NFE2L2

NFE2L2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases NFE2L2, NRF2, HEBP1, nuclear factor, erythroid 2 like 2
External IDs MGI: 108420 HomoloGene: 2412 GeneCards: NFE2L2
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

4780

18024

Ensembl

ENSG00000116044

ENSMUSG00000015839

UniProt

Q16236

Q60795

RefSeq (mRNA)

NM_010902

RefSeq (protein)

NP_001138884.1
NP_001138885.1
NP_006155.2
NP_001300829.1
NP_001300830.1

NP_035032.1

Location (UCSC) Chr 2: 177.23 – 177.39 Mb Chr 2: 75.68 – 75.7 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

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.[3] 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.[4] 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 and NFE2L1, 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.[5][6]

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.[7] 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.[8] 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,[9][10] and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with a small Maf protein and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription.[11]

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.[3]

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.[22] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.[23] 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.[24] 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.[23] 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.[25]

Tissue distribution

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[3]

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.[26] 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.[4]

The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is the best studied.[27] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[28] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity.[28] Oltipraz also generates superoxide radical, which can be toxic.[29]

Bardoxolone methyl, a synthetic oleanane triterpenoid compound, is under clinical investigation for the treatment of pulmonary hypertension.[30][31][32]

RTA 408 is a synthetic triterpenoid. Preclinical studies have demonstrated that it possesses antioxidative and anti-inflammatory activities,[33][34] as well as the potential to improve mitochondrial bioenergetics.[35] A Phase 2 clinical studies is evaluating RTA 408 for the prevention of radiation-induced dermatitis.[36][37]

Potential adverse effects of NRF2 activation

Genetic activation of NRF2 may promote the development of de novo cancerous tumors[38][39] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.[40] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.[40][41]

Interactions

NFE2L2 has been shown to interact with:

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. 1 2 3 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 44930Freely accessible. PMID 7937919.
  4. 1 2 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.
  5. ↑ 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.
  6. ↑ "Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2".
  7. ↑ 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 316370Freely accessible. PMID 9887101.
  8. ↑ 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 479737Freely accessible. PMID 15282312.
  9. ↑ 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 2293100Freely accessible. PMID 18268004.
  10. ↑ 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 2837771Freely accessible. PMID 19560482.
  11. ↑ 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.
  12. ↑ 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 26245Freely accessible. PMID 8962164.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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 2837916Freely accessible. PMID 19326073.
  16. ↑ 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.
  17. ↑ 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 2291147Freely accessible. PMID 17525142.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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 2675638Freely accessible. PMID 19246624.
  22. ↑ 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 404053Freely accessible. PMID 15087497.
  23. 1 2 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.
  24. ↑ 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 1316965Freely accessible. PMID 16314513.
  25. ↑ 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.
  26. ↑ "Highlights of prescribing information" (PDF). Biogen Idec. March 2013. Retrieved 8 October 2014.
  27. ↑ 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 2676710Freely accessible. PMID 19150646.
  28. 1 2 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.
  29. ↑ 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.
  30. ↑ "Reata Begins Enrollment For PAH – LARIAT Phase 2 Study Examining Bardoxolone Methyl for Treating Pulmonary Arterial Hypertension". Retrieved 6 October 2014.
  31. ↑ "Bardoxolone Methyl Evaluation in Patients With Pulmonary Arterial Hypertension (PAH) (LARIAT)". Retrieved 6 October 2014.
  32. ↑ Carroll, John (6 October 2014). "After a taste of disaster, Reata plans a comeback for bardoxolone".
  33. ↑ Reisman SA, Lee CY, Meyer CJ, Proksch JW, Ward KW (Jul 2014). "Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin". Archives of Dermatological Research. 306 (5): 447–54. doi:10.1007/s00403-013-1433-7. PMID 24362512.
  34. ↑ Reisman SA, Lee CY, Meyer CJ, Proksch JW, Sonis ST, Ward KW (May 2014). "Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis". Radiation Research. 181 (5): 512–20. doi:10.1667/RR13578.1. PMID 24720753.
  35. ↑ Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, Liby KT, Risingsong R, Sporn M, Beal MF, Kiaei M (Jul 2011). "Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis". Free Radical Biology & Medicine. 51 (1): 88–96. doi:10.1016/j.freeradbiomed.2011.03.027. PMC 3109235Freely accessible. PMID 21457778.
  36. ↑ "RTA 408 Lotion in Patients at Risk for Radiation Dermatitis (PRIMROSE)". 6 October 2014.
  37. ↑ "Reata Enrolls First Patient in the PRIMROSE Study, a Phase 2 Study Examining RTA 408 in Breast Cancer Patients at Risk for Radiation Dermatitis". Retrieved 6 October 2014.
  38. ↑ 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 3404470Freely accessible. PMID 21734707.
  39. ↑ "Natural antioxidants could scupper tumour's detox". New Scientist (2820). July 6, 2011. Retrieved 8 October 2014.
  40. 1 2 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. PMID 20947826.
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ 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.
  44. 1 2 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 230321Freely accessible. PMID 14517290.
  45. ↑ 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.
  46. 1 2 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 2533230Freely accessible. PMID 18757741.
  47. ↑ 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 2610481Freely accessible. PMID 18417180.
  48. ↑ 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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