooi et al., 2013). NFE2L2 polymorphisms |
Implicated in |
Note | |
Entity | Various cancers |
Note | The dual role of Nrf2: NFE2L2 has been found to have both cancer chemopreventive activity (by protecting cells from carcinogen-induced damage and transformation) and oncogenic activity (by conferring a survival advantage to pre-malignant or malignant cells). Thus, on the one hand, activation of Nrf2 upregulates various conjugating enzymes for the detoxification of chemical carcinogens and protects from carcinogenicity, mutagenicity and other forms of toxicity. Experimental disruption of Nrf2 is associated with increased susceptibility of cells to carcinogens. The chemopreventive properties of Nrf2 have been demonstrated in several experimental models of cancer including colon, bladder, lung, stomach, breast, skin and liver cancer. Importantly, inducers of Nrf2 pathway are being tested in clinic trials for cancer chemoprevention. On the other hand, in various cancers Nrf2 protein abundance and activity have been found to be increased, suggesting a role in tumour growth and survival. Gain of function somatic mutations in NFE2L2 gene which lead to disruption of the Nrf2-Keap1 binding interface complex result in upregulation of Nrf2 activity. These mutations have been identified in NSCLC, oesophageal squamous cell carcinoma, malignant melanoma, skin squamous cell carcinoma, head and neck carcinoma and cervical cancer. In addition, it has been reported that an indirect way of upregulation of Nrf2 activity is the loss of function KEAP1 somatic mutations. These mutations have been detected in various types of cancer [lung cancer (NSCLC), thyroid papillary cancer, oesophageal cancer, gastric adenocarcinoma, hepatocellular and cholangiocellular carcinoma, gallbladder cancer, colorectal adenocarcinoma, caecum carcinoma, breast ductal carcinoma and adenocarcinoma, endometrial adenocarcinoma, ovarian serous cancer and epithelial cancer, prostate adenocarcinoma, kidney and urinary tract cancer, malignant melanoma and neuroblastoma]. Another mechanism of constitutive activation of Nrf2 in cancer cells is the silence of KEAP1 gene caused by hypermethylation of KEAP1 gene promoter. This silencing mechanism of KEAP1 gene has been detected in human lung cancer tissue cells (squamous, adenocarcinoma, adenosquamous), lung cancer cell lines, human breast cancer tissues, colorectal cell lines, prostate cancer cell lines, human malignant gliomas and papillary thyroid cancer. Hypermethylation of CUL3 and RBX1 genes as well as CUL3, RBX1 and KEAP1 copy number losses have been proposed as further Nrf2 activation mechanisms in papillary thyroid carcinoma. Moreover, Nrf2 expression and activation can be induced by Nrf2 cross-talk with other signalling pathways. Specifically, it has been demonstrated that in acute myeloid leukaemia (AML) Nrf2 overexpression is driven by abnormal expression of Nuclear Factor-κB (NF-κB). In addition, in NSCLC cell lines constitutive activation of mutant epidermal growth factor receptor (EGFR) and RagD-mediated activation of mammalian target of rapamycin (m-TOR) signalling pathway cause overactivation of Nrf2 as well as Nrf2-mediated resistance to EGFR-tyrosine kinase inhibitor and m-TOR inhibitor, respectively. In renal cancer cells, Nrf2 activity has been found to be increased by downregulation of E-cadherin which normally forms a quanternary complex with Nrf2, Keap1 and β-catenin and facilitates Keap1-mediated ubiquitination of Nrf2. Finally, it has been observed that transcriptional coactivator amplified in breast cancer 1 (AIB1) stimulates Nrf2 activation in cholangiocarcinoma cells inducing tumour proliferation and chemoresistance. Thus, AIB1 has been proposed as a Nrf2 coactivator. In summary, the upregulation of Nrf2 has antioxidant as well as cytoprotective effect in cancer cells. Especially, cytoprotective activity of Nrf2 can be exploited by cancer cells not only to face their oxidant tumour microenvironment, but also confer chemo- or/and radio- resistance during anticancer therapies. Consequently, suppression of Nrf2 activity in cancer cells inhibits tumour growth and enhances the efficacy of chemotherapeutic agents. Therefore, Nrf2 could be a target not only for cancer chemoprevention (via activating compounds) but also for cancer treatment (via inhibitors) (Shibata et al., 2008a; Shibata T. et al, 2008b; Wang et al., 2008; Chen et al., 2010; Solis et al., 2010; Yoo et al., 2010; Kim et al., 2010; Shibata et al., 2010; Wang et al., 2010; Muscarella et al., 2011; Shibata et al., 2011; Chen Q et al., 2012; Guo et al., 2012; Hanada et al., 2012; Hu et al., 2012; Kim et al., 2012; Liao et al., 2012; Sporn and Liby, 2012; Yamadori et al., 2012; Barbano et al., 2013; Gañán-Gómez et al., 2013; Martinez et al., 2013; Shelton and Jaiswal, 2013; Shin et al., 2013; Ziros et al., 2013; Zhang et al., 2013; Funes et al., 2014; Gorrini et al., 2014; Ji et al., 2014; Onodera et al., 2014; Schultz et al., 2014). |
Disease | Lung cancer, thyroid cancer, ovarian cancer, breast cancer, prostate cancer, endometrial cancer, cervical cancer, gastric cancer, oesophagus cancer, colorectal cancer, gallbladder cancer, liver cancer, skin cancer, acute myeloid leukemia. |
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Exogenous Nrf2 inducers. | |
Entity | Airway diseases |
Note | Oxidative stress has been associated with the pathogenesis of many acute and chronic airway disorders. ALI and its severe form ARDS are characterised by severe systemic hypoxemia in seriously ill patients. Hypoxemia is associated with production of excessive ROS, and thus oxidative stress is a major contributor to the pathogenesis of ALI. In such hypoxic situations oxygen is one of the most commonly used supplemental therapeutic agents. However, oxygen supplementation-induced hyperoxia can also cause lung injury and airway inflammation. Nrf2 has been proposed as a hyperoxia susceptibility gene that modulates ALI in vivo. Emphysema is characterised by loss of pulmonary elasticity as a result of permanent alveolar wall destruction and represents the alveolar lesion in COPD. Cigarette smoke is a major contributor to emphysema and COPD pathogenesis. Chronic exposure to cigarette smoke in Nrf2 knockout (KO) mice causes more severe emphysema than in wild type mice. This is associated with greater levels of inflammation, oxidative stress and endothelial and epithelial cell apoptosis in the Nrf2 KO mice. LPS (lipo-polysaccharide)-induced septic shock in Nrf2 KO mice results in premature mortality in comparison with wild type mice, and non-lethal exposure to LPS results in greater lung inflammation and injury in Nrf2 KO mice. Regarding asthma disease, it has been observed that the disruption of Nrf2 can cause severe airway inflammation and airway hyper-responsiveness in mouse models of asthma. IPF is a fibroproliferative disease thought to be triggered by repeated alveolar epithelial cell injury. Rodent models of bleomycin-induced lung fibrosis have been used to study IPF. The pulmonary fibrogenic effects of bleomycin are antagonised by antioxidant enzymes like SODs in rodents. Moreover, it has been noticed that Nrf2 KO mice treated with bleomycin had elevated levels of TGF-β, the main fibrogenic factor. Finally, it has been reported that Nrf2 has a protective role against airway infection by RSV in mice (Reddy, 2008; Cho and Kleeberger, 2010). |
Disease | Acute lung injury (ALI), emphysema/chronic obstructive pulmonary disease (COPD), lung disorder during sepsis [LPS (lipo-polysaccharide)-induced septic shock], asthma/allergic airway diseases, idiopathic pulmonary fibrosis (IPF), viral airway disease (RSV - respiratory syncytial virus) |
Entity | Cardiovascular disease |
Note | Nrf2 is expressed in the cardiovascular system (heart and blood vessels), and Nrf2 signaling is implicated in the regulation of vascular homeostasis and in the prevention of cardiac hypertrophy and heart failure via suppression of oxidative stress. Although Nrf2 has been proposed as a therapeutic target in cardiovascular diseases like atherosclerosis, there is some evidence that reveal the role of Nrf2 as pro-atherogenic factor via a different mechanism. Nevertheless, modulation of Nrf2 has been supported for the prevention and the treatment of heart diseases (Sussan et al., 2008; Koenitzer and Freeman, 2010; Freigang et al., 2011). |
Entity | Diabetes, diabetic nephropathy, diabetic neuropathy |
Note | Nrf2-mediated expression of endogenous cytoprotective enzymes and other antioxidant molecules has been shown to be an adaptive defence mechanism against high glucose-induced oxidative damage in diabetes. Diabetic nephropathy and neuropathy have been studied in correlation with the activity of Nrf2 pathway, and it has been found that Nrf2 exerts a protective role against these long-term complications of diabetes (Jiang et al., 2010; Cheng et al., 2011; Negi et al., 2011). |
Entity | Obesity/metabolic syndrome |
Note | While it appears that the Nrf2 pathway is a regulator of energy metabolism, its precise effects and the underlying mechanisms are still controversial. In some contexts Nrf2 is protective and high-fat diet-induced obesity, while in others it is a contributing factor to metabolic disease. Nrf2 can induce several metabolic regulators in adipose tissue and liver such as PPARγ, C/EBPβ and AhR, and it can repress others such as FGF21. The exact mechanisms by which Nrf2 cross-talks with these factors are the focus of ongoing research (Chartoumpekis and Kensler, 2013). |
Entity | Liver and gastrointestinal diseases |
Note | Nrf2 has been demonstrated to be a key factor dictating susceptibility to oxidative and chemical-induced injury in the gastrointestinal system. In vivo experiments have revealed that Nrf2 KO mice are more susceptible to acetaminophen-induced hepatocellular injury, benzo(a)pyrene-induced tumour formation, and Fas- and TNFα-mediated hepatocellular apoptosis. In addition, Nrf2 may be important in protecting against liver fibrosis and gallstone development. Regarding intestinal diseases, it has been suggested that Nrf2 plays an important role in the maintenance of intestinal integrity and may serve as novel target for therapies to prevent or treat Crohn's disease or ulcerative colitis (Aleksunes and Manautou, 2007). |
Disease | Drug-induced hepatotoxicity, hepatocellular apoptosis, liver fibrosis, gallstone disease, bowel diseases (Crohn's disease and ulcerative colitis), chemical carcinogenesis in the gastrointestinal system |
Entity | Neurodegenerative diseases |
Note | Oxidative stress is involved in the pathogenesis of a wide range of chronic neurodegenerative diseases such as AD, PD and HD. AD is characterised by increased accumulation in the brain of neurotoxic and oxidative elements such as iron. In addition, increased oxidative damage of proteins and lipid peroxidation has been detected in the brain of AD patients. Reactive astrocytes and activated microglia contribute to the oxidative stress observed in AD brain. The expression profile of Nrf2 and ARE-regulated proteins in AD brain tissue supports the hypothesis that Nrf2 signalling may be involved in the early stages of AD. PD, the second most common neurodegenerative disease after AD, is characterised by the preferential loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction and neuroinflammation in PD play a crucial role in PD pathogenesis and the subsequent oxidative stress has been suggested to be responsible for the degeneration of nigral dopaminergic neurons. Nrf2 pathway may have a neuroprotective effect on PD and its activation may be a novel therapeutic approach. HD is a rare neurodegenerative disorder inherited in an autosomal dominant manner. Work in mouse model has shown that Nrf2 can have neuroprotective roles against HD and might be a novel treatment target for HD. Furthermore, it has been reported that Nrf2 can also potentially protect from neuronal damage in other neurological diseases such as ALS, Freidrich's ataxia, Down syndrome, multiple sclerosis, traumatic brain injury and cerebral haemorrhages (Ramsey et al., 2007; Calabrese et al., 2008; de Vries et al., 2008; Jazwa et al., 2011; Tufekci et al., 2011). |
Disease | Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease(HD), Freidrich's ataxia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Down syndrome, traumatic brain injury, cerebral haemorrhage |
Entity | Rheumatoid arthritis |
Note | ROS play an important role in the pathogenesis of rheumatoid arthritis (RA), and antioxidant substances and enzymes reduce cartilage damage in animal models of RA. It has been reported that a deficiency in Nrf2-mediated antioxidant defences plays a central role in pathogenesis of RA. Oxidative stress is one of the factors that contribute to RA, and Nrf2 could play an important role in alleviating its effects (Wruck et al., 2011). |
Entity | Uveitis |
Note | Uveitis is an inflammatory eye disease that can cause blindness. The main characteristic of uveitis is an inappropriate innate immune response resulting in local tissue injury. ROS production with secretion of inflammatory cytokines and leukocytes infiltration has been documented in a model of LPS-induced uveitis. In this model, due to an inadequate activation of Nrf2, the induction of antioxidant and anti-inflammatory responses is also incomplete. Potentiation of the antioxidant response with an Nrf2-inducing compound led to increased enzyme expression of protective enzymes, reduced cytokine expression, and decreased leukocyte adhension, suggesting Nrf2 as a potential therapeutic target in uveitis (Nagai, 2009). |
Entity | Aging |
Note | A popular "hypothesis" about the causes of aging is the "free radical theory", which considers aging as the result of progressive damage to macromolecules and cellular structures caused by exposure to endogenous and exogenous pro-oxidant substances, notably free radicals. Nrf2 and its homologues in invertebrate models of aging have been shown to exert anti-aging and pro-longevity functions. Nevertheless, Nrf2 activity generally declines with age, and this decline is associated with decreased expression and/or inducibility of antioxidant genes. Overall, it is believed that, if properly fine-tuned, the Nrf2 pathway can have life span-extending effects, and can therefore be a target for promoting longevity and extending the disease-free period of life (the "health span") (Sykiotis and Bohmann, 2010). |
To be noted |
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Citation |
This paper should be referenced as such : |
Stavroula D Manolakou, Panos G Ziros, Gerasimos P Sykiotis |
NFE2L2 (nuclear factor, erythroid 2-like 2) |
Atlas Genet Cytogenet Oncol Haematol. 2015;19(8):503-521. |
Free journal version : [ pdf ] [ DOI ] |
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