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Patra, Upayan, Urbi Mukhopadhyay, Arpita Mukherjee, Rakesh Sarkar i Mamta Chawla-Sarkar. "Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units". Oxidative Medicine and Cellular Longevity 2020 (6.04.2020): 1–48. http://dx.doi.org/10.1155/2020/7289120.
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Eukaryotic cells adopt highly tuned stress response physiology under threats of exogenous stressors including viruses to maintain cellular homeostasis. Not surprisingly, avoidance of cellular stress response pathways is an essential facet of virus-induced obligatory host reprogramming to invoke a cellular environment conducive to viral perpetuation. Adaptive cellular responses to oxidative and electrophilic stress are usually taken care of by an antioxidant defense system, core to which lies the redox-responsive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-driven transcriptional cascade. Deregulation of host redox balance and redox stress-sensitive Nrf2 antioxidant defense have been reported for many viruses. In the current study, we aimed to study the modulation of the Nrf2-based host cellular redox defense system in response to Rotavirus (RV) infection in vitro. Interestingly, we found that Nrf2 protein levels decline sharply with progression of RV infection beyond an initial upsurge. Moreover, Nrf2 decrease as a whole was found to be accompanied by active nuclear vacuity of Nrf2, resulting in lowered expression of stress-responsive Nrf2 target genes heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 1 both in the presence and absence of Nrf2-driven transcriptional inducers. Initial induction of Nrf2 concurred with RV-induced early burst of oxidative stress and therefore was sensitive to treatments with antioxidants. Reduction of Nrf2 levels beyond initial hours, however, was found to be independent of the cellular redox status. Furthermore, increasing the half-life of Nrf2 through inhibition of the Kelch-like erythroid cell-derived protein with CNC homology- (ECH-) associated protein 1/Cullin3-RING Box1-based canonical Nrf2 turnover pathway could not restore Nrf2 levels post RV-SA11 infection. Depletion of the Nrf2/HO-1 axis was subsequently found to be sensitive to proteasome inhibition with concurrent observation of increased K48-linked ubiquitination associated with Nrf2. Together, the present study describes robust downregulation of Nrf2-dependent cellular redox defense beyond initial hours of RV infection, justifying our previous observation of potent antirotaviral implications of Nrf2 agonists.
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Kondratenko, N. D., L. A. Zinovkina i R. A. Zinovkin. "Transcription Factor NRF2 in Endothelial Functions". Молекулярная биология 57, nr 6 (1.11.2023): 1058–76. http://dx.doi.org/10.31857/s0026898423060101.
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The transcription factor NRF2 is the major regulator of cellular antioxidant defense. NRF2 is activated by various stimuli, such as oxidants and electrophiles, which induce the transcription of a number of genes whose products are involved in xenobiotic metabolism and contribute to the reduction of oxidative stress. NRF2 is one of the key transcription factors for endothelial cell function. Endothelium is a cell layer lining the inner cavity of blood vessels, which performs various homeostatic functions: it controls migration of leukocytes, regulates thrombosis and vascular tone, and drives angiogenesis. Endothelial dysfunction is often accompanied by inflammation and oxidative stress, which may lead to cellular aging as well as cell death by apoptosis, necrosis, and ferroptosis. Endothelial dysfunction contributes to the development of such common cardiovascular diseases as hypertension, diabetes, and atherosclerosis. Many pathophysiological processes in the endothelium, including senile changes, are associated with decreased NRF2 activity, leading to inflammatory activation and decreased activity of cellular antioxidant defense systems. Activation of the NRF2 signaling pathway generally contributes to the resolution of inflammation and oxidative stress. This review focuses on the importance of NRF2 in the basic functions of endothelium in normal and pathological conditions. In addition, the advantages and disadvantages of NRF2 activation as a way to prevent and treat cardiovascular diseases are discussed.
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Plafker, Kendra S., i Scott M. Plafker. "The ubiquitin-conjugating enzyme UBE2E3 and its import receptor importin-11 regulate the localization and activity of the antioxidant transcription factor NRF2". Molecular Biology of the Cell 26, nr 2 (15.01.2015): 327–38. http://dx.doi.org/10.1091/mbc.e14-06-1057.
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The transcription factor NF-E2 p45–related factor (Nrf2) induces the expression of cytoprotective proteins that maintain and restore redox homeostasis. Nrf2 levels and activity are tightly regulated, and three subcellular populations of the transcription factor have been identified. During homeostasis, the majority of Nrf2 is degraded in the cytoplasm by ubiquitin (Ub)-mediated degradation. A second population is transcriptionally active in the nucleus, and a third population localizes to the outer mitochondrial membrane. Still unresolved are the mechanisms and factors that govern Nrf2 distribution between its subcellular locales. We show here that the Ub-conjugating enzyme UBE2E3 and its nuclear import receptor importin 11 (Imp-11) regulate Nrf2 distribution and activity. Knockdown of UBE2E3 reduces nuclear Nrf2, decreases Nrf2 target gene expression, and relocalizes the transcription factor to a perinuclear cluster of mitochondria. In a complementary manner, Imp-11 functions to restrict KEAP1, the major suppressor of Nrf2, from prematurely extracting the transcription factor off of a subset of target gene promoters. These findings identify a novel pathway of Nrf2 modulation during homeostasis and support a model in which UBE2E3 and Imp-11 promote Nrf2 transcriptional activity by restricting the transcription factor from partitioning to the mitochondria and limiting the repressive activity of nuclear KEAP1.
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Scoazec, Jean-Yves. "Facteurs de transcription : quelles applications diagnostiques ?" Annales de Pathologie 32, nr 5 (listopad 2012): S32—S33. http://dx.doi.org/10.1016/j.annpat.2012.08.003.
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He, Feng, Xiaoli Ru i Tao Wen. "NRF2, a Transcription Factor for Stress Response and Beyond". International Journal of Molecular Sciences 21, nr 13 (6.07.2020): 4777. http://dx.doi.org/10.3390/ijms21134777.
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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. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell’s response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.
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Tamir, Tigist Y., Brittany M. Bowman, Megan J. Agajanian, Dennis Goldfarb, Travis P. Schrank, Trent Stohrer, Andrew E. Hale i in. "Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor". Journal of Cell Science 133, nr 14 (16.06.2020): jcs241356. http://dx.doi.org/10.1242/jcs.241356.
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ABSTRACTNuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, but conversely NRF2 activity diminishes with age and in neurodegenerative and metabolic disorders. Although NRF2-activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here, we describe use of a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the under-studied protein kinase brain-specific kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives 5′-AMP-activated protein kinase α2 (AMPK) signaling and suppresses the mTOR pathway. As a result, BRSK2 kinase activation suppresses ribosome-RNA complexes, global protein synthesis and NRF2 protein levels. Collectively, our data illuminate the BRSK2 and BRSK1 kinases, in part by functionally connecting them to NRF2 signaling and mTOR. This signaling axis might prove useful for therapeutically targeting NRF2 in human disease.This article has an associated First Person interview with the first author of the paper.
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Malloy, Melanie Theodore, Deneshia J. McIntosh, Treniqka S. Walters, Andrea Flores, J. Shawn Goodwin i Ifeanyi J. Arinze. "Trafficking of the Transcription Factor Nrf2 to Promyelocytic Leukemia-Nuclear Bodies". Journal of Biological Chemistry 288, nr 20 (29.03.2013): 14569–83. http://dx.doi.org/10.1074/jbc.m112.437392.
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Ubiquitylation of Nrf2 by the Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase complex targets Nrf2 for proteasomal degradation in the cytoplasm and is an extensively studied mechanism for regulating the cellular level of Nrf2. Although mechanistic details are lacking, reports abound that Nrf2 can also be degraded in the nucleus. Here, we demonstrate that Nrf2 is a target for sumoylation by both SUMO-1 and SUMO-2. HepG2 cells treated with As2O3, which enhances attachment of SUMO-2/3 to target proteins, increased SUMO-2/3-modification (polysumoylation) of Nrf2. We show that Nrf2 traffics, in part, to promyelocytic leukemia-nuclear bodies (PML-NBs). Cell fractions harboring key components of PML-NBs did not contain biologically active Keap1 but contained modified Nrf2 as well as RING finger protein 4 (RNF4), a poly-SUMO-specific E3 ubiquitin ligase. Overexpression of wild-type RNF4, but not the catalytically inactive mutant, decreased the steady-state levels of Nrf2, measured in the PML-NB-enriched cell fraction. The proteasome inhibitor MG-132 interfered with this decrease, resulting in elevated levels of polysumoylated Nrf2 that was also ubiquitylated. Wild-type RNF4 accelerated the half-life (t½) of Nrf2, measured in PML-NB-enriched cell fractions. These results suggest that RNF4 mediates polyubiquitylation of polysumoylated Nrf2, leading to its subsequent degradation in PML-NBs. Overall, this work identifies Nrf2 as a target for sumoylation and provides a novel mechanism for its degradation in the nucleus, independent of Keap1.
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Kondratenko, N. D., L. A. Zinovkina i R. A. Zinovkin. "Transcription Factor NRF2 in Endothelial Functions". Molecular Biology 57, nr 6 (grudzień 2023): 1052–69. http://dx.doi.org/10.1134/s0026893323060092.
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McIntosh, Deneshia J., Treniqka S. Walters, Ifeanyi J. Arinze i Jamaine Davis. "Arkadia (RING Finger Protein 111) Mediates Sumoylation-Dependent Stabilization of Nrf2 Through K48-Linked Ubiquitination". Cellular Physiology and Biochemistry 46, nr 1 (2018): 418–30. http://dx.doi.org/10.1159/000488475.
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Background/Aims: The transcription factor Nrf2 is a master regulator of the antioxidant defense system, protecting cells from oxidative damage. We previously reported that the SUMO-targeted E3 ubiquitin ligase (STUbL), RING finger protein 4 (RNF4) accelerated the degradation rate of Nrf2 in promyelocytic leukemia-nuclear body (PML-NB)-enriched fractions and decreased Nrf2-mediated gene transcription. The mechanisms that regulate Nrf2 nuclear levels are poorly understood. In this study, we aim to explore the role of the second mammalian STUbL, Arkadia/RNF111 on Nrf2. Methods: Arkadia mediated ubiquitination was detected using co-immunoprecipitation assays in which whole cell lysates were immunoprecipated with anti-Nrf2 antibody and Western blotted with anti-hemagglutinin (HA) antibody or anti-Lys-48 ubiquitin-specific antibody. The half-life of Nrf2 was detected in whole cell lysates and promyelocytic leukemia-nuclear body enriched fractions by cycloheximide-chase. Reporter gene assays were performed using the antioxidant response element (ARE)-containing promoter Heme oxygenase-1 (HO-1). Results: We show that Arkadia/RNF111 is able to ubiquitinate Nrf2 resulting in the stabilization of Nrf2. This stabilization was mediated through Lys-48 ubiquitin chains, contrary to traditionally degradative role of Lys-48 ubiquitination, suggesting that Lys-48 ubiquitination of Nrf2 protects Nrf2 from degradation thereby allowing Nrf2-dependent gene transcription. Conclusion: Collectively, these findings highlight a novel mechanism to positively regulate nuclear Nrf2 levels in response to oxidative stress through Arkadia-mediated K48-linked ubiquitination of Nrf2.
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Maruyama, Atsushi, Keizo Nishikawa, Yukie Kawatani, Junsei Mimura, Tomonori Hosoya, Nobuhiko Harada, Masayuki Yamamato i Ken Itoh. "The novel Nrf2-interacting factor KAP1 regulates susceptibility to oxidative stress by promoting the Nrf2-mediated cytoprotective response". Biochemical Journal 436, nr 2 (13.05.2011): 387–97. http://dx.doi.org/10.1042/bj20101748.
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The transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) co-ordinately regulates ARE (antioxidant-response element)-mediated induction of cytoprotective genes in response to electrophiles and oxidative stress; however, the molecular mechanism controlling Nrf2-dependent gene expression is not fully understood. To identify factors that regulate Nrf2-dependent transcription, we searched for proteins that interact with the Nrf2-NT (N-terminal Nrf2 transactivation domain) by affinity purification from HeLa nuclear extracts. In the present study, we identified KAP1 [KRAB (Krüppel-associated box)-associated protein 1] as a novel Nrf2-NT-interacting protein. Pull-down analysis confirmed the interaction between KAP1 and Nrf2 in cultured cells and demonstrated that the N-terminal region of KAP1 binds to Nrf2-NT in vitro. Reporter assays showed that KAP1 facilitates Nrf2 transactivation activity in a dose-dependent manner. Furthermore, the induction of the Nrf2-dependent expression of HO-1 (haem oxygenase-1) and NQO1 [NAD(P)H quinone oxidoreductase 1] by DEM (diethyl maleate) was attenuated by KAP1 knockdown in NIH 3T3 fibroblasts. This finding established that KAP1 acts as a positive regulator of Nrf2. Although Nrf2 nuclear accumulation was unaffected by KAP1 knockdown, the ability of Nrf2 to bind to the regulatory region of HO-1 and NQO1 was reduced. Moreover, KAP1 knockdown enhanced the sensitivity of NIH 3T3 cells to tert-butylhydroquinone, H2O2 and diamide. These results support our contention that KAP1 participates in the oxidative stress response by maximizing Nrf2-dependent transcription.
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Jamaluddin, Mohammad, Aline Haas de Mello, Nisha Tapryal, Tapas K. Hazra, Roberto P. Garofalo i Antonella Casola. "NRF2 Regulates Cystathionine Gamma-Lyase Expression and Activity in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus". Antioxidants 11, nr 8 (16.08.2022): 1582. http://dx.doi.org/10.3390/antiox11081582.
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Cystathionine-y-lyase (CSE) is a critical enzyme for hydrogen sulfide (H2S) biosynthesis and plays a key role in respiratory syncytial virus (RSV) pathogenesis. The transcription factor NRF2 is the master regulator of cytoprotective and antioxidant gene expression, and is degraded during RSV infection. While some evidence supports the role of NRF2 in CSE gene transcription, its role in CSE expression in airway epithelial cells is not known. Here, we show that RSV infection decreased CSE expression and activity in primary small airway epithelial (SAE) cells, while treatment with tert-butylhydroquinone (tBHQ), an NRF2 inducer, led to an increase of both. Using reporter gene assays, we identified an NRF2 response element required for the NRF2 inducible expression of the CSE promoter. Electrophoretic mobility shift assays demonstrated inducible specific NRF2 binding to the DNA probe corresponding to the putative CSE promoter NRF2 binding sequence. Using chromatin immunoprecipitation assays, we found a 50% reduction in NRF2 binding to the endogenous CSE proximal promoter in SAE cells infected with RSV, and increased binding in cells stimulated with tBHQ. Our results support the hypothesis that NRF2 regulates CSE gene transcription in airway epithelial cells, and that RSV-induced NRF2 degradation likely accounts for the observed reduced CSE expression and activity.
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Zhang, Jianyong, Tomonori Hosoya, Atsushi Maruyama, Keizo Nishikawa, Jonathan M. Maher, Tsutomu Ohta, Hozumi Motohashi i in. "Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes". Biochemical Journal 404, nr 3 (29.05.2007): 459–66. http://dx.doi.org/10.1042/bj20061611.
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The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) contains two transcription activation domains, Neh4 (Nrf2 ECH homology 4) and Neh5, which co-ordinately regulate transactivation of cytoprotective genes. In the present study we aimed to clarify the role of the Neh5 domain in Nrf2-mediated gene regulation. Deletion of the complete Neh5 domain reduces expression of endogenous Nrf2 target genes, such as HO-1 (haem oxygenase 1), NQO1 [NAD(P)H:quinone oxidoreductase 1] and GCLM (glutamate cysteine ligase modulatory subunit), in human kidney epithelial cells. Furthermore, the deletion of Neh5 markedly repressed CBP [CREB (cAMP-response-element-binding protein)-binding protein] and BRG1 (Brahma-related gene 1) from associating with Nrf2, diminishing their co-operative enhancement of HO-1 promoter activity. Mutational analysis of the Neh5 domain revealed a motif that shares significant homology with β-actin and ARP1 (actin-related protein 1). Mutagenesis of this motif selectively decreased HO-1, but not NQO1 and GCLM, expression. Taken together, these results indicate that the Neh5 domain has the ability to regulate Nrf2 target gene transcription, yet the role of the Neh5 domain in transcription varies from gene to gene.
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Huang, Jiansheng, Imene Tabbi-Anneni, Viswanath Gunda i Li Wang. "Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism". American Journal of Physiology-Gastrointestinal and Liver Physiology 299, nr 6 (grudzień 2010): G1211—G1221. http://dx.doi.org/10.1152/ajpgi.00322.2010.
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Nuclear factor erythroid-2 related factor 2 (Nrf2) plays a pivotal role in cytoprotection against both endogenous and exogenous stresses. Here, we establish a novel molecular link between Nrf2, nuclear receptor small heterodimer partner (SHP; NROB2), lipogenic genes, and hepatic lipid homeostasis. Deletion of Nrf2 ( Nrf2−/−) in mice resulted in a reduced liver weight, a decrease in fatty acid content of hepatic triacylglycerol, as well as concomitant increases in the levels of serum VLDL-triglyceride (TG), HDL cholesterol, and ketone bodies at 6 mo of age. Liver weight and hepatic TG content were consistently lower in Nrf2−/− mice upon a high-fat challenge. This phenotype was accompanied by downregulation of genes in lipid synthesis and uptake and upregulation of genes in lipid oxidation in older Nrf2−/− mice. Interestingly, SHP expression was induced with age in Nrf2+/+ mice but decreased by Nrf2 deficiency. Forced expression and activation of Nrf2 by Nrf2 activators consistently induced SHP expression, and Nrf2 was identified as a novel activator of the SHP gene transcription. We also identified PPAR-γ, Fas, Scd1, and Srebp-1 as direct targets of Nrf2 activation. These findings provide evidence for a role of Nrf2 in the modulation of hepatic lipid homeostasis through transcriptional activation of SHP and lipogenic gene expression.
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Mata, Ana, i Susana Cadenas. "The Antioxidant Transcription Factor Nrf2 in Cardiac Ischemia–Reperfusion Injury". International Journal of Molecular Sciences 22, nr 21 (3.11.2021): 11939. http://dx.doi.org/10.3390/ijms222111939.
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Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that controls cellular defense responses against toxic and oxidative stress by modulating the expression of genes involved in antioxidant response and drug detoxification. In addition to maintaining redox homeostasis, Nrf2 is also involved in various cellular processes including metabolism and inflammation. Nrf2 activity is tightly regulated at the transcriptional, post-transcriptional and post-translational levels, which allows cells to quickly respond to pathological stress. In the present review, we describe the molecular mechanisms underlying the transcriptional regulation of Nrf2. We also focus on the impact of Nrf2 in cardiac ischemia–reperfusion injury, a condition that stimulates the overproduction of reactive oxygen species. Finally, we analyze the protective effect of several natural and synthetic compounds that induce Nrf2 activation and protect against ischemia–reperfusion injury in the heart and other organs, and their potential clinical application.
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Kahn, A. "Domaine POU-homéo et facteurs de transcription". médecine/sciences 5, nr 3 (1989): 172. http://dx.doi.org/10.4267/10608/3940.
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Rockwell, Cheryl E., Patrick E. Fields, Robert B. Crawford, Norbert E. Kaminski i Curtis D. Klaassen. "Nrf2 activation suppresses production of T cell cytokines and IgM in C57BL/6 mice (90.26)". Journal of Immunology 182, nr 1_Supplement (1.04.2009): 90.26. http://dx.doi.org/10.4049/jimmunol.182.supp.90.26.
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Abstract Nrf2 is a transcription factor that upregulates cytoprotective genes in response to cellular stress. Nrf2 gene expression is induced in CD3+ cells by tert-butylhydroquinone (tBHQ), a known Nrf2 activator. In addition, tBHQ upregulates the Nrf2 target genes, Ho-1, Nqo1, and Gclc in wild-type, but not Nrf2-null CD3+ T cells. Furthermore, tBHQ and butylated hydroxyanisole (BHA), another Nrf2 activator, markedly inhibit IFNγ transcription in wild-type activated T cells, but have little effect on IFNγ transcription in Nrf2-null T cells. Likewise, tBHQ inhibits binding to both the AP-1 and NFκB response elements in wild-type CD3+ cells, but only modestly inhibits AP-1/NFκB binding in Nrf2-null CD3+ cells. Production of TNFα and IL-2 by activated T cells is also suppressed by tBHQ. In accordance with the aforementioned findings, tBHQ-treated mice exhibited diminished antibody production to sheep RBC, a T cell-dependent immune response. Collectively, the current studies suggest Nrf2 activation in CD3+ cells markedly inhibits T cell cytokine production and consequently, T cell-dependent responses, in vivo. The present studies suggest Nrf2 may represent a novel regulatory mechanism in mature murine T cells and thus may be a useful target for the development of new anti-inflammatory therapeutics. (Supported by NIH grants ES09716, ES07079, ES013714, ES09649, and RR021940.)
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Song, Pengjie, Chen Liu, Mingkun Sun, Jianguo Liu, Pengfei Lin, Huatao Chen, Dong Zhou, Keqiong Tang, Aihua Wang i Yaping Jin. "Transcription Factor Nrf2 Modulates Lipopolysaccharide-Induced Injury in Bovine Endometrial Epithelial Cells". International Journal of Molecular Sciences 24, nr 13 (7.07.2023): 11221. http://dx.doi.org/10.3390/ijms241311221.
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Endometritis in high-yield dairy cows adversely affects lactation length, milk quality, and the economics of dairy products. Endoplasmic reticulum stress (ERS) in bovine endometrial epithelial cells (BEECs) occurs as a consequence of diverse post-natal stressors, and plays a key role in a variety of inflammatory diseases. Nuclear-factor-erythroid-2-related factor 2 (Nrf2) is an important protective regulatory factor in numerous inflammatory responses. However, the mechanism by which Nrf2 modulates inflammation by participating in ERS remains unclear. The objective of the present study was to explore the role of Nrf2 in lipopolysaccharide (LPS)-induced injury to BEECs and to decipher the underlying molecular mechanisms of this injury. The expression of Nrf2- and ERS-related genes increased significantly in bovine uteri with endometritis. Isolated BEECs were treated with LPS to stimulate the inflammatory response. The expression of Nrf2 was significantly higher in cells exposed to LPS, which also induced ERS in BEECs. Activation of Nrf2 led to enhanced expression of the genes for the inflammation markers TNF-α, p65, IL-6, and IL-8 in BEECs. Moreover, stimulation of Nrf2 was accompanied by activation of ERS. In contrast, Nrf2 knockdown reduced the expression of TNF-α, p65, IL-6, and IL-8. Additionally, Nrf2 knockdown decreased expression of ERS-related genes for the GRP78, PERK, eIF2α, ATF4, and CHOP proteins. Collectively, our findings demonstrate that Nrf2 and ERS are activated during inflammation in BEECs. Furthermore, Nrf2 promotes the inflammatory response by activating the PERK pathway in ERS and inducing apoptosis in BEECs.
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Sekine, Hiroki, Keito Okazaki, Nao Ota, Hiroki Shima, Yasutake Katoh, Norio Suzuki, Kazuhiko Igarashi, Mitsuhiro Ito, Hozumi Motohashi i Masayuki Yamamoto. "The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression". Molecular and Cellular Biology 36, nr 3 (16.11.2015): 407–20. http://dx.doi.org/10.1128/mcb.00785-15.
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The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2-dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption ofMed16significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia-induced gene expression, suggesting a specific requirement for MED16 in NRF2-dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles inMed16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent inMed16-deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2-activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes.
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Jyrkkänen, Henna-Kaisa, Suvi Kuosmanen, Merja Heinäniemi, Heidi Laitinen, Emilia Kansanen, Eero Mella-Aho, Hanna Leinonen, Seppo Ylä-Herttuala i Anna-Liisa Levonen. "Novel insights into the regulation of antioxidant-response-elementmediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2". Biochemical Journal 440, nr 2 (14.11.2011): 167–74. http://dx.doi.org/10.1042/bj20110526.
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A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2-activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1 by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene regulation.
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Yastani, Deasyka, i Sri Widia A. Jusman. "The role of Nrf2 transcription factors in various physiological and pathological states". Acta Biochimica Indonesiana 6, nr 2 (30.06.2024): 103. http://dx.doi.org/10.32889/actabioina.103.
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Since its first report in 1994, understanding of the nuclear factor erythroid 2-related factor 2 (Nrf2) has continued to grow. Initially recognized for its role in cellular response to oxidative stress, Nrf2 is now known to be involved in a variety of regulatory process, including metabolic regulation, autophagy, protein homeostasis (proteostasis), and mitochondrial biogenesis. The expression of Nrf2 target genes is highly dependent on stimulus activation and interactions with transcription factors, activators, and repressors. Nrf2 activation serves as a defense mechanism under physiological conditions, but in the context of cancer, it can trigger the development of cancer cells due to its complex roles. Nrf2 is strongly associated with the onset and development of many diseases, including those caused by metabolic disorders and inflammation. Understanding Nrf2's diverse functions offers valuable insights into disease pathogenesis and potential therapeutic approaches. This review explores the pleiotropic role of Nrf2 regulation.
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Kurinna, Svitlana, Kristin Seltmann, Andreas L. Bachmann, Andreas Schwendimann, Lalitha Thiagarajan, Paulina Hennig, Hans-Dietmar Beer, Maria Rosaria Mollo, Caterina Missero i Sabine Werner. "Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis". Nucleic Acids Research 49, nr 7 (25.03.2021): 3748–63. http://dx.doi.org/10.1093/nar/gkab167.
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Abstract Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2–p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2–p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.
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De Plano, Laura Maria, Giovanna Calabrese, Maria Giovanna Rizzo, Salvatore Oddo i Antonella Caccamo. "The Role of the Transcription Factor Nrf2 in Alzheimer’s Disease: Therapeutic Opportunities". Biomolecules 13, nr 3 (17.03.2023): 549. http://dx.doi.org/10.3390/biom13030549.
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Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of the antioxidant response in cells. Under low ROS levels, Nrf2 is kept in the cytoplasm. However, an increase in ROS production leads to a translocation of Nrf2 into the nucleus, where it activates the transcription of several genes involved in the cells’ antioxidant response. Additionally, Nrf2 activation increases autophagy function. However, in AD, the accumulation of Aβ and tau reduces Nrf2 levels, decreasing the antioxidant response. The reduced Nrf2 levels contribute to the further accumulation of Aβ and tau by impairing their autophagy-mediated turnover. In this review, we discuss the overwhelming evidence indicating that genetic or pharmacological activation of Nrf2 is as a potential approach to mitigate AD pathology.
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Kurinna, Svitlana, i Sabine Werner. "NRF2 and microRNAs: new but awaited relations". Biochemical Society Transactions 43, nr 4 (1.08.2015): 595–601. http://dx.doi.org/10.1042/bst20140317.
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The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor is a key player in the cellular antioxidant response and it also controls various other functions in a cell-type specific manner. Due to these key functions, a tight control of NRF2 expression and activity is essential. This regulation is exerted at multiple levels, including transcriptional regulation and proteasomal degradation. Recent studies revealed important roles of miRNAs (miRs) in the control of NRF2 activity through direct targeting of the NRF2 mRNA and of mRNAs encoding proteins that control the level and activity of NRF2. In addition, NRF2 itself has been identified as a regulator of miRs, which exert some of the functions of NRF2 in metabolic regulation and also novel functions in the regulation of cell adhesion. Here, we summarize the roles and mechanisms of action of miRs in the regulation of NRF2 activity and as downstream effectors of this transcription factor.
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Zhang, Donna D., i Eli Chapman. "The role of natural products in revealing NRF2 function". Natural Product Reports 37, nr 6 (2020): 797–826. http://dx.doi.org/10.1039/c9np00061e.
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NRF2 is a transcription factor that is activated by many natural products for chemoprevention, but aberrant NRF2 activation can lead to disease and natural products have been used to inhibit the NRF2 pathway.
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Potteti, Haranatha R., Lalith K. Venkareddy, Patrick M. Noone, Aparna Ankireddy, Chandramohan R. Tamatam, Dolly Mehta, Chinnaswamy Tiruppathi i Sekhar P. Reddy. "Nrf2 Regulates Anti-Inflammatory A20 Deubiquitinase Induction by LPS in Macrophages in Contextual Manner". Antioxidants 10, nr 6 (26.05.2021): 847. http://dx.doi.org/10.3390/antiox10060847.
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The aberrant regulation of inflammatory gene transcription following oxidant and inflammatory stimuli can culminate in unchecked systemic inflammation leading to organ dysfunction. The Nrf2 transcription factor dampens cellular stress and controls inflammation by upregulating antioxidant gene expression and TNFα-induced Protein 3 (TNFAIP3, aka A20) deubiquitinase by controlling NF-kB signaling dampens tissue inflammation. Here, we report that Nrf2 is required for A20 induction by inflammatory stimuli LPS in monocyte/bone marrow derived macrophages (MDMΦs) but not in lung-macrophages (LDMΦs). LPS-induced A20 expression was significantly lower in Nrf2−/− MDMΦs and was not restored by antioxidant supplementation. Nrf2 deficiency markedly impaired LPS-stimulated A20 mRNA expression Nrf2−/− MDMΦs and ChIP assays showed Nrf2 enrichment at the promoter Nrf2−/− MDMΦs upon LPS stimulation, demonstrating that Nrf2 directly regulates A20 expression. Contrary to MDMΦs, LPS-stimulated A20 expression was not largely impaired in Nrf2−/− LDMΦs ex vivo and in vivo and ChIP assays showed lack of increased Nrf2 binding at the A20 promoter in LDMΦ following LPS treatment. Collectively, these results demonstrate a crucial role for Nrf2 in optimal A20 transcriptional induction in macrophages by endotoxin, and this regulation occurs in a contextual manner.
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Cores, Ángel, Marta Piquero, Mercedes Villacampa, Rafael León i J. Carlos Menéndez. "NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases". Biomolecules 10, nr 6 (14.06.2020): 904. http://dx.doi.org/10.3390/biom10060904.
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NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and critical overview of the main mechanisms of NRF2 regulation and their actual or potential use as targets for the treatment of neurodegenerative diseases.
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Sun, Zheng, Y. Eugene Chin i Donna D. Zhang. "Acetylation of Nrf2 by p300/CBP Augments Promoter-Specific DNA Binding of Nrf2 during the Antioxidant Response". Molecular and Cellular Biology 29, nr 10 (9.03.2009): 2658–72. http://dx.doi.org/10.1128/mcb.01639-08.
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ABSTRACT To maintain intracellular redox homeostasis, genes encoding many antioxidants and detoxification enzymes are transcriptionally upregulated upon deleterious oxidative stress through the cis antioxidant responsive elements (AREs) in their promoter regions. Nrf2 is the critical transcription factor responsible for ARE-dependent transcription. We and others have previously demonstrated that Nrf2 is targeted for ubiquitin-mediated degradation by Keap1 in a redox-sensitive manner through modifications of distinct cysteine residues of Keap1. Here, we report that p300/CBP directly acetylates Nrf2 in response to arsenite-induced stress. We have identified multiple acetylated lysine residues within the Nrf2 Neh1 DNA-binding domain. Combined lysine-to-arginine mutations on the acetylation sites, with no effects on Nrf2 protein stability, compromised the DNA-binding activity of Nrf2 in a promoter-specific manner. These findings demonstrated that acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 and established acetylation as a novel regulatory mechanism that functions in concert with Keap1-mediated ubiquitination in modulating the Nrf2-dependent antioxidant response.
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Basu, Paramita, Dayna L. Averitt, Camelia Maier i Arpita Basu. "The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain". Antioxidants 11, nr 2 (21.02.2022): 430. http://dx.doi.org/10.3390/antiox11020430.
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Oxidative stress, resulting from an imbalance between the formation of damaging free radicals and availability of protective antioxidants, can contribute to peripheral neuropathic pain conditions. Reactive oxygen and nitrogen species, as well as products of the mitochondrial metabolism such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are common free radicals. Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor encoded by the NFE2L2 gene and is a member of the cap ‘n’ collar subfamily of basic region leucine zipper transcription factors. Under normal physiological conditions, Nrf2 remains bound to Kelch-like ECH-associated protein 1 in the cytoplasm that ultimately leads to proteasomal degradation. During peripheral neuropathy, Nrf2 can translocate to the nucleus, where it heterodimerizes with muscle aponeurosis fibromatosis proteins and binds to antioxidant response elements (AREs). It is becoming increasingly clear that the Nrf2 interaction with ARE leads to the transcription of several antioxidative enzymes that can ameliorate neuropathy and neuropathic pain in rodent models. Current evidence indicates that the antinociceptive effects of Nrf2 occur via reducing oxidative stress, neuroinflammation, and mitochondrial dysfunction. Here, we will summarize the preclinical evidence supporting the role of Nrf2 signaling pathways and Nrf2 inducers in alleviating peripheral neuropathic pain.
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Haque, Effi, Magdalena Śmiech, Kamila Łuczyńska, Marie France Bouchard, Robert Viger, Hidetoshi Kono, Mariusz Pierzchała i Hiroaki Taniguchi. "NRF2 DLG Domain Mutations Identified in Japanese Liver Cancer Patients Affect the Transcriptional Activity in HCC Cell Lines". International Journal of Molecular Sciences 22, nr 10 (18.05.2021): 5296. http://dx.doi.org/10.3390/ijms22105296.
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Geographically, East Asia had the highest liver cancer burden in 2017. Besides this, liver cancer-related deaths were high in Japan, accounting for 3.90% of total deaths. The development of liver cancer is influenced by several factors, and genetic alteration is one of the critical factors among them. Therefore, the detailed mechanism driving the oncogenic transformation of liver cells needs to be elucidated. Recently, many researchers have focused on investigating the liver cancer genome and identified somatic mutations (MTs) of several transcription factors. In this line, next-generation sequencing of the cancer genome identified that oxidative stress-related transcription factor NRF2 (NFE2L2) is mutated in different cancers, including hepatocellular carcinoma (HCC). Here, we demonstrated that NRF2 DLG motif mutations (NRF2 D29A and L30F), found in Japanese liver cancer patients, upregulate the transcriptional activity of NRF2 in HCC cell lines. Moreover, the transcriptional activity of NRF2 mutations is not suppressed by KEAP1, presumably because NRF2 MTs disturb proper NRF2-KEAP1 binding and block KEAP1-mediated degradation of NRF2. Additionally, we showed that both MTs upregulate the transcriptional activity of NRF2 on the MMP9 promoter in Hepa1-6 and Huh7 cells, suggesting that MT derived gain-of-function of NRF2 may be important for liver tumor progression. We also found that ectopic overexpression of oncogenic BRAF WT and V600E increases the transcriptional activity of NRF2 WT on both the 3xARE reporter and MMP9 promoter. Interestingly, NRF2 D29A and L30F MTs with oncogenic BRAF V600E MT synergistically upregulate the transcription activity of NRF2 on the 3xARE reporter and MMP9 promoter in Hepa1-6 and Huh7 cells. In summary, our findings suggest that MTs in NRF2 have pathogenic effects, and that NRF2 MTs together with oncogenic BRAF V600E MT synergistically cause more aberrant transcriptional activity. The high activity of NRF2 MTs in HCC with BRAF MT warrants further exploration of the potential diagnostic, prognostic, and therapeutic utility of this pathway in HCC.
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Bindschedler, Annina, Jacqueline Schmuckli-Maurer, Rahel Wacker, Nicolas Kramer, Ruth Rehmann, Reto Caldelari i Volker T. Heussler. "Plasmodium berghei-Mediated NRF2 Activation in Infected Hepatocytes Enhances Parasite Survival". Cellular Microbiology 2022 (12.03.2022): 1–17. http://dx.doi.org/10.1155/2022/7647976.
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The protozoan parasite Plasmodium, causative agent of malaria, initially invades and develops in hepatocytes where it resides in a parasitophorous vacuole (PV). A single invaded parasite develops into thousands of daughter parasites. Survival of the host cell is crucial for successful completion of liver stage development. Nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a transcription factor known to induce transcription of cytoprotective genes when activated. Here we show that NRF2 is activated in Plasmodium berghei-infected hepatocytes. We observed that this NRF2 activation depends on PV membrane resident p62 recruiting KEAP1, the negative regulator of NRF2. Disrupting the NRF2 gene results in reduced parasite survival, indicating that NRF2 signaling is an important event for parasite development in hepatocytes. Together, our observations uncovered a novel mechanism of how Plasmodium parasites ensure host cell survival during liver stage development.
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Sykiotis, Gerasimos P. "Keap1/Nrf2 Signaling Pathway". Antioxidants 10, nr 6 (22.05.2021): 828. http://dx.doi.org/10.3390/antiox10060828.
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Nuclear factor, erythroid 2-like transcription factor 2 (Nrf2) and its cytoplasmic inhibitor, kelch-like ECH-associated protein 1 (Keap1), comprise a redox-responsive endogenous antioxidant defense module that orchestrates the expression of cytoprotective genes to maintain homeostasis [...]
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Jessen, Christina, Julia K. C. Kreß, Apoorva Baluapuri, Anita Hufnagel, Werner Schmitz, Susanne Kneitz, Sabine Roth i in. "The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression". Oncogene 39, nr 44 (25.09.2020): 6841–55. http://dx.doi.org/10.1038/s41388-020-01477-8.
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AbstractThe transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.
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Chen, Bo, Yanrong Lu, Younan Chen i Jingqiu Cheng. "The role of Nrf2 in oxidative stress-induced endothelial injuries". Journal of Endocrinology 225, nr 3 (27.04.2015): R83—R99. http://dx.doi.org/10.1530/joe-14-0662.
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Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)–antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1–ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.
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Kobayashi, Eri, Takafumi Suzuki i Masayuki Yamamoto. "Roles Nrf2 Plays in Myeloid Cells and Related Disorders". Oxidative Medicine and Cellular Longevity 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/529219.
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The Keap1-Nrf2 system protects animals from oxidative and electrophilic stresses. Nrf2 is a transcription factor that induces the expression of genes essential for detoxifying reactive oxygen species (ROS) and cytotoxic electrophiles. Keap1 is a stress sensor protein that binds to and ubiquitinates Nrf2 under unstressed conditions, leading to the rapid proteasomal degradation of Nrf2. Upon exposure to stress, Keap1 is modified and inactivated, which allows Nrf2 to accumulate and activate the transcription of a battery of cytoprotective genes. Antioxidative and detoxification activities are important for many types of cells to avoid DNA damage and cell death. Accumulating lines of recent evidence suggest that Nrf2 is also required for the primary functions of myeloid cells, which include phagocytosis, inflammation regulation, and ROS generation for bactericidal activities. In fact, results from several mouse models have shown that Nrf2 expression in myeloid cells is required for the proper regulation of inflammation, antitumor immunity, and atherosclerosis. Moreover, several molecules generated upon inflammation activate Nrf2. Although ROS detoxification mediated by Nrf2 is assumed to be required for anti-inflammation, the entire picture of the Nrf2-mediated regulation of myeloid cell primary functions has yet to be elucidated. In this review, we describe the Nrf2 inducers characteristic of myeloid cells and the contributions of Nrf2 to diseases.
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DeBlasi, Janine M., i Gina M. DeNicola. "Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer". Cancers 12, nr 10 (17.10.2020): 3023. http://dx.doi.org/10.3390/cancers12103023.
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The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.
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McSweeney, Shane R., Eiji Warabi i Richard C. M. Siow. "Nrf2 as an Endothelial Mechanosensitive Transcription Factor". Hypertension 67, nr 1 (styczeń 2016): 20–29. http://dx.doi.org/10.1161/hypertensionaha.115.06146.
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Gañán-Gómez, Irene, Yue Wei, Hui Yang, María Carmen Boyano-Adánez i Guillermo García-Manero. "Oncogenic functions of the transcription factor Nrf2". Free Radical Biology and Medicine 65 (grudzień 2013): 750–64. http://dx.doi.org/10.1016/j.freeradbiomed.2013.06.041.
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Bendavit, Gabriel, Tahar Aboulkassim, Khalid Hilmi, Sujay Shah i Gerald Batist. "Nrf2 Transcription Factor Can Directly Regulate mTOR". Journal of Biological Chemistry 291, nr 49 (26.10.2016): 25476–88. http://dx.doi.org/10.1074/jbc.m116.760249.
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Wu, Weiwei, Andrew Hendrix, Sharad Nair i Taixing Cui. "Nrf2-Mediated Dichotomy in the Vascular System: Mechanistic and Therapeutic Perspective". Cells 11, nr 19 (28.09.2022): 3042. http://dx.doi.org/10.3390/cells11193042.
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Nuclear factor-erythroid 2-related factor 2 (Nrf2), a transcription factor, controls the expression of more than 1000 genes that can be clustered into different categories with distinct functions ranging from redox balance and metabolism to protein quality control in the cell. The biological consequence of Nrf2 activation can be either protective or detrimental in a context-dependent manner. In the cardiovascular system, most studies have focused on the protective properties of Nrf2, mainly as a key transcription factor of antioxidant defense. However, emerging evidence revealed an unexpected role of Nrf2 in mediating cardiovascular maladaptive remodeling and dysfunction in certain disease settings. Herein we review the role of Nrf2 in cardiovascular diseases with a focus on vascular disease. We discuss the negative effect of Nrf2 on the vasculature as well as the potential underlying mechanisms. We also discuss the clinical relevance of targeting Nrf2 pathways for the treatment of cardiovascular and other diseases.
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Shin, Soona, Nobunao Wakabayashi, Vikas Misra, Shyam Biswal, Gum Hwa Lee, Elin S. Agoston, Masayuki Yamamoto i Thomas W. Kensler. "NRF2 Modulates Aryl Hydrocarbon Receptor Signaling: Influence on Adipogenesis". Molecular and Cellular Biology 27, nr 20 (20.08.2007): 7188–97. http://dx.doi.org/10.1128/mcb.00915-07.
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ABSTRACT The NF-E2 p45-related factor 2 (NRF2) and the aryl hydrocarbon receptor (AHR) are transcription factors controlling pathways modulating xenobiotic metabolism. AHR has recently been shown to affect Nrf2 expression. Conversely, this study demonstrates that NRF2 regulates expression of Ahr and subsequently modulates several downstream events of the AHR signaling cascade, including (i) transcriptional control of the xenobiotic metabolism genes Cyp1a1 and Cyp1b1 and (ii) inhibition of adipogenesis in mouse embryonic fibroblasts (MEFs). Constitutive expression of AHR was affected by Nrf2 genotype. Moreover, a pharmacological activator of NRF2 signaling, CDDO-IM {1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole}, induced Ahr, Cyp1a1, and Cyp1b1 transcription in Nrf2 +/+ MEFs but not in Nrf2 −/− MEFs. Reporter analysis and chromatin immunoprecipitation assay revealed that NRF2 directly binds to one antioxidant response element (ARE) found in the −230-bp region of the promoter of Ahr. Since AHR negatively controls adipocyte differentiation, we postulated that NRF2 would inhibit adipogenesis through the interaction with the AHR pathway. Nrf2 −/− MEFs showed markedly accelerated adipogenesis upon stimulation, while Keap1 −/− MEFs (which exhibit higher NRF2 signaling) differentiated slowly compared to their congenic wild-type MEFs. Ectopic expression of Ahr and dominant-positive Nrf2 in Nrf2 −/− MEFs also substantially delayed differentiation. Thus, NRF2 directly modulates AHR signaling, highlighting bidirectional interactions of these pathways.
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Xue, Mingzhan, Hiroshi Momiji, Naila Rabbani, Till Bretschneider, David A. Rand i Paul J. Thornalley. "Frequency modulated translocational oscillations of Nrf2, a transcription factor functioning like a wireless sensor". Biochemical Society Transactions 43, nr 4 (1.08.2015): 669–73. http://dx.doi.org/10.1042/bst20150060.
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The discovery that nuclear factor erythroid 2-related factor 2 (Nrf2) undergoes translocational oscillations from cytoplasm to nucleus in human cells with frequency modulation linked to activation of a stress-stimulated cytoprotective response raises the prospect that the Nrf2 works mechanistically analogous to a wireless sensor. Herein, we consider how this new model of Nrf2 oscillation resolves previous inexplicable experimental findings on Nrf2 regulation and why it is fit-for-purpose. Further investigation is required to assess how generally applicable the oscillatory mechanism is and if characteristics of this regulatory control can be found in vivo. It suggests there are multiple, potentially re-enforcing receptors for Nrf2 activation, indicating that potent Nrf2 activation for improved health and treatment of disease may be achieved through combination of Nrf2 system stimulants.
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Deng, JiaLi, Na Li, Liyuan Hao, Shenghao Li, Nie Aiyu, Junli Zhang i XiaoYu Hu. "Transcription factor NF-E2-related factor 2 plays a critical role in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) by regulating ferroptosis". PeerJ 12 (30.07.2024): e17692. http://dx.doi.org/10.7717/peerj.17692.
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NRF2 is an important transcription factor that regulates redox homeostasis in vivo and exerts its anti-oxidative stress and anti-inflammatory response by binding to the ARE to activate and regulate the transcription of downstream protective protein genes, reducing the release of reactive oxygen species. Ferroptosis is a novel iron-dependent, lipid peroxidation-driven cell death mode, and recent studies have shown that ferroptosis is closely associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). NRF2 is able to regulate ferroptosis through the regulation of the transcription of its target genes to ameliorate ALI/ARDS. Therefore, This article focuses on how NRF2 plays a role in ALI/ARDS by regulating ferroptosis. We further reviewed the literature and deeply analyzed the signaling pathways related to ferroptosis which were regulated by NRF2. Additionally, we sorted out the chemical molecules targeting NRF2 that are effective for ALI/ARDS. This review provides a relevant theoretical basis for further research on this theory and the prevention and treatment of ALI/ARDS. The intended audience is clinicians and researchers in the field of respiratory disease.
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Ran, Caroline, Karin Wirdefeldt, Lovisa Brodin, Mehrafarin Ramezani, Marie Westerlund, Fengqing Xiang, Anna Anvret i in. "Genetic Variations and mRNA Expression of NRF2 in Parkinson’s Disease". Parkinson's Disease 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/4020198.
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Nuclear factor erythroid 2-like 2 (NRF2) encodes a transcription factor regulating mechanisms of cellular protection and is activated by oxidative stress. NRF2 has therefore been hypothesized to confer protection against Parkinson’s disease and so far an NRF2 haplotype has been reported to decrease the risk of developing disease and delay disease onset. Also NRF2 adopts a nuclear localization in Parkinson’s disease, which is indicative of increased NRF2 activity. We have investigated the association between NRF2 and Parkinson’s disease in a Swedish case-control material and whether NRF2 expression levels correlate with NRF2 genetic variants, disease, or disease onset. Using pyrosequencing, we genotyped one intronic and three promoter variants in 504 patients and 509 control subjects from Stockholm. Further, we quantified NRF2 mRNA expression in EBV transfected human lymphocytes from patients and controls using quantitative real-time reverse transcription PCR. We found that one of the promoter variants, rs35652124, was associated with age of disease onset (Χ2 = 14.19, p value = 0.0067). NRF2 mRNA expression levels however did not correlate with the rs35652124 genotype, Parkinson’s disease, or age of onset in our material. More detailed studies on NRF2 are needed in order to elucidate how this gene affects pathophysiology of Parkinson’s disease.
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Ludtmann, Marthe H. R., Plamena R. Angelova, Ying Zhang, Andrey Y. Abramov i Albena T. Dinkova-Kostova. "Nrf2 affects the efficiency of mitochondrial fatty acid oxidation". Biochemical Journal 457, nr 3 (10.01.2014): 415–24. http://dx.doi.org/10.1042/bj20130863.
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Transcription factor Nrf2 affects fatty acid oxidation; the mitochondrial oxidation of long-chain (palmitic) and short-chain (hexanoic) saturated fatty acids is depressed in the absence of Nrf2 and accelerated when Nrf2 is constitutively activated, affecting ATP production and FADH2 utilization.
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Cheng, Junning, Chang Ding, Huying Tang, Haonan Zhou, Mingdong Wu i Yikuan Chen. "An Autophagy-Associated MITF–GAS5–miR-23 Loop Attenuates Vascular Oxidative and Inflammatory Damage in Sepsis". Biomedicines 11, nr 7 (24.06.2023): 1811. http://dx.doi.org/10.3390/biomedicines11071811.
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Background: Sepsis induces GAS5 expression in the vascular endothelium, but the molecular mechanism is unclear, as is the role of GAS5 in sepsis. Methods and results: We observed that GAS5 expression in the endothelium was significantly upregulated in a sepsis mouse model. ChIP-PCR and EMSA confirmed that the oxidative stress (OS)-activated MiT–TFE transcription factor (MITF, TFE3, and TFEB)-mediated GAS5 transcription. In vitro, GAS5 overexpression attenuated OS and inflammation in endothelial cells (ECs) while maintaining the structural and functional integrity of mitochondria. In vivo, GAS5 reduced tissue ROS levels, maintained vascular barrier function to reduce leakage, and ultimately attenuated sepsis-induced lung injury. Luciferase reporter assays revealed that GAS5 protected MITF from degradation by sponging miR-23, thereby forming a positive feedback loop consisting of MITF, GAS5, and miR-23. Despite the fact that the OS-activated MITF–GAS5–miR-23 loop boosted MITF-mediated p62 transcription, ECs do not need to increase mitophagy to exert mitochondrial quality control since MITF-mediated Nrf2 transcription exists. Compared to mitophagy, MITF-transcribed p62 prefers to facilitate the autophagic degradation of Keap1 through a direct interaction, thereby relieving the inhibition of Nrf2 by Keap1, indicating that MITF can upregulate Nrf2 at both the transcriptional and posttranscriptional levels. Following this, ChIP-PCR demonstrated that Nrf2 can also transcribe MITF, revealing that there is a reciprocal positive regulatory association between MITF and Nrf2. Conclusion: In sepsis, the ROS-activated MITF–GAS5–miR-23 loop integrated the antioxidant and autophagy systems through MITF-mediated transcription of Nrf2 and p62, which dynamically regulate the level and type of autophagy, as well as exert antioxidant and anti-inflammatory effects.
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Mukhopadhyay, Pramiti, Nicklas Bassani i Alexander J. Bishop. "Abstract 1702: Loss of KEAP1 promotes R-loop formation independent of NRF2". Cancer Research 84, nr 6_Supplement (22.03.2024): 1702. http://dx.doi.org/10.1158/1538-7445.am2024-1702.
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Abstract This study investigates the mechanism of R-loop formation as a consequence of KEAP1 depletion. R-loops, described as three-stranded nucleic acid structures consisting of a DNA:RNA hybrid and a non-template single-stranded DNA, are assemblies often attributed with pathological consequences like genomic instability and replication stress. However, they have significant physiological roles, inter alia, regulation of transcription initiation, splicing and termination. Loss in R-loop resolution factors (like RNaseH nucleases, senataxin) can result in “unscheduled” or “pathological” R-loops, which can compromise genome stability. R-loops are commonly associated with an active transcription bubble, with nascent RNA trailing the RNA polymerase re-annealing to the template DNA strand. Increased transcriptional stress can lead to accumulation of R-loops. In a 2016 eLife study by Stork et al., estrogen induction resulted in concomitantly increased transcription and R-loop formation in the same subset of genes. Similar to estrogen induction, activation of the NRF2/KEAP1 pathway upon oxidative stress causes NRF2 to be released from KEAP1 and enter the nucleus to turn on transcription of its target genes. Kelch-like ECH associated protein 1, encoded by the KEAP1 gene, is a canonical binding partner of NRF2. Under basal conditions, KEAP1 binds NRF2 and targets it for degradation. Mutations in KEAP1 and epigenetic modifications have been reported in lung and breast cancer phenotypes. In lieu of chemical manipulation, NRF2 can be activated by knocking down KEAP1 via RNAi. We therefore asked whether transcription activation downstream of the NRF2/KEAP1 pathway can lead to accumulation of R-loops.We have observed the consequences of depleting KEAP1 (for NRF2 activation) with RNAi on global transcription using ethynyl uridine (EU) incorporation with click-iT chemistry and flow cytometry, on R-loop levels using S9.6 antibody immunocytochemistry and on transcriptional profile changes with RNA-seq. We observe that loss of KEAP1 leads to an increased accumulation of R-loops. Surprisingly, this is not accompanied by an expected increase in transcription as measured quantitatively with EU flow cytometry. This phenomenon was found to consistently occur in various cell lines across cancer types (breast, lung). Interestingly, depleting NRF2 cannot mitigate the effects of KEAP1 loss, suggesting that KEAP1 loss-associated R-loop formation is independent of NRF2 activation. Analysis of RNA-seq data shows that TOP2 is downregulated in KEAP1 deficient cells. As TOP2 has been previously known to regulate R-loop formation, we predict that KEAP1 loss can sensitize cells to topoisomerase inhibitors.In conclusion, interaction of KEAP1 with other players in its interactome outside of NRF2 may regulate R-loop formation and therefore R-loop-induced genome instability. Citation Format: Pramiti Mukhopadhyay, Nicklas Bassani, Alexander J. Bishop. Loss of KEAP1 promotes R-loop formation independent of NRF2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1702.
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Hiebert, Paul, i Sabine Werner. "Regulation of Wound Healing by the NRF2 Transcription Factor—More Than Cytoprotection". International Journal of Molecular Sciences 20, nr 16 (8.08.2019): 3856. http://dx.doi.org/10.3390/ijms20163856.
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The nuclear factor-erythroid 2-related factor 2 (NRF2) transcription factor plays a central role in mediating the cellular stress response. Due to their antioxidant properties, compounds activating NRF2 have received much attention as potential medications for disease prevention, or even for therapy. Accumulating evidence suggests that activation of the NRF2 pathway also has a major impact on wound healing and may be beneficial in the treatment of chronic wounds, which remain a considerable health and economic burden. While NRF2 activation indeed shows promise, important considerations need to be made in light of corresponding evidence that also points towards pro-tumorigenic effects of NRF2. In this review, we discuss the evidence to date, highlighting recent advances using gain- and loss-of-function animal models and how these data fit with observations in humans.
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Sekine, Hiroki, i Hozumi Motohashi. "Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer". Cancers 13, nr 3 (1.02.2021): 541. http://dx.doi.org/10.3390/cancers13030541.
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Cancer cells exhibit unique metabolic features and take advantage of them to enhance their survival and proliferation. While the activation of NRF2 (nuclear factor erythroid 2-like 2; NFE2L2), a CNC (cap‘n’collar) family transcription factor, is effective for the prevention and alleviation of various diseases, NRF2 contributes to cancer malignancy by promoting aggressive tumorigenesis and conferring therapeutic resistance. NRF2-mediated metabolic reprogramming and increased antioxidant capacity underlie the malignant behaviors of NRF2-activated cancer cells. Another member of the CNC family, NRF1, plays a key role in the therapeutic resistance of cancers. Since NRF1 maintains proteasome activity by inducing proteasome subunit genes in response to proteasome inhibitors, NRF1 protects cancer cells from proteotoxicity induced by anticancer proteasome inhibitors. An important metabolite that activates NRF1 is UDP-GlcNAc (uridine diphosphate N-acetylglucosamine), which is abundantly generated in many cancer cells from glucose and glutamine via the hexosamine pathway. Thus, the metabolic signatures of cancer cells are closely related to the oncogenic and tumor-promoting functions of CNC family members. In this review, we provide a brief overview of NRF2-mediated cancer malignancy and elaborate on NRF1-mediated drug resistance affected by an oncometabolite UDP-GlcNAc.
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Braun, Susanne, Christine Hanselmann, Marcus G. Gassmann, Ulrich auf dem Keller, Christiane Born-Berclaz, Kaimin Chan, Yuet Wai Kan i Sabine Werner. "Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound". Molecular and Cellular Biology 22, nr 15 (1.08.2002): 5492–505. http://dx.doi.org/10.1128/mcb.22.15.5492-5505.2002.
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ABSTRACT Keratinocyte growth factor (KGF) is a potent mitogen for epithelial cells, and it promotes survival of these cells under stress conditions. In a search for KGF-regulated genes in keratinocytes, we identified the gene encoding the transcription factor NF-E2-related factor 2 (Nrf2). Nrf2 is a key player in the cellular stress response. This might be of particular importance during wound healing, where large amounts of reactive oxygen species are produced as a defense against invading bacteria. Therefore, we studied the wound repair process in Nrf2 knockout mice. Interestingly, the expression of various key players involved in wound healing was significantly reduced in early wounds of the Nrf2 knockout animals, and the late phase of repair was characterized by prolonged inflammation. However, these differences in gene expression were not reflected by obvious histological abnormalities. The normal healing rate appears to be at least partially due to an up-regulation of the related transcription factor Nrf3, which was also identified as a target of KGF and which was coexpressed with Nrf2 in the healing skin wound. Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair.
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Blumenfeld, M., i M. Vasseur. "Oligonucléotides "sens" : ligands rationnels des facteurs de transcription". médecine/sciences 10, nr 3 (1994): 274. http://dx.doi.org/10.4267/10608/2605.
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