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{{Infobox_gene}}
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'''Nuclear factor (erythroid-derived 2)-like 2''', also known as '''NFE2L2''' or '''Nrf2''', is a [[transcription factor]] that in humans is encoded by the ''NFE2L2'' [[gene]].<ref name="pmid7937919">{{cite journal | vauthors = Moi P, Chan K, Asunis I, Cao A, Kan YW | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 21 | pages = 9926–30 | date = Oct 1994 | pmid = 7937919 | pmc = 44930 | doi = 10.1073/pnas.91.21.9926 }}</ref> Nrf2  is a [[bZIP domain|basic leucine zipper]] (bZIP) protein that regulates the expression of [[antioxidant]] proteins that protect against [[oxidative stress|oxidative damage]] triggered by injury and inflammation.<ref name="Gold">{{cite journal | vauthors = Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT | title = Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis | journal = The New England Journal of Medicine | volume = 367 | issue = 12 | pages = 1098–107 | date = Sep 2012 | pmid = 22992073 | doi = 10.1056/NEJMoa1114287 }}</ref> Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Nuclear factor (erythroid-derived 2)-like 2
| HGNCid = 7782
| Symbol = NFE2L2
| AltSymbols =; NRF2
| OMIM = 600492
| ECnumber = 
| Homologene = 2412
| MGIid = 108420
| GeneAtlas_image1 = PBB_GE_NFE2L2_201146_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0016563 |text = transcription activator activity}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046983 |text = protein dimerization activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0006366 |text = transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0030968 |text = unfolded protein response}} {{GNF_GO|id=GO:0045893 |text = positive regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0045995 |text = regulation of embryonic development}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4780
    | Hs_Ensembl = ENSG00000116044
    | Hs_RefseqProtein = NP_006155
    | Hs_RefseqmRNA = NM_006164
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 2
    | Hs_GenLoc_start = 177803285
    | Hs_GenLoc_end = 177965671
    | Hs_Uniprot = Q16236
    | Mm_EntrezGene = 18024
    | Mm_Ensembl = ENSMUSG00000015839
    | Mm_RefseqmRNA = NM_010902
    | Mm_RefseqProtein = NP_035032
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 75476352
    | Mm_GenLoc_end = 75505480
    | Mm_Uniprot = Q05DU7
  }}
}}
'''Nuclear factor (erythroid-derived 2)-like 2''', also known as '''NFE2L2''', is a human [[gene]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
NFE2L2 and other genes, such as [[NFE2]], [[NFE2L1]] and [[NFE2L3]], encode basic [[leucine zipper]] ([[bZIP domain|bZIP]]) [[transcription factor]]s. They share highly conserved regions that are distinct from other bZIP families, such as [[C-jun|JUN]] and [[C-Fos|FOS]], although remaining regions have diverged considerably from each other.<ref name="pmid7868116">{{cite journal | vauthors = Chan JY, Cheung MC, Moi P, Chan K, Kan YW | title = Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization | journal = Human Genetics | volume = 95 | issue = 3 | pages = 265–9 | date = Mar 1995 | pmid = 7868116 | doi = 10.1007/BF00225191 }}</ref><ref>{{cite web | title = Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2| url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4780| accessdate = }}</ref>
{{PBB_Summary
| section_title =
| summary_text = NFE2 (MIM 601490), NFE2L1 (MIM 163260), and NFE2L2 comprise a family of human genes encoding basic leucine zipper (bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN (MIM 165160) and FOS (MIM 164810), although remaining regions have diverged considerably from each other (Chan et al., 1995).[supplied by OMIM]<ref>{{cite web | title = Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4780| accessdate = }}</ref>
}}


==References==
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.
{{reflist|2}}
 
==Further reading==
Nrf2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 ([[KEAP1]]) and [[Cullin 3]] which degrade Nrf2 by [[ubiquitination]].<ref name="pmid9887101">{{cite journal | vauthors = Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M | title = Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain | journal = Genes & Development | volume = 13 | issue = 1 | pages = 76–86 | date = Jan 1999 | pmid = 9887101 | pmc = 316370 | doi = 10.1101/gad.13.1.76 }}</ref> 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.<ref name="pmid15282312">{{cite journal | vauthors = Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M | title = Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 | journal = Molecular and Cellular Biology | volume = 24 | issue = 16 | pages = 7130–9 | date = Aug 2004 | pmid = 15282312 | pmc = 479737 | doi = 10.1128/MCB.24.16.7130-7139.2004 }}</ref> [[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,<ref name="pmid18268004">{{cite journal | vauthors = Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M | title = Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity | journal = Molecular and Cellular Biology | volume = 28 | issue = 8 | pages = 2758–70 | date = Apr 2008 | pmid = 18268004 | pmc = 2293100 | doi = 10.1128/MCB.01704-07 }}</ref><ref name="pmid19560482">{{cite journal | vauthors = Sekhar KR, Rachakonda G, Freeman ML | title = Cysteine-based regulation of the CUL3 adaptor protein Keap1 | journal = Toxicology and Applied Pharmacology | volume = 244 | issue = 1 | pages = 21–6 | date = Apr 2010 | pmid = 19560482 | pmc = 2837771 | doi = 10.1016/j.taap.2009.06.016 }}</ref> and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with one of [[small Maf]] proteins ([[MAFF (gene)|MAFF]], [[MAFG]], [[MAFK]]) and binds to the antioxidant response element (ARE) in the upstream [[promoter region]] of many antioxidative genes, and initiates their transcription.<ref name="pmid9240432">{{cite journal | vauthors = Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y | title = An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements | journal = Biochemical and Biophysical Research Communications | volume = 236 | issue = 2 | pages = 313–22 | date = Jul 1997 | pmid = 9240432 | doi = 10.1006/bbrc.1997.6943 }}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
== Target genes ==
| citations =
 
*{{cite journal  | author=Alam J, Cook JL |title=Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway. |journal=Curr. Pharm. Des. |volume=9 |issue= 30 |pages= 2499-511 |year= 2003 |pmid= 14529549 |doi= }}
Activation of Nrf2 results in the induction of many [[antioxidant|cytoprotective proteins]]. These include, but are not limited to, the following:
*{{cite journal  | author=Zhang DD |title=Mechanistic studies of the Nrf2-Keap1 signaling pathway. |journal=Drug Metab. Rev. |volume=38 |issue= 4 |pages= 769-89 |year= 2007 |pmid= 17145701 |doi= 10.1080/03602530600971974 }}
 
*{{cite journal | author=Aleksunes LM, Manautou JE |title=Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. |journal=Toxicologic pathology |volume=35 |issue= 4 |pages= 459-73 |year= 2007 |pmid= 17562481 |doi= 10.1080/01926230701311344 }}
* NAD(P)H quinone oxidoreductase 1 ([[NAD(P)H dehydrogenase (quinone 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]].<ref name="pmid8962164">{{cite journal | vauthors = Venugopal R, Jaiswal AK | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 25 | pages = 14960–5 | date = Dec 1996 | pmid = 8962164 | pmc = 26245 | doi = 10.1073/pnas.93.25.14960 }}</ref>
*{{cite journal | author=Chan JY, Cheung MC, Moi P, ''et al.'' |title=Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. |journal=Hum. Genet. |volume=95 |issue= 3 |pages= 265-9 |year= 1995 |pmid= 7868116 |doi= }}
* [[Glutamate-cysteine ligase]], catalytic (Gclc) and glutamate-cysteine ligase, modifier ([[GCLM]]) subunits 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.<ref name="pmid12007577">{{cite journal | vauthors = Solis WA, Dalton TP, Dieter MZ, Freshwater S, Harrer JM, He L, Shertzer HG, Nebert DW | title = Glutamate-cysteine ligase modifier subunit: mouse Gclm gene structure and regulation by agents that cause oxidative stress | journal = Biochemical Pharmacology | volume = 63 | issue = 9 | pages = 1739–54 | date = May 2002 | pmid = 12007577 | doi = 10.1016/S0006-2952(02)00897-3 }}</ref>
*{{cite journal | author=Moi P, Chan K, Asunis I, ''et al.'' |title=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. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 21 |pages= 9926-30 |year= 1994 |pmid= 7937919 |doi= }}
* [[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]].<ref>{{cite journal | vauthors = Neumann CA, Cao J, Manevich Y | title = Peroxiredoxin 1 and its role in cell signaling | journal = Cell Cycle | volume = 8 | issue = 24 | pages = 4072–8 | date = Dec 2009 | pmid = 19923889 | doi = 10.4161/cc.8.24.10242 | url = https://www.landesbioscience.com/journals/cc/11NeumannCC8-24.pdf }}</ref><ref>{{cite journal | vauthors = Soriano FX, Baxter P, Murray LM, Sporn MB, Gillingwater TH, Hardingham GE | title = Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin | journal = Molecules and Cells | volume = 27 | issue = 3 | pages = 279–82 | date = Mar 2009 | pmid = 19326073 | pmc = 2837916 | doi = 10.1007/s10059-009-0050-y }}</ref>
*{{cite journal  | author=Toki T, Itoh J, Kitazawa J, ''et al.'' |title=Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif. |journal=Oncogene |volume=14 |issue= 16 |pages= 1901-10 |year= 1997 |pmid= 9150357 |doi= 10.1038/sj.onc.1201024 }}
* Heme oxygenase-1 ([[HMOX1]], [[Heme oxygenase 1|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.<ref name="pmid19146802">{{cite journal | vauthors = Jarmi T, Agarwal A | title = Heme oxygenase and renal disease | journal = Current Hypertension Reports | volume = 11 | issue = 1 | pages = 56–62 | date = Feb 2009 | pmid = 19146802 | doi = 10.1007/s11906-009-0011-z }}</ref> In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after [[intracerebral hemorrhage]].<ref name="pmid17525142">{{cite journal | vauthors = Wang J, Doré S | title = Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage | journal = Brain | volume = 130 | issue = Pt 6 | pages = 1643–52 | date = Jun 2007 | pmid = 17525142 | pmc = 2291147 | doi = 10.1093/brain/awm095 }}</ref>
*{{cite journal  | author=Venugopal R, Jaiswal AK |title=Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. |journal=Oncogene |volume=17 |issue= 24 |pages= 3145-56 |year= 1999 |pmid= 9872330 |doi= 10.1038/sj.onc.1202237 }}
* The [[glutathione S-transferase]] (GST) family includes cytosolic, [[Mitochondrion|mitochondrial]], and [[microsomal]] enzymes that catalyze the conjugation of GSH with endogenous and [[xenobiotic]] [[electrophile]]s.  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.<ref name="pmid10816095">{{cite journal | vauthors = Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M | title = 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 | journal = Biochemical Society Transactions | volume = 28 | issue = 2 | pages = 33–41 | date = Feb 2000 | pmid = 10816095 | doi = 10.1042/bst0280033}}</ref>
*{{cite journal  | author=Itoh K, Wakabayashi N, Katoh Y, ''et al.'' |title=Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. |journal=Genes Dev. |volume=13 |issue= 1 |pages= 76-86 |year= 1999 |pmid= 9887101 |doi= }}
* 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.<ref name="pmid17259171">{{cite journal | vauthors = Yueh MF, Tukey RH | title = Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice | journal = The Journal of Biological Chemistry | volume = 282 | issue = 12 | pages = 8749–58 | date = Mar 2007 | pmid = 17259171 | doi = 10.1074/jbc.M610790200 }}</ref>
*{{cite journal  | author=Wang Y, Devereux W, Stewart TM, Casero RA |title=Cloning and characterization of human polyamine-modulated factor-1, a transcriptional cofactor that regulates the transcription of the spermidine/spermine N(1)-acetyltransferase gene. |journal=J. Biol. Chem. |volume=274 |issue= 31 |pages= 22095-101 |year= 1999 |pmid= 10419538 |doi= }}
* [[ABCC2|Multidrug resistance-associated protein]]s (Mrps) are important [[membrane transporter]]s 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.<ref name="pmid17668877">{{cite journal | vauthors = Maher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, Scheffer GL, Chan JY, Manautou JE, Chen Y, Dalton TP, Yamamoto M, Klaassen CD | title = Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway | journal = Hepatology | volume = 46 | issue = 5 | pages = 1597–610 | date = Nov 2007 | pmid = 17668877 | doi = 10.1002/hep.21831 }}</ref><ref name="pmid19246624">{{cite journal | vauthors = Reisman SA, Csanaky IL, Aleksunes LM, Klaassen CD | title = Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice | journal = Toxicological Sciences | volume = 109 | issue = 1 | pages = 31–40 | date = May 2009 | pmid = 19246624 | pmc = 2675638 | doi = 10.1093/toxsci/kfp047 }}</ref>
*{{cite journal | author=Ohtsubo T, Kamada S, Mikami T, ''et al.'' |title=Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases. |journal=Cell Death Differ. |volume=6 |issue= 9 |pages= 865-72 |year= 2000 |pmid= 10510468 |doi= 10.1038/sj.cdd.4400566 }}
 
*{{cite journal  | author=Nguyen T, Huang HC, Pickett CB |title=Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. |journal=J. Biol. Chem. |volume=275 |issue= 20 |pages= 15466-73 |year= 2000 |pmid= 10747902 |doi= 10.1074/jbc.M000361200 }}
== Structure ==
*{{cite journal | author=Ikeda Y, Sugawara A, Taniyama Y, ''et al.'' |title=Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor gamma in macrophages via an interaction with NRF2. |journal=J. Biol. Chem. |volume=275 |issue= 42 |pages= 33142-50 |year= 2000 |pmid= 10930400 |doi= 10.1074/jbc.M002319200 }}
 
*{{cite journal  | author=Dhakshinamoorthy S, Jaiswal AK |title=Small maf (MafG and MafK) proteins negatively regulate antioxidant response element-mediated expression and antioxidant induction of the NAD(P)H:Quinone oxidoreductase1 gene. |journal=J. Biol. Chem. |volume=275 |issue= 51 |pages= 40134-41 |year= 2001 |pmid= 11013233 |doi= 10.1074/jbc.M003531200 }}
Nrf2 is a basic leucine zipper ([[bZIP domain|bZip]]) [[transcription factor]] with a Cap “n” Collar (CNC) structure.<ref name="pmid7937919"/> Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains.   The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with [[small Maf]] proteins ([[MAFF (gene)|MAFF]], [[MAFG]], [[MAFK]]).<ref name="pmid15087497">{{cite journal | vauthors = Motohashi H, Katsuoka F, Engel JD, Yamamoto M | title = Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 17 | pages = 6379–84 | date = Apr 2004 | pmid = 15087497 | pmc = 404053 | doi = 10.1073/pnas.0305902101 }}</ref> The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.<ref name="pmid15519281">{{cite journal | vauthors = Motohashi H, Yamamoto M | title = Nrf2-Keap1 defines a physiologically important stress response mechanism | journal = Trends in Molecular Medicine | volume = 10 | issue = 11 | pages = 549–57 | date = Nov 2004 | pmid = 15519281 | doi = 10.1016/j.molmed.2004.09.003 }}</ref>
*{{cite journal  | author=Huang HC, Nguyen T, Pickett CB |title=Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 23 |pages= 12475-80 |year= 2001 |pmid= 11035812 |doi= 10.1073/pnas.220418997 }}
The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.<ref name="pmid16314513">{{cite journal | vauthors = Nioi P, Nguyen T, Sherratt PJ, Pickett CB | title = The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation | journal = Molecular and Cellular Biology | volume = 25 | issue = 24 | pages = 10895–906 | date = Dec 2005 | pmid = 16314513 | pmc = 1316965 | doi = 10.1128/MCB.25.24.10895-10906.2005 }}</ref>
*{{cite journal  | author=Wang Y, Devereux W, Stewart TM, Casero RA |title=Characterization of the interaction between the transcription factors human polyamine modulated factor (PMF-1) and NF-E2-related factor 2 (Nrf-2) in the transcriptional regulation of the spermidine/spermine N1-acetyltransferase (SSAT) gene. |journal=Biochem. J. |volume=355 |issue= Pt 1 |pages= 45-9 |year= 2001 |pmid= 11256947 |doi= }}
The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein ([[CREB]]), which possesses intrinsic [[histone acetyltransferase]] activity.<ref name="pmid15519281"/>
*{{cite journal | author=He CH, Gong P, Hu B, ''et al.'' |title=Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. |journal=J. Biol. Chem. |volume=276 |issue= 24 |pages= 20858-65 |year= 2001 |pmid= 11274184 |doi= 10.1074/jbc.M101198200 }}
The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.<ref name="pmid15143058">{{cite journal | vauthors = McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD | title = 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 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 30 | pages = 31556–67 | date = Jul 2004 | pmid = 15143058 | doi = 10.1074/jbc.M403061200 }}</ref>
*{{cite journal  | author=Dhakshinamoorthy S, Jaiswal AK |title=Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. |journal=Oncogene |volume=20 |issue= 29 |pages= 3906-17 |year= 2001 |pmid= 11439354 |doi= 10.1038/sj.onc.1204506 }}
 
*{{cite journal | author=Katoh Y, Itoh K, Yoshida E, ''et al.'' |title=Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. |journal=Genes Cells |volume=6 |issue= 10 |pages= 857-68 |year= 2002 |pmid= 11683914 |doi= }}
== Tissue distribution ==
*{{cite journal | author=Wang Y, Devereux W, Stewart TM, Casero RA |title=Polyamine-modulated factor 1 binds to the human homologue of the 7a subunit of the Arabidopsis COP9 signalosome: implications in gene expression. |journal=Biochem. J. |volume=366 |issue= Pt 1 |pages= 79-86 |year= 2002 |pmid= 12020345 |doi= 10.1042/BJ20020211 }}
 
*{{cite journal  | author=Tirumalai R, Rajesh Kumar T, Mai KH, Biswal S |title=Acrolein causes transcriptional induction of phase II genes by activation of Nrf2 in human lung type II epithelial (A549) cells. |journal=Toxicol. Lett. |volume=132 |issue= 1 |pages= 27-36 |year= 2002 |pmid= 12084617 |doi=  }}
Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.<ref name="pmid7937919"/>
}}
 
{{refend}}
== Clinical drug target ==
 
[[Tecfidera]] ([[dimethyl fumarate]] or BG-12), marketed by [[Biogen Idec]], was approved by the [[Food and Drug Administration]] (FDA) on March 27, 2013 following the conclusion of [[Phase 3 clinical trial]]s which demonstrated that the drug reduced relapse rates and increased time to progression of disability in patients with [[multiple sclerosis]]. The mechanism by which Tecfidera exerts its therapeutic effect is unknown. Tecfidera (and its metabolite, monomethyl fumarate) activates the Nrf2 pathway and has been identified as a [[nicotinic acid]] receptor [[agonist]] in vitro.<ref>{{cite web|title=Highlights of prescribing information|url=https://www.tecfidera.com/pdfs/full-prescribing-information.pdf|publisher=Biogen Idec|accessdate=8 October 2014|date=March 2013}}</ref> Adverse events associated with Tecfidera include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased [[lymphocyte]] counts and elevated liver [[aminotransferase]] levels.<ref name="Gold"/>
 
The dithiolethiones are a class of organosulfur compounds, of which [[oltipraz]], an NRF2 inducer, is the best studied.<ref name="pmid19150646">{{cite journal | vauthors = Prince M, Li Y, Childers A, Itoh K, Yamamoto M, Kleiner HE | title = Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice | journal = Toxicology Letters | volume = 185 | issue = 3 | pages = 180–6 | date = Mar 2009 | pmid = 19150646 | pmc = 2676710 | doi = 10.1016/j.toxlet.2008.12.014 }}</ref> Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.<ref name="pmid15252150">{{cite journal | vauthors = Zhang Y, Gordon GB | title = A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway | journal = Molecular Cancer Therapeutics | volume = 3 | issue = 7 | pages = 885–93 | date = Jul 2004 | pmid = 15252150 | doi =  }}</ref> However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity.<ref name="pmid15252150"/> Oltipraz also generates [[superoxide radical]], which can be toxic.<ref name="pmid15680910">{{cite journal | vauthors = Velayutham M, Villamena FA, Fishbein JC, Zweier JL | title = Cancer chemopreventive oltipraz generates superoxide anion radical | journal = Archives of Biochemistry and Biophysics | volume = 435 | issue = 1 | pages = 83–8 | date = Mar 2005 | pmid = 15680910 | doi = 10.1016/j.abb.2004.11.028 }}</ref>
 
==Potential adverse effects of NRF2 activation==
Genetic activation of NRF2 may promote the development of [[wikt: de novo|''de novo'']] cancerous tumors<ref name=DeNicola>{{cite journal | vauthors = DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA | title = Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis | journal = Nature | volume = 475 | issue = 7354 | pages = 106–9 | date = Jul 2011 | pmid = 21734707 | doi = 10.1038/nature10189 | url = http://www.nature.com/nature/journal/v475/n7354/full/nature10189.html | pmc=3404470}}</ref><ref name=NewSci>{{cite journal|title=Natural antioxidants could scupper tumour's detox|journal=[[New Scientist]]|date=July 6, 2011|issue=2820|url=https://www.newscientist.com/article/mg21128204.500-natural-antioxidants-could-scupper-tumours-detox.html#.VDW3Tfl4pcR|accessdate=8 October 2014}}</ref> as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.<ref name=Barajas/> It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.<ref name=Barajas>{{cite journal | vauthors = Barajas B, Che N, Yin F, Rowshanrad A, Orozco LD, Gong KW, Wang X, Castellani LW, Reue K, Lusis AJ, Araujo JA | title = NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 31 | issue = 1 | pages = 58–66 | date = Jan 2011 | pmid = 20947826 | doi = 10.1161/ATVBAHA.110.210906 | pmc=3037185}}</ref><ref name=Araujo>{{cite journal|last1=Araujo|first1=Jesus A|title=Nrf2 and the promotion of atherosclerosis: lessons to be learned|journal=Clin. Lipidol|date=2012|volume=7|issue=2|pages=123–126|url=http://www.futuremedicine.com/doi/pdf/10.2217/clp.12.5|accessdate=10 October 2014|doi=10.2217/clp.12.5}}</ref>
 
== Interactions ==
 
NFE2L2 has been shown to [[Protein-protein interaction|interact]] with [[MAFF (gene)|MAFF]], [[MAFG]], [[MAFK]], [[C-jun]],<ref name = pmid9872330>{{cite journal | vauthors = Venugopal R, Jaiswal AK | title = Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes | journal = Oncogene | volume = 17 | issue = 24 | pages = 3145–56 | date = Dec 1998 | pmid = 9872330 | doi = 10.1038/sj.onc.1202237 }}</ref>  [[CREB-binding protein|CREBBP]],<ref name = pmid11683914>{{cite journal | vauthors = Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M | title = Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription | journal = Genes to Cells | volume = 6 | issue = 10 | pages = 857–68 | date = Oct 2001 | pmid = 11683914 | doi = 10.1046/j.1365-2443.2001.00469.x }}</ref> [[EIF2AK3]],<ref name = pmid14517290/> [[KEAP1]],<ref>{{cite journal | vauthors = Guo Y, Yu S, Zhang C, Kong AN | title = Epigenetic regulation of Keap1-Nrf2 signaling | journal = Free Radical Biology & Medicine | volume = 88 | issue = Pt B | pages = 337–49 | date = November 2015 | pmid = 26117320 | doi = 10.1016/j.freeradbiomed.2015.06.013 }}</ref><ref name = pmid14517290>{{cite journal | vauthors = Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA | title = Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival | journal = Molecular and Cellular Biology | volume = 23 | issue = 20 | pages = 7198–209 | date = Oct 2003 | pmid = 14517290 | pmc = 230321 | doi = 10.1128/MCB.23.20.7198-7209.2003 }}</ref><ref name = pmid18757741>{{cite journal | vauthors = Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S | title = Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 36 | pages = 13568–73 | date = Sep 2008 | pmid = 18757741 | pmc = 2533230 | doi = 10.1073/pnas.0806268105 }}</ref><ref name = pmid18417180>{{cite journal | vauthors = Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD | title = Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction | journal = Toxicology and Applied Pharmacology | volume = 230 | issue = 3 | pages = 383–9 | date = Aug 2008 | pmid = 18417180 | pmc = 2610481 | doi = 10.1016/j.taap.2008.03.003 }}</ref> and [[Ubiquitin C|UBC]].<ref name = pmid18757741/><ref name = pmid18358244>{{cite journal | vauthors = Patel R, Maru G | title = Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs | journal = Free Radical Biology & Medicine | volume = 44 | issue = 11 | pages = 1897–911 | date = Jun 2008 | pmid = 18358244 | doi = 10.1016/j.freeradbiomed.2008.02.006 }}</ref>
{{Div col end}}
 
== References ==
{{Reflist|33em}}


== External links ==
== External links ==
* {{MeshName|NFE2L2+protein,+human}}
* {{MeshName|NFE2L2+protein,+human}}


{{NLM content}}
{{Transcription factors|g1}}


{{protein-stub}}
{{DEFAULTSORT:Nfe2l2}}
{{NLM content}}
{{Transcription factors}}
[[Category:Transcription factors]]
[[Category:Transcription factors]]
{{WikiDoc Sources}}

Revision as of 02:32, 22 November 2017

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Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene.[1] Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.[2] Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.

Function

NFE2L2 and other genes, such as NFE2, NFE2L1 and NFE2L3, encode basic leucine zipper (bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other.[3][4]

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.[5] 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.[6] 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,[7][8] 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.[9]

Target genes

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

Structure

Nrf2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure.[1] Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins (MAFF, MAFG, MAFK).[20] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.[21] The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.[22] The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CREB), which possesses intrinsic histone acetyltransferase activity.[21] The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.[23]

Tissue distribution

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[1]

Clinical drug target

Tecfidera (dimethyl fumarate or BG-12), marketed by Biogen Idec, was approved by the Food and Drug Administration (FDA) on March 27, 2013 following the conclusion of Phase 3 clinical trials which demonstrated that the drug reduced relapse rates and increased time to progression of disability in patients with multiple sclerosis. The mechanism by which Tecfidera exerts its therapeutic effect is unknown. Tecfidera (and its metabolite, monomethyl fumarate) activates the Nrf2 pathway and has been identified as a nicotinic acid receptor agonist in vitro.[24] Adverse events associated with Tecfidera include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.[2]

The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is the best studied.[25] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[26] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity.[26] Oltipraz also generates superoxide radical, which can be toxic.[27]

Potential adverse effects of NRF2 activation

Genetic activation of NRF2 may promote the development of de novo cancerous tumors[28][29] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.[30] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.[30][31]

Interactions

NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun,[32] CREBBP,[33] EIF2AK3,[34] KEAP1,[35][34][36][37] and UBC.[36][38]

References

  1. ↑ 1.0 1.1 1.2 Moi P, Chan K, Asunis I, Cao A, Kan YW (Oct 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. doi:10.1073/pnas.91.21.9926. PMC 44930. PMID 7937919.
  2. ↑ 2.0 2.1 Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (Sep 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. PMID 22992073.
  3. ↑ Chan JY, Cheung MC, Moi P, Chan K, Kan YW (Mar 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.
  4. ↑ "Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2".
  5. ↑ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (Jan 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.
  6. ↑ Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (Aug 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.
  7. ↑ Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M (Apr 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.
  8. ↑ Sekhar KR, Rachakonda G, Freeman ML (Apr 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.
  9. ↑ Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (Jul 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.
  10. ↑ Venugopal R, Jaiswal AK (Dec 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. doi:10.1073/pnas.93.25.14960. PMC 26245. PMID 8962164.
  11. ↑ Solis WA, Dalton TP, Dieter MZ, Freshwater S, Harrer JM, He L, Shertzer HG, Nebert DW (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.
  12. ↑ Neumann CA, Cao J, Manevich Y (Dec 2009). "Peroxiredoxin 1 and its role in cell signaling" (PDF). Cell Cycle. 8 (24): 4072–8. doi:10.4161/cc.8.24.10242. PMID 19923889.
  13. ↑ Soriano FX, Baxter P, Murray LM, Sporn MB, Gillingwater TH, Hardingham GE (Mar 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.
  14. ↑ Jarmi T, Agarwal A (Feb 2009). "Heme oxygenase and renal disease". Current Hypertension Reports. 11 (1): 56–62. doi:10.1007/s11906-009-0011-z. PMID 19146802.
  15. ↑ Wang J, Doré S (Jun 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.
  16. ↑ Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M (Feb 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.
  17. ↑ Yueh MF, Tukey RH (Mar 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.
  18. ↑ Maher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, Scheffer GL, Chan JY, Manautou JE, Chen Y, Dalton TP, Yamamoto M, Klaassen CD (Nov 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.
  19. ↑ 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.
  20. ↑ Motohashi H, Katsuoka F, Engel JD, Yamamoto M (Apr 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. doi:10.1073/pnas.0305902101. PMC 404053. PMID 15087497.
  21. ↑ 21.0 21.1 Motohashi H, Yamamoto M (Nov 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.
  22. ↑ Nioi P, Nguyen T, Sherratt PJ, Pickett CB (Dec 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.
  23. ↑ McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (Jul 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.
  24. ↑ "Highlights of prescribing information" (PDF). Biogen Idec. March 2013. Retrieved 8 October 2014.
  25. ↑ Prince M, Li Y, Childers A, Itoh K, Yamamoto M, Kleiner HE (Mar 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.
  26. ↑ 26.0 26.1 Zhang Y, Gordon GB (Jul 2004). "A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway". Molecular Cancer Therapeutics. 3 (7): 885–93. PMID 15252150.
  27. ↑ Velayutham M, Villamena FA, Fishbein JC, Zweier JL (Mar 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.
  28. ↑ DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA (Jul 2011). "Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis". Nature. 475 (7354): 106–9. doi:10.1038/nature10189. PMC 3404470. PMID 21734707.
  29. ↑ "Natural antioxidants could scupper tumour's detox". New Scientist (2820). July 6, 2011. Retrieved 8 October 2014.
  30. ↑ 30.0 30.1 Barajas B, Che N, Yin F, Rowshanrad A, Orozco LD, Gong KW, Wang X, Castellani LW, Reue K, Lusis AJ, Araujo JA (Jan 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.
  31. ↑ Araujo, Jesus A (2012). "Nrf2 and the promotion of atherosclerosis: lessons to be learned". Clin. Lipidol. 7 (2): 123–126. doi:10.2217/clp.12.5. Retrieved 10 October 2014.
  32. ↑ Venugopal R, Jaiswal AK (Dec 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.
  33. ↑ Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (Oct 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.
  34. ↑ 34.0 34.1 Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (Oct 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.
  35. ↑ Guo Y, Yu S, Zhang C, Kong AN (November 2015). "Epigenetic regulation of Keap1-Nrf2 signaling". Free Radical Biology & Medicine. 88 (Pt B): 337–49. doi:10.1016/j.freeradbiomed.2015.06.013. PMID 26117320.
  36. ↑ 36.0 36.1 Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (Sep 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. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741.
  37. ↑ Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (Aug 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.
  38. ↑ Patel R, Maru G (Jun 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.

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