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NFE2L2
Estructuras disponibles
PDBBúsqueda de ortólogos: PDBe RCSB
Lista de códigos de identificación de PDB

2FLU , 2LZ1 , 3ZGC , 4IFL

Identificadores
AliasNFE2L2 , NRF2, HEBP1, factor nuclear, eritroide 2 como 2, IMDDHH, Nrf-2
Identificaciones externasOMIM : 600492 MGI : 108420 HomoloGene : 2412 GeneCards : NFE2L2
Ubicación de genes ( humanos )
Chromosome 2 (human)
Chr.Cromosoma 2 (humano) [1]
Chromosome 2 (human)
Genomic location for NFE2L2
Genomic location for NFE2L2
Banda2q31.2Comienzo177,227,595 pb [1]
Final177,392,697 pb [1]
Ubicación de genes ( ratón )
Chromosome 2 (mouse)
Chr.Cromosoma 2 (ratón) [2]
Chromosome 2 (mouse)
Genomic location for NFE2L2
Genomic location for NFE2L2
Banda2 C3 | 2 44,75 cmComienzo75,675,513 pb [2]
Final75.704.641 pb [2]
Patrón de expresión de ARN
PBB GE NFE2L2 201146 at fs.png
Más datos de expresión de referencia
Ontología de genes
Función molecular• GO: 0000980 ARN polimerasa II cis-reguladora de ADN región de secuencia específica
• la unión al ADN
• específica de la secuencia de unión a ADN
• unión específica de proteínas de dominio
• GO: 0001204 de unión a ADN de la transcripción: 0001131, GO: 0001151, GO: 0001130, GO actividad del factor
• GO: 0000975 unión a la región reguladora cis de la transcripción
• GO: 0001077, GO: 0001212, GO: 0001213, GO: 0001211, GO: 0001205 Actividad activadora de la transcripción de unión al ADN, específica de la ARN polimerasa II
• GO: unión a proteínas 0001948
• transcripción coregulator vinculante
• factor de transcripción vinculante
• GO: 0001200, GO: 0001133, GO: 0001201 Actividad del factor de transcripción de unión al ADN, específico de la ARN polimerasa II
Componente celular• citoplasma
• citosol
• centrosoma
• membrana plasmática
• complejo proteína-ADN
• cromatina
• núcleo
• nucleoplasma
• aparato de Golgi
Proceso biológico• regulación positiva de la importación de glucosa
• regulación negativa del proceso apoptótico de las células endoteliales
• regulación negativa de la diferenciación de células madre hematopoyéticas
• regulación del desarrollo embrionario
• respuesta celular a la falta de glucosa
• regulación de la transcripción, plantilla de ADN
• respuesta celular al estrés por cizallamiento del fluido laminar
• regulación positiva de la transcripción del promotor de la ARN polimerasa II en respuesta al estrés
• respuesta celular al factor de necrosis tumoral
• proceso catabólico proteasomal de la proteína independiente de ubiquitina
• regulación negativa de la muerte celular
• respuesta celular al estrés por cizallamiento del fluido
• homeostasis redox celular
• respuesta de proteína desplegada mediada por PERK
• regulación positiva del proceso biosintético del glutatión
• transcripción, plantilla de ADN
• respuesta al estrés del retículo endoplásmico
• regulación positiva del proceso catabólico de la proteína dependiente de ubiquitina asociada a ER
• regulación positiva de la transcripción, plantilla de ADN
• respuesta proteica desplegada del retículo endoplásmico
• respuesta celular al fármaco
• regulación positiva de la expresión génica
• regulación positiva del proceso metabólico de las especies reactivas del oxígeno
• regulación positiva de la coagulación sanguínea
• regulación positiva de la transcripción del promotor de la ARN polimerasa II en respuesta al estrés oxidativo
• ubiquitinación de proteínas
• respuesta celular al estrés oxidativo
• regulación negativa de la vía de señalización apoptótica intrínseca inducida por estrés oxidativo
• regulación negativa de células inducidas por peróxido de hidrógeno muerte
• respuesta inflamatoria
• regulación de la eliminación de radicales superóxido
• regulación positiva de la transcripción por la ARN polimerasa II
• respuesta celular al peróxido de hidrógeno
• proteína dependiente de ubiquitina mediada por proteasoma proceso catabólico
• regulación positiva de la migración de las células endoteliales de los vasos sanguíneos
• envejecimiento
• respuesta celular a la hipoxia
• regulación negativa de la migración de las células del músculo liso asociada a los vasos
• regulación negativa del proceso apoptótico de las células del músculo cardíaco
• transcripción por la ARN polimerasa II
• regulación positiva de la angiogénesis
• regulación positiva de desarrollo de la proyección neuronal
• proceso catabólico de aflatoxinas
• respuesta celular a la angiotensina
• regulación positiva de la transcripción del promotor de la ARN polimerasa II en respuesta a la hipoxia
• GO: 0022415 proceso viral
Fuentes: Amigo / QuickGO
Ortólogos
EspeciesHumanoRatón
Entrez

4780

18024

Ensembl

ENSG00000116044

ENSMUSG00000015839

UniProt

Q16236

Q60795

RefSeq (ARNm)
NM_006164
NM_001145412
NM_001145413
NM_001313900
NM_001313901

NM_001313902
NM_001313903
NM_001313904

NM_010902

RefSeq (proteína)
NP_001138884
NP_001138885
NP_001300829
NP_001300830
NP_001300831

NP_001300832
NP_001300833
NP_006155

NP_035032

Ubicación (UCSC)Cr 2: 177,23 - 177,39 MbCrónicas 2: 75,68 - 75,7 Mb
Búsqueda en PubMed[3][4]
Wikidata
Ver / editar humanoVer / Editar mouse

El factor 2 relacionado con el factor nuclear eritroide 2 ( NRF2 ), también conocido como factor nuclear 2 derivado del eritroide 2 , es un factor de transcripción que en los seres humanos está codificado por el gen NFE2L2 . [5] NRF2 es una proteína de cremallera de leucina básica (bZIP) que puede regular la expresión de proteínas antioxidantes que protegen contra el daño oxidativo provocado por lesiones e inflamación, según una investigación preliminar. [6] In vitro , NRF2 se une a elementos de respuesta antioxidante (ARE) en el núcleo, lo que lleva a la transcripción de genes ARE. [7] NRF2 aumenta hemo oxigenasa 1 que conduce a un aumento de las enzimas de fase II in vitro. [8] NRF2 también inhibe la NLRP3 inflamasoma . [9]

El NRF2 parece participar en una red reguladora compleja y desempeña un papel pleiotrópico en la regulación del metabolismo, la inflamación, la autofagia, la proteostasis, la fisiología mitocondrial y las respuestas inmunitarias. [10] Se están estudiando varios fármacos que estimulan la vía NFE2L2 para el tratamiento de enfermedades causadas por el estrés oxidativo. [6] [11]

Estructura [ editar ]

NRF2 es un factor de transcripción básico de cremallera de leucina ( bZip ) con una estructura de collar Cap “n” (CNC). [5] NRF2 posee seis dominios altamente conservados llamados dominios de homología NRF2-ECH (Neh). El dominio Neh1 es un dominio CNC-bZIP que permite que Nrf2 se heterodimerice con pequeñas proteínas Maf ( MAFF , MAFG , MAFK ). [12] El dominio Neh2 permite la unión de NRF2 a su represor citosólico Keap1. [13] El Neh3El dominio puede desempeñar un papel en la estabilidad de la proteína NRF2 y puede actuar como un dominio de transactivación, interactuando con un componente del aparato transcripcional. [14] Los dominios Neh4 y Neh5 también actúan como dominios de transactivación, pero se unen a una proteína diferente llamada proteína de unión al elemento de respuesta cAMP ( CREB ), que posee actividad intrínseca de histona acetiltransferasa . [13] El dominio Neh6 puede contener un degron que está involucrado en un proceso de degradación insensible a redox de NRF2. Esto ocurre incluso en células estresadas, que normalmente prolongan la vida media de la proteína NRF2 en relación con las condiciones no estresadas al suprimir otras vías de degradación. [15]

Localización y función [ editar ]

Activación de entradas y salidas funcionales de la vía NRF2

NFE2L2 y otros genes, como NFE2 , NFE2L1 y NFE2L3 , codifican factores de transcripción de cremallera de leucina básica ( bZIP ) . Comparten regiones altamente conservadas que son distintas de otras familias de bZIP, como JUN y FOS , aunque las regiones restantes han divergido considerablemente entre sí. [16] [17]

Under normal or unstressed conditions, NRF2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, NRF2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.

NRF2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 (KEAP1) and Cullin 3, which degrade NRF2 by ubiquitination.[18] Cullin 3 ubiquitinates NRF2, while Keap1 is a substrate adaptor protein that facilitates the reaction. Once NRF2 is ubiquitinated, it is transported to the proteasome, where it is degraded and its components recycled. Under normal conditions, NRF2 has a half-life of only 20 minutes.[19] Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When NRF2 is not ubiquitinated, it builds up in the cytoplasm,[20][21] and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with one of small Maf proteins (MAFF, MAFG, MAFK) and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription.[22]

Target genes[edit]

Activation of NRF2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical NRF2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.[23]
  • Glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase regulatory subunit (GCLM) form a heterodimer, which is the rate-limiting step in the synthesis of glutathione (GSH), a very powerful endogenous antioxidant. Both Gclc and Gclm are characteristic NRF2 target genes, which establish NRF2 as a regulator of glutathione, one of the most important antioxidants in the body.[24]
  • Sulfiredoxin 1 (SRXN1) and Thioredoxin reductase 1 (TXNRD1) support the reduction and recovery of peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including hydrogen peroxide and peroxynitrite.[25][26]
  • Heme oxygenase-1 (HMOX1, HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, the anti-inflammatory agent carbon monoxide, and iron. HO-1 is a NRF2 target gene that has been shown to protect from a variety of pathologies, including sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain.[27] In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.[28]
  • The glutathione S-transferase (GST) family includes cytosolic, mitochondrial, and microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic electrophiles. After detoxification by glutathione (GSH) conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by NRF2 activation and represent an important route of detoxification.[29]
  • The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water-soluble and readily excreted. Important substrates for glucuronidation include bilirubin and acetaminophen. NRF2 has been shown to induce UGT1A1 and UGT1A6.[30]
  • Multidrug resistance-associated proteins (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by NRF2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.[31][32]
  • Kelch-like ECH-associated protein 1 is also a primary target of NFE2L2. Several interesting studies have also identified this hidden circuit in NRF2 regulations. In the mouse Keap1 (INrf2) gene, Lee and colleagues [33] found that an AREs located on a negative strand can subtly connect Nrf2 activation to Keap1 transcription. When examining NRF2 occupancies in human lymphocytes, Chorley and colleagues identified an approximately 700 bp locus within the KEAP1 promoter region was consistently top rank enriched, even at the whole-genome scale.[34] These basic findings have depicted a mutually influenced pattern between NRF2 and KEAP1. NRF2-driven KEAP1 expression characterized in human cancer contexts, especially in human squamous cell cancers,[35] implicated a new perspective in understanding NRF2 signaling regulation.

Tissue distribution[edit]

NRF2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[5]

Clinical relevance[edit]

Dimethyl fumarate, marketed as Tecfidera by Biogen Idec, was approved by the Food and Drug Administration in March 2013 following the conclusion of a Phase III clinical trial which demonstrated that the drug reduced relapse rates and increased time to progression of disability in people with multiple sclerosis.[6] The mechanism by which it exerts its therapeutic effect is unknown. Dimethyl fumarate (and its metabolite, monomethyl fumarate) activates the NRF2 pathway and has been identified as a nicotinic acid receptor agonist in vitro.[36] The label includes warnings about the risk of anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia, and liver damage; other adverse effects include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain.[36]

The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is the best studied.[37] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[38] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity.[38] Oltipraz also generates superoxide radical, which can be toxic.[39]

Associated pathology[edit]

Genetic activation of NRF2 may promote the development of de novo cancerous tumors[40][41] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.[42] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.[42][43]

Interactions[edit]

NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun,[44] CREBBP,[45] EIF2AK3,[46] KEAP1,[47][46][48][49] and UBC.[48][50]

See also[edit]

  • Heme oxygenase
  • Carbon monoxide-releasing molecules

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000116044 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015839 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c Moi P, Chan K, Asunis I, Cao A, Kan YW (October 1994). "Isolation of NF-E2-related factor 2 (NRF2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region". Proceedings of the National Academy of Sciences of the United States of America. 91 (21): 9926–30. Bibcode:1994PNAS...91.9926M. doi:10.1073/pnas.91.21.9926. PMC 44930. PMID 7937919.
  6. ^ a b c Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. (September 2012). "Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis". The New England Journal of Medicine. 367 (12): 1098–107. doi:10.1056/NEJMoa1114287. hdl:2078.1/124401. PMID 22992073.
  7. ^ Gureev AP, Popov VN, Starkov AA (2020). "Crosstalk between the mTOR and Nrf2/ARE signaling pathways as a target in the improvement of long-term potentiation". Experimental Gerontology. 328: 113285. doi:10.1016/j.expneurol.2020.113285. PMC 7145749. PMID 32165256.
  8. ^ Zhu Y, Yang Q, Liu H, Chen W (2020). "Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer". European Journal of Pharmacology. 887: 173588. doi:10.1016/j.ejphar.2020.173588. PMID 32961170.
  9. ^ Ahmed S, Luo L, Tang X (2017). "Nrf2 signaling pathway: Pivotal roles in inflammation". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1863 (2): 585–597. doi:10.1016/j.bbadis.2016.11.005. PMID 27825853.
  10. ^ He F, Ru X, Wen T (January 2020). "NRF2, a Transcription Factor for Stress Response and Beyond". International Journal of Molecular Sciences. 21 (13): 4777. doi:10.3390/ijms21134777. PMC 7369905. PMID 32640524.
  11. ^ Dodson M, de la Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD (January 2019). "Modulating NRF2 in Disease: Timing Is Everything". Annual Review of Pharmacology and Toxicology. 59: 555–575. doi:10.1146/annurev-pharmtox-010818-021856. PMC 6538038. PMID 30256716.
  12. ^ Motohashi H, Katsuoka F, Engel JD, Yamamoto M (April 2004). "Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway". Proceedings of the National Academy of Sciences of the United States of America. 101 (17): 6379–84. Bibcode:2004PNAS..101.6379M. doi:10.1073/pnas.0305902101. PMC 404053. PMID 15087497.
  13. ^ a b Motohashi H, Yamamoto M (November 2004). "Nrf2-Keap1 defines a physiologically important stress response mechanism". Trends in Molecular Medicine. 10 (11): 549–57. doi:10.1016/j.molmed.2004.09.003. PMID 15519281.
  14. ^ Nioi P, Nguyen T, Sherratt PJ, Pickett CB (December 2005). "The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation". Molecular and Cellular Biology. 25 (24): 10895–906. doi:10.1128/MCB.25.24.10895-10906.2005. PMC 1316965. PMID 16314513.
  15. ^ McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (July 2004). "Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron". The Journal of Biological Chemistry. 279 (30): 31556–67. doi:10.1074/jbc.M403061200. PMID 15143058.
  16. ^ Chan JY, Cheung MC, Moi P, Chan K, Kan YW (March 1995). "Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization". Human Genetics. 95 (3): 265–9. doi:10.1007/BF00225191. PMID 7868116. S2CID 23774837.
  17. ^ "Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2".
  18. ^ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (January 1999). "Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain". Genes & Development. 13 (1): 76–86. doi:10.1101/gad.13.1.76. PMC 316370. PMID 9887101.
  19. ^ Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. (August 2004). "Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2". Molecular and Cellular Biology. 24 (16): 7130–9. doi:10.1128/MCB.24.16.7130-7139.2004. PMC 479737. PMID 15282312.
  20. ^ Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M (April 2008). "Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity". Molecular and Cellular Biology. 28 (8): 2758–70. doi:10.1128/MCB.01704-07. PMC 2293100. PMID 18268004.
  21. ^ Sekhar KR, Rachakonda G, Freeman ML (April 2010). "Cysteine-based regulation of the CUL3 adaptor protein Keap1". Toxicology and Applied Pharmacology. 244 (1): 21–6. doi:10.1016/j.taap.2009.06.016. PMC 2837771. PMID 19560482.
  22. ^ Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, et al. (July 1997). "An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements". Biochemical and Biophysical Research Communications. 236 (2): 313–22. doi:10.1006/bbrc.1997.6943. PMID 9240432.
  23. ^ Venugopal R, Jaiswal AK (December 1996). "Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene". Proceedings of the National Academy of Sciences of the United States of America. 93 (25): 14960–5. Bibcode:1996PNAS...9314960V. doi:10.1073/pnas.93.25.14960. PMC 26245. PMID 8962164.
  24. ^ Solis WA, Dalton TP, Dieter MZ, Freshwater S, Harrer JM, He L, et al. (May 2002). "Glutamate-cysteine ligase modifier subunit: mouse Gclm gene structure and regulation by agents that cause oxidative stress". Biochemical Pharmacology. 63 (9): 1739–54. doi:10.1016/S0006-2952(02)00897-3. PMID 12007577.
  25. ^ Neumann CA, Cao J, Manevich Y (December 2009). "Peroxiredoxin 1 and its role in cell signaling" (PDF). Cell Cycle. 8 (24): 4072–8. doi:10.4161/cc.8.24.10242. PMC 7161701. PMID 19923889.
  26. ^ Soriano FX, Baxter P, Murray LM, Sporn MB, Gillingwater TH, Hardingham GE (March 2009). "Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin". Molecules and Cells. 27 (3): 279–82. doi:10.1007/s10059-009-0050-y. PMC 2837916. PMID 19326073.
  27. ^ Jarmi T, Agarwal A (February 2009). "Heme oxygenase and renal disease". Current Hypertension Reports. 11 (1): 56–62. doi:10.1007/s11906-009-0011-z. PMID 19146802. S2CID 36932369.
  28. ^ Wang J, Doré S (June 2007). "Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage". Brain. 130 (Pt 6): 1643–52. doi:10.1093/brain/awm095. PMC 2291147. PMID 17525142.
  29. ^ Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, et al. (February 2000). "The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin". Biochemical Society Transactions. 28 (2): 33–41. doi:10.1042/bst0280033. PMID 10816095.
  30. ^ Yueh MF, Tukey RH (March 2007). "Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice". The Journal of Biological Chemistry. 282 (12): 8749–58. doi:10.1074/jbc.M610790200. PMID 17259171.
  31. ^ Maher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, et al. (November 2007). "Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway". Hepatology. 46 (5): 1597–610. doi:10.1002/hep.21831. PMID 17668877. S2CID 19513808.
  32. ^ Reisman SA, Csanaky IL, Aleksunes LM, Klaassen CD (May 2009). "Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice". Toxicological Sciences. 109 (1): 31–40. doi:10.1093/toxsci/kfp047. PMC 2675638. PMID 19246624.
  33. ^ Lee OH, Jain AK, Papusha V, Jaiswal AK (December 2007). "An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance". The Journal of Biological Chemistry. 282 (50): 36412–20. doi:10.1074/jbc.M706517200. PMID 17925401.
  34. ^ Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, et al. (August 2012). "Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha". Nucleic Acids Research. 40 (15): 7416–29. doi:10.1093/nar/gks409. PMID 22581777.
  35. ^ Tian Y, Liu Q, Yu S, Chu Q, Chen Y, Wu K, Wang L (October 2020). "NRF2-Driven KEAP1 Transcription in Human Lung Cancer". Molecular Cancer Research. 18 (10): 1465–1476. doi:10.1158/1541-7786.MCR-20-0108. PMID 32571982.
  36. ^ a b "Dimethyl fumarate label" (PDF). FDA. December 2017. Retrieved 19 July 2018. For label updates see FDA index page for NDA 204063
  37. ^ Prince M, Li Y, Childers A, Itoh K, Yamamoto M, Kleiner HE (March 2009). "Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice". Toxicology Letters. 185 (3): 180–6. doi:10.1016/j.toxlet.2008.12.014. PMC 2676710. PMID 19150646.
  38. ^ a b Zhang Y, Gordon GB (July 2004). "A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway". Molecular Cancer Therapeutics. 3 (7): 885–93. PMID 15252150.
  39. ^ Velayutham M, Villamena FA, Fishbein JC, Zweier JL (March 2005). "Cancer chemopreventive oltipraz generates superoxide anion radical". Archives of Biochemistry and Biophysics. 435 (1): 83–8. doi:10.1016/j.abb.2004.11.028. PMID 15680910.
  40. ^ DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. (July 2011). "Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis". Nature. 475 (7354): 106–9. doi:10.1038/nature10189. PMC 3404470. PMID 21734707.
  41. ^ "Natural antioxidants could scupper tumour's detox". New Scientist (2820). July 6, 2011. Retrieved 8 October 2014.
  42. ^ a b Barajas B, Che N, Yin F, Rowshanrad A, Orozco LD, Gong KW, et al. (January 2011). "NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (1): 58–66. doi:10.1161/ATVBAHA.110.210906. PMC 3037185. PMID 20947826.
  43. ^ Araujo JA (2012). "Nrf2 and the promotion of atherosclerosis: lessons to be learned". Clin. Lipidol. 7 (2): 123–126. doi:10.2217/clp.12.5. S2CID 73042634.
  44. ^ Venugopal R, Jaiswal AK (December 1998). "Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes". Oncogene. 17 (24): 3145–56. doi:10.1038/sj.onc.1202237. PMID 9872330.
  45. ^ Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (October 2001). "Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription". Genes to Cells. 6 (10): 857–68. doi:10.1046/j.1365-2443.2001.00469.x. PMID 11683914. S2CID 22999855.
  46. ^ a b Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (October 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology. 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
  47. ^ Guo Y, Yu S, Zhang C, Kong AN (November 2015). "Epigenetic regulation of Keap1-Nrf2 signaling". Free Radical Biology & Medicine. 88 (Pt B): 337–349. doi:10.1016/j.freeradbiomed.2015.06.013. PMC 4955581. PMID 26117320.
  48. ^ a b Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, et al. (September 2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proceedings of the National Academy of Sciences of the United States of America. 105 (36): 13568–73. Bibcode:2008PNAS..10513568S. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741.
  49. ^ Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (August 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicology and Applied Pharmacology. 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. PMC 2610481. PMID 18417180.
  50. ^ Patel R, Maru G (June 2008). "Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs". Free Radical Biology & Medicine. 44 (11): 1897–911. doi:10.1016/j.freeradbiomed.2008.02.006. PMID 18358244.

External links[edit]

  • NFE2L2+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.