Nrf2 target genes. Target Genes and Antioxidant Defense.


Nrf2 target genes The authors attribute this Aug 15, 2022 · interaction. e. NRF2 possesses a bZIP-containing C-terminal domain, capable of heterodimerizing with small NRF2 mRNA level was positively correlated with expression of investigated NRF2-target genes. 202 However, in primary astrocytomas, an Next, to elucidate the role of these NRF2-target genes regulated by GAS41 in ferroptosis defense, we restored SLC7A11, GCLC, and NQO1 expression in A549 sgGAS41 cells, respectively, and tested . Fig. In glioma model, pelargonidine has been reported to deploy its activities via inhibition of phosphorylation of Akt, PI3K The obvious upregulation of Nrf2 target genes in mouse aortic ECs only between days 10 and 14, after the onset of inflammation and LPO, suggests a potential causal relationship with Nrf2 activation. These results highlight the non Sep 21, 2023 · Luteolin induced the degradation of Nrf2 mRNA in A549 cells , resulting in the downregulation of Nrf2 target genes and increased sensitivity of A549 NSCLC cells to chemotherapy drugs . 18 μg/L). (A) Wt and AMPK −/− MEFs were treated with DMSO (0. The aim of our study was to determine the effect of 3-pyridinylboronic acid in rotenone-exposed zebrafish embryos, focusing on oxidant-antioxidant parameters and gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes gclm, gclc, hmox1a, nqo1, and PD related genes, brain-derived neurotrophic factor, dj1, and tnfα. Hmox-1 versus Gclc) was not confined to Sfn, but recapitulated by xanthohumol, CDDO-Im or tert-butylhydroquinone, other well-known Nrf2 activators [28, 29] (Supplemental Fig. Genome-wide search for Nrf2 target genes has led to the identification of an array of ARE-regulated genes, providing a rational explanation for the multiple functions of Nrf2 (5, 12, 17). ML385 is an inhibitor of the Nov 18, 2024 · Elucidating how Nrf2 preferentially upregulates target genes to avert various forms of oxidative cell death could facilitate the design of new treatments and preventative strategies for iron Jun 30, 2022 · NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. NRF2 has become a prime target for research in the field of inflammation, cancer metabolism, cancer prevention and cancer treatment. AMPK-mediated boosted transcription of selected Nrf2 target genes is confirmed by qPCR analysis. Furthermore, stable knockdown of NRF2 negative regulator KEAP1 Aug 12, 2023 · Interestingly, following transfection of NRF2 siRNA, the SMN mRNA level was dramatically reduced concomitantly with the reduced mRNA levels of the well-known NRF2 target genes heme oxygenase 1 (HO Dec 9, 2021 · Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and To further explore the mechanism underlying NRF2-dependent cisplatin resistance, we stably overexpressed or knocked down NRF2 in parental and cisplatin-resistant human ovarian cancer cells, respectively. Other recent studies have shown that sulfiredoxin induction via Nrf2 may form an important part of the protective response to oxidative stress in the lung, preventing peroxiredoxin hyperoxidation and, in Similarly, in primary cardiomyocytes, high glucose concentrations induce ROS production that is associated with increased mRNA and protein expression levels of Nrf2 and several of its target genes; however, in Nrf2 KO Moreover, the Nrf2–EpRE pathway is attenuated at the time of Aβ deposition in the transgenic mice APP/PS1. The transcription factors Bach1 and Bach2 belong to a family of factors with a leucine zipper in the basic region. Luteolin induced the degradation of Nrf2 mRNA in A549 cells , resulting in the downregulation of Nrf2 target genes and increased sensitivity of A549 NSCLC cells to chemotherapy drugs . Aberrant activation or inhibition Pelargonidin also decreases the DNA methylation in the Nrf2 promoter region, and increases expression of downstream target genes of Nrf2 e. Interestingly, the induction of frrs1c and gclc in liver and nose, respectively, was quite low and that of hmox1a was restricted in the liver. Importantly, in vitro Nrf2 over-expression protects against neurotoxicity of Aβ. Molecular weight marker sizes (kD) are shown on the left of the blots. The stability of NRF2 can be rapidly increased when the cell suffers from oxidative or electrophilic stress, resulting in the upregulation of NRF2 and subsequently increased expression of NRF2 target genes [42, 43]. et al. Mol Cell Biol. Oct 23, 2018 · The C-terminal Neh3 domain harbors transactivation activity and functions in concert with the Neh4 and Neh5 domains to activate transcription of Nrf2 target genes (71, 120, 143). The potential cooperation of this with the activity-dependent induction of astrocytic Nrf2 reported by Habas et al. 10 ± 15. Since the previous pathway analyses were done with a program not searching for Nrf2 target genes, respective genes were manually selected and confirmed by qPCR. IL-6 signaling activates and phosphorylates the The Neh4 and Neh5 domains are also important for the transactivation of NRF2 target genes and interact with cAMP response element-binding protein (CREB)-binding protein (CBP) and/or receptor-associated coactivator (RAC) [37,38]. Presence of an inhibitor of AMPK significantly reduced the levels of NRF2 and knockdown of NRF2 decreased the beneficial effect of CTRP9 in HG-stressed cells. Nrf2 is a major transcription factor that significantly regulates—directly or indirectly—more than 2000 genes. Aug 8, 2024 · Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox-regulatory capacity. The Bach1/Maf dimer competes with the Nrf2/Maf heterodimer, which binds to the same binding site in the ARE, leading to the activation and inhibition of downstream target genes of Nrf2 under different conditions [34], [35]. Feb 1, 2020 · Mitochondrial dynamics regulate the fate and metabolic identity of NSCs by modifying physiological ROS signaling and activating developmental gene expression via a Nrf2-dependent retrograde pathway [63]. May 25, 2013 · 1. Target Genes and Antioxidant Defense. The Neh6 domain negatively regulates NRF2 through DSGIS and DSAPGS motifs, β-transducin repeat-containing protein In fact, NRF2 target genes are involved in glutathione synthesis, peroxide reduction, xenobiotic detoxification, proteasome assembly, autophagy, transport and storage of iron, lipid catabolism, and carbohydrate metabolism (Dodson et al. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. Oct 25, 2011 · The Keap1-Nrf2 system serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than one hundred cytoprotective proteins, including antioxidants and phase 2 detoxifying Five novel NRF2 target genes were chosen for followup: AMBP, ABCB6, FECH, HRG-1 (SLC48A1), and TBXAS1. By acting as a physiological repressor of NRF2 target genes at the ARE-binding site, knockdown or nuclear exclusion of BACH1 holds promising potential for reactivating the downregulated activity of NRF2 associated with disease. , 1994 ), and has been widely used Dec 10, 2024 · Nrf2 target genes such as HO-1 and NQO-1 have been demonstrated to be implicated in this process. Mar 1, 2023 · Inducible transcription factor NRF2 (encoded by NFE2L2) is a member of the human cap’n’collar (CNC) basic-region leucine zipper transcription factor family. The multivariate linear regression adjusting for selenium status showed that plasma Se level was significantly inversely associated only with expression of GSTP1 (β-coef. These targets can be divided into three broad classes: iron/metal metabolism, intermediate metabolism The Nrf2 gene itself was dominantly expressed in these three tissues, implying that tissue-restricted induction of Nrf2 target genes is defined by tissue-specific expression of Nrf2. A central theme emerging from the identification of these target genes and their functions is resistance to oxidants and Aug 29, 2024 · (b) (One-way ANOVA with Sidak’s post hoc test; at least N = 3). Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. A decrease in NRF2-target gene mRNA and protein product levels were observed after brusatol treatment in multiple cell lines with high basal NRF2 levels, indicating disruption of the NRF2 pathway. However, it has been shown that the level of Nrf2 decreases with age and GENE-BASED THERAPIES TO TARGET MUTANT NRF2 IN CANCER CELLS Strategies to attenuate Nrf2 overactivation. Transient activation of NRF2 in healthy tissues has been long recognized as a cellular defense mechanism and is critical to prevent cancer initiation by carcinogens. NQO1 and HO-1 at concentrations upto 50 µM . Pharmacological activation of NRF2 is supposed to improve renal function, but data concerning the NRF2 activity in human CKD are lacking. 009), PRDXR1 (β-coef. Biotinylated wild type (WT; ATGACTCAGCA) or mutant (MT; AACTCTCACGA) ARE‐containing oligonucleotides were incubated with A549 WT or NRF2 knockout (KO) cell lysate and e Western blot analyses of NRF2 target genes in the AA2G-primed hES-MSCs and hUC-MSCs expressing shCTR or shATF2. This great expansion in the regulatory capacity of Feb 20, 2022 · NRF2 target genes are involved in almost every aspect of metabolism, including maintaining redox homeostasis, mediating lipid, carbohydrate and iron processing, coordinating phase I, II and III xenobiotic metabolism, and controlling proteostasis []. A549 cells (upper Apr 1, 2015 · Mean plasma Se level was found to be 51. Because OSGIN1 gene expression is activated prior to classical NRF2 targets, OSGIN1 may function to induce P53 translocation to the nucleus where it can interact with NRF2 to regulate other NRF2 target genes. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can increase the sensitivity of the cells to oxidants and electrophiles. The The first miRNA to be identified as a negative regulator of Nrf2 expression was miR-144, which suppresses Nrf2 expression and the activation of its target genes through targeting of two distinct sites at positions 265–271 and 370–377 of the As discussed here, the proximal AP-1 site of the sulfiredoxin promoter is embedded within the ARE, as is common with Nrf2 target genes. While many of these genes are involved in maintaining redox balance, others are involved in maintaining balance among metabolic pathways that are seemingly unrelated to oxidative stress. J. , SLC7A11, GPX-4, and autophagy protein ATG5, that are responsible for preventing lipid peroxidation and thus combating ferroptosis are Nrf2 target genes [31]. Therefore, in a cancer context, the loss of NRF2 as a result of aging can lead to tumorigenesis, mainly as a result of We would like to show you a description here but the site won’t allow us. We designed a cell-based RNAi screen to identify factors that affect transcription Jan 9, 2023 · Inducible transcription factor NRF2 (encoded by NFE2L2) is a member of the human cap’n’collar (CNC) basic-region leucine zipper transcription factor family. Many proteins and enzymes, i. The authors conclude that the hepatic activation of Nrf2 is more important for detoxification than for antioxidant defense. Oct 19, 2022 · Currently, many NRF2 target genes have been found to participate in the regulation of ferroptosis, and exactly which one plays a dominant role seems unclear. At the same time, NRF2 and its downstream genes are overexpressed in many human cancer tissues, providing a Previous studies suggested that Nrf2 and its target genes are involved in antioxidant responses under the exposure of environmental contaminants both in vivo and in vitro (Li et al. This likelihood is further supported by the observation that treatment with TNF-α, 4-HNE, erastin and Fer increased the expression of Nrf2 target Nrf2 is a key regulator of the cellular antioxidant response and controls the expression of genes that resist oxidative and electrophilic stress. Biol. Oxidative stress can be caused by an imbalance between the production of reactive oxygen and the system’s ability to Apr 21, 2014 · Habas et al. The protein products of its target genes perform versatile Jun 1, 2021 · Since its initial discovery over 25 ago [1], nuclear factor-erythroid 2-related factor 2 (Nrf2) has become known as one of the most important factors in the cell that regulates cytoprotective responses to environmental stressors [2, 3]. The Neh6 domain is a serine-rich region that is involved in the negative regulation of Nrf2 stability independent of Keap1. The protein products of its target genes perform versatile cytoprotective functions, including antioxidant, anti-inflammatory, metabolic, and drug-metabolising, and also have roles in the maintenance of May 23, 2016 · In contrast to the situation that Nrf2 directly binds to a number of detoxifying and antioxidant target genes through ARE and activates expression of these genes, IL6 gene appears to be regulated Jul 17, 2024 · Nrf2 target genes, including solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), glutamate cysteine ligase (GCL), and glutathione synthetase (GSS), are Jul 6, 2020 · Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. would be an intriguing topic for further investigation. However, there is increasing evidence that Nrf2 and its downstream target genes are overexpressed in many types of human cancer 34 and that it may play an important role in the development and Habas et al. Jun 3, 2024 · In this study, we demonstrated that oncogenic transcription factor KLF5, acting as a NRF2 target gene, activates the transcription of SLC1A5 via a specific GC-rich motif sequence. However, cancer cells frequently Jan 4, 2019 · Jain, A. The authors attribute this Jul 1, 2017 · Previous studies suggested that Nrf2 and its target genes are involved in antioxidant responses under the exposure of environmental contaminants both in vivo and in vitro (Li et al. , 2020). 1%) or sulforaphane (Sfn, 5 μM) for 4 h before RNA was isolated, reversely transcribed and subjected to qPCR analysis for hmox1, akr1c14, nqo1, gclc, txnrd1 and gsta4 as indicated (hprt1 as reference gene). Moreover, NRF2 target genes are also critical mediators to enhance the metabolism of pro-tumorigenic xenobiotics. 25 μg/L (range 23. Protection achieved is associated to an increase in the expression of Nrf2 target genes, and the consequent reduction of oxidative stress. in their recent analysis of the response of NRF2 target genes and other relevant categories of biomarkers across a large Accordingly, p21 −/− mice show reduced levels of Nrf2 protein and Nrf2 target genes . It is noteworthy that sustained activation of Nrf2 lies in its genetic alterations, which encompass DNA amplification and somatic point mutations, suggesting the potential application of gene therapy targeting the gene for Nrf2. Breakdown products of neoglucobrassicin inhibit activation of Nrf2 target genes mediated by myrosinase-derived glucoraphanin hydrolysis products as typical phase 2 enzyme, and glutathione peroxidase 2 (GPx2) as novel Nrf2 target in HepG2 cells. The transcription factor NRF2 coordinates the expression of a vast array of cytoprotective and metabolic genes in response to various stress inputs to restore cellular homeostasis. A central theme emerging from the identification of these target genes and their functions is resistance to oxidants and NRF2 is a key transcription factor in the antioxidant and anti-inflammatory response []. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant Feb 1, 2024 · The regulation of canonical Nrf2 target genes by TAp63 identified via our comparison across epithelial tissues is noteworthy, because it may underlie the commonalities shared by mouse models lacking either of these transcription factors, such as reduced fatty acid oxidation, increased fatty acid synthesis, insulin resistance, and liver steatosis . 3. The transcription factor Nrf2 is the major modulator of the redox biology in mammalian cells. , 2014; To et al. Marcos Roberto de Oliveira, in Oxidative Stress and Dietary Antioxidants in Neurological Diseases, 2020. reported that the novel Nrf2 target gene, ABCF2, plays a critical role in cisplatin resistance in ovarian cancer, and targeting Nrf2 signaling may be a potential strategy to improve B RNA sequencing revealed that the Nrf2 target genes NQO1, GCLM, and HMOX1 were upregulated after 48 h of CEP treatment of AGS cells, while the SOD2 gene was downregulated. Jan 5, 2022 · Exposure of oxidative insults halts polyubiquitination of NRF2, which causes NRF2 to translocate into the nucleus and initiates transcriptional activation of phase II cytoprotective enzymes by binding to the antioxidant response element (ARE), a cis-acting motif sequence existing in the promoter of NRF2 target genes . Breakdown products of nGBS potently inhibit both GRA-mediated stimulation of NQO1 enzyme and Gpx2 Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. 2024 Feb 1 ΔNp63 physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes, thus ultimately leading to the regulation of unique transcriptional programs and Target Genes and Antioxidant Defense. Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox-regulatory capacity. , 2005, Osburn and Kensler, 2008). Data from other labs have already identified the ability of P53 and OSGIN1 to interact in the cytoplasm, but there may also be a role for Of the NRF2 target genes, Nqo1 encodes a representative marker enzyme that has been exploited for the evaluation of NRF2 activity . A total of 260 This, in turn, hinders the proper functioning of the KEAP1-CUL3 E3 ubiquitin ligase complex, which is responsible for ubiquitinating and degrading NRF2. a Sep 4, 2021 · Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. These two pairs of stable cell lines were then subjected to microarray analysis, where we identified 18 putative NRF2 target genes. This study proposes that FSP1 is the key effector in NRF2-mediated ferroptosis resistance and radioresistance in KEAP-deficient lung cancer cells, as we discussed in the manuscript. Furthermore, the mRNA levels of NRF2 target genes, including GSTP1, GSTM1 and heme oxygenase-1 (HO-1), are reduced in D117E- and Q141H-expressing 293T cells compared with cells expressing wild-type NRF2, and these NRF2 variants are proposed to be associated with the pathogenesis of Parkinson’s disease in Chinese populations . Additionally, it has been verified that p62 is a downstream target gene of NRF2, creating a positive feedback loop. Regulation of NRF2 Recent studies have identified new NRF2 target genes and revealed several new functions of NRF2 that go beyond its redox-regulating capacities, including regulation of inflammation, Nrf2-mediated regulation of gene expression depends on the cellular context, the inducing agent, the levels of Nrf2 activation, the recognition of the ARE, binding partners, cofactors and competitors, the crosstalk with other signaling Jun 1, 2024 · Our findings are in agreement with those of Yagishita et al. While NRF2 activation has Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Sulforaphane and its modulation of brain redox status: The mitochondria as a target. Oxidant stress stimulates expression of the human peroxiredoxin 6 gene by a transcriptional mechanism involving an antioxidant response element. These are both Nrf2 target genes, as confirmed below: the Nrf2 activator tert-Butylhydroquinone (tBHQ) Because OSGIN1 gene expression is activated prior to classical NRF2 targets, OSGIN1 may function to induce P53 translocation to the nucleus where it can interact with NRF2 to regulate other NRF2 In order to further assess the relationship between NRF2 and NFE2 in erythroid cells, we selected five novel NRF2 candidate target genes identified by overlap between NRF2 ChIP-seq in lymphoid cells and NFE2 ChIP-seq in K562 cells. Nrf2 also modulates substrate utilization for In the liver of Nrf2 −/− mice, most of the known Nrf2 target genes were down-regulated, whereas mainly enzymes for detoxification were increased in Keap1 knockdown mice characterized by an increased Nrf2 activation . When the promoter region of CpG island is methylated, it is difficult for transcription factors to recognize the promoter, and gene expression is turned off, thus blocking the transcription of Nrf2 target genes . NRF2 activity was assessed across ~9840 microarray comparisons from ~1460 studies examining the effects of ~2260 chemicals in human cell lines. Reduced nuclear factor erythroid 2-related factor 2 (NRF2) pathway activity was reported in models of chronic kidney disease (CKD). After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to Aug 10, 2013 · Aims: The signaling molecule hydrogen sulfide (H2S) protects cells against oxidative stress and activates NF-E2 p45-related factor 2 (Nrf2), a transcription factor that regulates antioxidant genes. b ChIP-seq profiles at the NOTCH3 locus. As a result Aug 1, 2016 · NRF2 is activated in LKO skin and Lce1 genes are transcriptionally upregulated along with other known NRF2 target genes in LKO skin. g. NRF2 mRNA level was positively correlated with expression of investigated NRF2-target genes. While demethylation of CpG island enhances the expression of Nrf2 in cells . These genes are known to be involved in heme metabolism and iron homeostasis, and we evaluated their protein and NRF2 target genes are also critical mediators of xenobiotic/drug metabolism, which plays an important role in processing harmful xenobiotics into their less toxic forms, preventing carcinogen accumulation and cancer initiation. It mediates the induction of phase II antioxidant defense enzymes, activating transcription through the ARE sequence present in the promoter region of target genes []. Transient Nrf2 activation, by its specific activators, has protective Sep 7, 2021 · Triptolide Inhibits NRF2 Target Genes by Increasing Cytoplasmic Localization of NRF2 in A549 Cells. mRNA expression of the Nrf2-target genes HO-1 (c) and NQO1 (d) were analyzed by reverse transcription quantitative PCR (RT-qPCR Download Table | Antioxidant genes regulated by Nrf2. Mar 27, 2013 · To evaluate NRF2-inducible genes in normal human cells, we monitored the expression pattern of NRF2 target genes following the treatment of HK-2 with already characterized chemical activators. Aug 29, 2023 · Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. The other Nrf2/Maf dimer target genes are those for Severe selenium-deficiency has been found previously to influence Nrf2-regulated genes of the adaptive response. Jan 1, 2017 · The first miRNA to be identified as a negative regulator of Nrf2 expression was miR-144, which suppresses Nrf2 expression and the activation of its target genes through targeting of two distinct sites at positions 265–271 and 370–377 of the Jul 24, 2024 · A more recently established target in the antioxidant pathway is BACH1, which serves as a negative regulator of NRF2. Overall, the observed AMPK-mediated boost in transactivation of a subset of Nrf2 target genes involves downregulation of Bach1 and subsequent favored binding of activating Nrf2 over repressing Bach1 to the May 11, 2012 · This validation set is not comprehensive, and additional genes remain to be validated by silencing and ChIP-PCR, but these experiments reveal a number of potentially important new NRF2 target genes, particularly RXRA. Nrf2 is a member of the cap'n'collar family of transcription factors whose major function is to facilitate the transcription of genes To this group belongs HO-1, catalyzing heme molecule breakdown, and subunits of the ferritin complex, responsible for iron transport and storage: a ferritin light-chain protein encoded by the FTL gene, and a ferritin heavy polypeptide that is a ferroxidase enzyme encoded by the FTH1 gene. p62 is a target of Nrf2, indicating that a feedback loop is present in the p62-Keap1–Nrf2 axis. ML385 is an inhibitor of the More recent studies have identified numerous new NRF2 target genes and had revealed several new functions of NRF2 that go beyond its redox-regulating capacity. In contrast, during tumor progression, Nrf2 activity can contribute to chemoresistance and the ability of tumor cells to circumvent apoptosis, whereas the inhibition of Nrf2 provokes cancer drug susceptibility and the loss of Dec 1, 2019 · Nuclear factor erythroid 2-like factor 2 (Nrf2) is a transcription factor that controls both the basal and inducible expression of a battery of cytoprotective genes which protect cells from damage by intracellular oxidative stress and extracellular oxidizing agents, and create intracellular redox homeostasis via transcriptional activity and interaction with kelch-like ECH Jul 13, 2020 · Figure 2. ML385 is Our studies suggest that, while Nrf2 activators alone cannot induce Nrf2-target gene expression or α-synuclein clearance in cortical neurons, epigenetic de-repression of Nrf2 prior to Nrf2 One of the negative regulators of the Nrf2 pathway is BACH1 (BTB domain and CNC homolog 1), which competes for binding to the promoters of Nrf2 target genes such as HMOX-1 and p62 . Oct 24, 2024 · In vivo, both ADJ-310 and PRL-295 improved wound healing in Leprdb/db diabetic mice and upregulated known downstream NRF2 target genes in treated tissue. Identification of expression signature of genes regulated by KEAP1-NRF2-CUL3 axis in TCGA-HNSCC. In an attempt to find out a novel NRF2 inhibitor, we have exposed A549-ARE-GFP-luciferase cells and H1299-ARE-GFP-luciferase cells to 10 nM of 2,650 chemicals from a natural compound library for 24 h . promoting nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes (PubMed Sep 28, 2020 · The biomarker was comprised of many well-known NRF2 target genes (AKR1B10, AKR1C1, NQO1, TXNRD1, SRXN1, GCLC, GCLM), 69% of which were found to be bound directly by NRF2 using ChIP-Seq. Importantly, p21-dependent protection from oxidative stress requires Nrf2, as colorectal cancer HCT116 cells overexpressing p21 demonstrate enhanced Jul 6, 2020 · Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of Jan 9, 2023 · In both cases, newly synthesised NRF2 accumulates, undergoes nuclear translocation, and as a heterodimer with a small musculoaponeurotic fibrosarcoma (sMAF) transcription factor, binds to specific sequences called Aug 15, 2022 · Activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is emerging as an attractive therapeutic approach to counteract oxidative stress, Jan 6, 2022 · The transcription factor NRF2 coordinates the expression of a vast array of cytoprotective and metabolic genes in response to various stress inputs to restore cellular Jul 6, 2020 · Recent studies have identified new NRF2 target genes and revealed several new functions of NRF2 that go beyond its redox-regulating capacities, including regulation of inflammation, autophagy, metabolism, proteostasis, and Similarly, in primary cardiomyocytes, high glucose concentrations induce ROS production that is associated with increased mRNA and protein expression levels of Nrf2 and several of its target genes; however, in Nrf2 KO cells, ROS levels Mar 1, 2024 · This prevents the formation of the NRF2-KEAP1-CUL3 complex required for NRF2 degradation, resulting in NRF2 accumulation and constitutive activation of its target genes 80,81. 86–96. IL-6 is a pleomorphic cytokine generated by multiple tissues throughout the body. Nrf2 also modulates substrate utilization for Apr 10, 2024 · To evaluate the impact of these NRF2 target genes on TNBC prognosis, we plotted the significance (−log 10 of p-values) of logrank tests for DEGs downregulated by Cyss depletion using the Kaplan May 20, 2021 · NRF2 is a short-life protein whose basic level and half-life time can vary dramatically among cell lines [37]. In NRF2-induction experiments utilizing cell culture systems, Nqo1 mRNA is usually highly upregulated approximately 12 h and longer after exposure to electrophilic NRF2-inducers . Note that TRIM21, a ubiquitin E3 ligase, negatively regulates the p62-Keap1–Nrf2 axis by undoing p62 oligomerization following Bao et al. Further analysis will be needed to establish their functional importance within the NRF2-regulated pathway. An NRF2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. 8). We sought to establish whether H2S requires Nrf2 to protect against oxidative stress, and whether activation of Nrf2 by H2S involves antagonism of Kelch-like ECH Low levels of Nrf2-target genes (reducing ROS levels and eliminating xenobiotics) can lead to tumorigenesis upon stress. Dysregulation is associated with chemoresistance and For example, we and colleagues have studied the transcriptional regulation of sulfiredoxin 1 (Srxn1) and xCT (2, 3). Nrf2 target genes are closely associated with inhibiting the ferroptotic cascade [9]. For example, NQO1 overexpression in macrophages through the activation of Nrf2 derives in a Sep 28, 2021 · Nuclear Keap1 facilitates nuclear export of Nrf2, and the cycle of Keap1-mediated ubiquitinylation and degradation in the cytosol resumes. The decline in rat NSCs with age correlates with reduced Nrf2 expression and the Nrf2 target gene GCLM [64]. 12 This transcription factor is maintained in the cytoplasm in an Sep 11, 2020 · Nuclear factor-E2-related factor 2 (Nrf2) is a key transcription factor known to be involved in maintaining cell redox balance and signal transduction and plays central role in reducing intracellular oxidative stress damage, delaying cell senescence and preventing age-related diseases. Thus, determining how NRF2 and its downstream effectors promote tumor survival and resistance in Jan 1, 2020 · The boosted induction of selected Nrf2 target genes in the presence of AMPK (i. 2005;25:4914–23. 2009. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. qPCR revealed an induction of phase II (Nqo1, Gsts, Sult1b1 and Ugt1a6 Dec 25, 2024 · Complete information for NFE2L2 gene (Protein Coding), NFE2 Like BZIP Transcription Factor 2, including: function, proteins, disorders, pathways, orthologs, and expression. These events effectively “turn off” the transcription of the Nrf2 target genes, and the May 1, 2019 · NRF2 target genes are involved in preventing lipid peroxidation and ferroptosis. While, given the Feb 1, 2024 · Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses Cancer Res Commun. , 2015). Keap1 is degraded together with the autophagic cargo. Scale bars = 20 μm. 0-CRTP9. 1%) or sulforaphane (Sfn, 5 μM) for 4 h before RNA was isolated, reversely transcribed and subjected to qPCR analysis for hmox1, akr1c14, nqo1, gclc, txnrd1 and gsta4 as indicated (hprt1 as Nov 23, 2020 · Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer’s disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. from publication: The Nrf2 System as a Potential Target for the Development of Indirect Antioxidants | Oxidative stress causes damage to Jul 14, 2020 · We here examined the influence of AMPK on Nrf2-dependent gene transcription and the potential interplay of the two cellular stress hubs. We investigated the NRF2 target NAD(P)H:quinone oxidoreductase 1 (NQO1) as a readout A more recently established target in the antioxidant pathway is BACH1, which serves as a negative regulator of NRF2. Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to We further found that CsA treatment significantly repressed NRF2-driven luciferase activity and inhibited the expression of two classical NRF2 target genes, heme oxygenase 1 (HMOX1) and NAD(P)H Currently, many NRF2 target genes have been found to participate in the regulation of ferroptosis, and exactly which one plays a dominant role seems unclear. observe that in mixed neuronal/astrocyte rat hippocampal cultures, electrical activity induced by GABA A receptor inhibition in the presence of the K + channel antagonist 4-aminopyridine induces the known Nrf2 target genes Gclc (glutamate-cysteine ligase, catalytic subunit) and Nqo1 (NAD(P)H dehydrogenase, quinone 1). The transcription factor Nrf2. Nov 23, 2020 · Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Emerging evidence suggests that upregulation of Nrf2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase neurogenesis. Article CAS PubMed PubMed Central Google Scholar Cho H-Y, van Houten B, Wang X, Miller-DeGraff L, Fostel J, Gladwell W, et Dec 1, 2019 · Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Chowdhury I, Mo Y, Gao L, Kazi A, Fisher AB, Feinstein SI. Main methods: Nov 29, 2021 · Neh 7 is the region of NRF2, which is inhibited by the DNA binding domain of retinoid X receptor α (RXRα) so the expression of NRF2-target genes may be inhibited by the interaction between RXRα Jan 6, 2018 · Notably, we didn’t observe any previously reported NRF2 target genes among all downregulated genes. (A) Sequence and upstream location of putative CHML antioxidant response element (ARE; −1622 ATGACTCAGCA ‐1612). NRF2 silencing showed reduced expression in lymphoid, lung, and hepatic cells. 270, p=0. (a) Immunohistochemistry was performed on formalin-fixed paraffin-embedded sections from back skin. A transcriptional decrease of xenobiotic-metabolizing genes may be a key driver of cancer initiation in an aging population. Nuclear accumulation of NRF2 was seen in LKO epidermis. Covalent modification of histones can promote nuclear Free Nrf2 enables activation of various target genes. Apr 21, 2014 · Habas et al. NRF2 is a master regulator of the antioxidant response and has been shown to regulate the activity of several ferroptosis and lipid peroxidation-related proteins. 2024 Feb 1 ΔNp63 physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes, thus ultimately leading to the regulation of unique transcriptional programs and Luteolin induced the degradation of Nrf2 mRNA in A549 cells , resulting in the downregulation of Nrf2 target genes and increased sensitivity of A549 NSCLC cells to chemotherapy drugs . However, the role of Nrf2 and its downstream target genes in the detoxification of DCF has not been fully elucidated in fish. In addition to antioxidant Feb 25, 2016 · An RNAi screen for mediators of Nrf2 target gene activation identifies Cdk12, an RNA polymerase II kinase. Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses Cancer Res Commun. e Western blot analyses of NRF2 target genes in the AA2G-primed hES-MSCs and hUC-MSCs expressing shCTR or shATF2. 017) and SOD2 with an inverse The Nrf2 activators, DMF and the synthetic oleanane triterpenoids, activate the Nrf2 pathway as well as regulate different subsets of Nrf2 target genes and Nrf2-independent genes in lung cancer (Chian et al. , 2019). Cancer Res 67:546-54 25. Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. There is increasing evidence that activation of Nrf2 can prevent ferroptotic cell death in MicroRNAs (miRNAs), as a class of nonprotein-coding RNAs, post-transcriptionally regulate the expression of target genes by base pairing to 3’-untranslated regions (3'‐UTRs). In both cases, newly synthesised NRF2 accumulates, undergoes nuclear translocation, and as a heterodimer with a small musculoaponeurotic fibrosarcoma (sMAF) transcription factor, binds to specific sequences called antioxidant response elements (AREs) in the regulatory regions of NRF2-target genes, and activates their transcription. HK-2 cell line is a model of well-differentiated proximal tubular cells derived from adult human kidney ( Ryan et al. observe that in mixed neuronal/astrocyte rat hippocampal cultures, electrical activity induced by GABA A receptor inhibition in the presence of the K + channel antagonist 4-aminopyridine induces the Focusing on selected genes with positive regulation by Nrf2 and either positive or no further regulation by AMPK, we revealed that altered Nrf2 levels could not account for the distinct extent of transactivation of certain Nrf2 targets in wt and AMPK -/- We define a core set of 14 upregulated NRF2 target genes from seven RNA-Sequencing databases that we generated and analyzed, which we validated this gene set through analyses of published databases and gene sets. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. =-0. Introduction. 245, p=0. In Nrf2-activated tumors, inhibition of Nrf2 has emerged as an attractive therapeutic strategy to combat this acquired resistance. SFN-induced gene expression in erythroid K562 and lymphoid cells were compared for each target gene. For efficiently targeting Nrf2, it is critical to profile the genotype of this transcription factor in every single cell from either tumor bulks or CTCs, and not to mention, to consider not only Nrf2 but the entire genetic background as they might define overall behaviors of Nrf2. Cotreatment of multiple NSCLC cell lines with platinum-based compounds and brusatol led to increased intracellular platinum levels greater than To evaluate the impact of these NRF2 target genes on TNBC prognosis, we plotted the significance (−log 10 of p-values) of logrank tests for DEGs downregulated by Cyss depletion using the Kaplan Aspalathin is capable of activating Nrf2 target gene expression by activating the Nrf2 pathway to up-regulate p62 expression to protect cells from oxidative stress, STZ and glucose toxicity (Moens et al. Furthermore, levels of p-AMPK, NRF2 and NRF2 target gene products such as HMOX1 and NQO1, were enhanced/restored when the cells were transfected with pcDNA3. CHML/Rep2 is an NRF2 target gene. Nuclear factor E2-related factor 2 (Nrf2) has been identified as a critical component of the antioxidant defense mechanism. Targeting Nrf2 by use of small molecules or gene-based therapies Pharmacological modulation of Nrf2 to induce or inhibit ferroptosis is a promising area of research. Apr 12, 2022 · However, there is increasing evidence that Nrf2 and its downstream target genes are overexpressed in many types of human cancer 34 and that it may play an important role in the development and May 6, 2014 · Regardless, neuronal activity has the capacity to induce at least some Nrf2 target genes independently of Nrf2 and astrocytes within the neurons themselves. Evidence has shown that NRF2 regulates more than 200 genes involved in cellular processes, cytoprotection, metabolism, and gene transcription, as listed in Table 1. These are Abstract. Red indicates high gene Examining the NRF2 pathway in the context of IDH mutations, in gliomas with mutated IDH1/2, the expression levels of NRF2 target genes, NQO1 and GCLM, were notably elevated and were significantly linked to poorer patient survival, whereas the expression of NRF2 itself did not exhibit such an association. Sep 27, 2024 · The GI-GPx gene is a target for Nrf2. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. Nov 20, 2020 · a NRF2-activated cancer-specific NRF2 target genes and canonical NRF2 target genes based on the presence of NRF2-dependent enhancers. NRF2 (encoded by nuclear factor-erythroid p45-related factor 2, NFE2L2) is the master regulator of antioxidant and phase II detoxification genes that collectively resist cellular damage due to electrophilic and oxidative stress [1, 2]. usbxj yvni opbt hupb rhh phd ywfm sydtmw flpf otyqd