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Nfe2l2

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Nfe2l2

Nuclear factor, erythroid 2-like 2
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; NRF2
External IDs ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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 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.[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 its substrate, Nrf2. Keap1 is a substrate adaptor, which helps Cullin 3 ubiquitinate Nrf2. When 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 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.[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.[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 [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]

Bardoxolone methyl, a synthetic oleanane triterpenoid compound, is under clinical investigation for the treatment of pulmonary hypertension.[28][29][30]

RTA 408 is a synthetic triterpenoid. Preclinical studies have demonstrated that it possesses antioxidative and anti-inflammatory activities,[31][32] as well as the potential to improve mitochondrial bioenergetics.[33] A Phase 2 clinical studies is evaluating RTA 408 for the prevention of radiation-induced dermatitis.[34][35]

Potential adverse effects of NRF2 activation

Activation of NRF2 may promote the development of de novo cancerous tumors.[36][37] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.[38] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.[38][39]

Interactions

NFE2L2 has been shown to interact with:

References

  1. ^ 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". Proc. Natl. Acad. Sci. U.S.A. 91 (21): 9926–30.  
  2. ^ a b Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (September 2012). "Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis". N. Engl. J. Med. 367 (12): 1098–107.  
  3. ^ 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". Hum. Genet. 95 (3): 265–9.  
  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 (January 1999). "Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain". Genes Dev. 13 (1): 76–86.  
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  7. ^ 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". Mol. Cell. Biol. 28 (8): 2758–70.  
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  10. ^ 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". Proc. Natl. Acad. Sci. U.S.A. 93 (25): 14960–5.  
  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". Biochem. Pharmacol. 63 (9): 1739–54.  
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  14. ^ Jarmi T, Agarwal A (February 2009). "Heme oxygenase and renal disease". Curr. Hypertens. Rep. 11 (1): 56–62.  
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  16. ^ Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M (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". Biochem. Soc. Trans. 28 (2): 33–41.  
  17. ^ Yueh MF, Tukey RH (March 2007). "Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice". J. Biol. Chem. 282 (12): 8749–58.  
  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 (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.  
  19. ^ Reisman SA, Csanaky IL, Aleksunes LM, Klaassen CD (May 2009). "Altered Disposition of Acetaminophen in Nrf2-null and Keap1-knockdown Mice". Toxicol. Sci. 109 (1): 31–40.  
  20. ^ 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". Proc Natl Acad Sci U S A. 101 (17): 6379–84.  
  21. ^ a b Motohashi H, Yamamoto M (November 2004). "Nrf2-Keap1 defines a physiologically important stress response mechanism". Trends Mol Med 10 (11): 549–57.  
  22. ^ Nioi P, Nguyen T, Sherratt PJ, Pickett CB (December 2005). "The Carboxy-Terminal Neh3 Domain of Nrf2 Is Required for Transcriptional Activation". Mol. Cell. Biol. 25 (24): 10895–906.  
  23. ^ 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". J. Biol. Chem. 279 (30): 31556–67.  
  24. ^ "Highlights of prescribing information". Biogen Idec. March 2013. Retrieved 8 October 2014. 
  25. ^ 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". Toxicol. Lett. 185 (3): 180–6.  
  26. ^ a b Zhang Y, Gordon GB (July 2004). "A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway". Mol. Cancer Ther. 3 (7): 885–93.  
  27. ^ Velayutham M, Villamena FA, Fishbein JC, Zweier JL (March 2005). "Cancer chemopreventive oltipraz generates superoxide anion radical". Arch. Biochem. Biophys. 435 (1): 83–8.  
  28. ^ "Reata Begins Enrollment For PAH – LARIAT Phase 2 Study Examining Bardoxolone Methyl for Treating Pulmonary Arterial Hypertension". Retrieved 6 October 2014. 
  29. ^ "Bardoxolone Methyl Evaluation in Patients With Pulmonary Arterial Hypertension (PAH) (LARIAT)". Retrieved 6 October 2014. 
  30. ^ Carroll, John (6 October 2014). "After a taste of disaster, Reata plans a comeback for bardoxolone". 
  31. ^ Reisman SA, Lee CY, Meyer CJ et al. (2014). "Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin.". Arch Dermatol Res 306 (5): 447–57.  
  32. ^ Reisman SA, Lee CY, Meyer CJ, et al. (2014). "Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis.". Radiat Res 181 (5): 512–20.  
  33. ^ Neymotin A, Calingasan NY, Wille E, et al. (2011). "Neuroprotective effect of Nrf2/ARE Activators, CDDO-ethylamide and CDDO-trifluoroethylamide in a Mouse Model of Amyotrophic Lateral Sclerosis". Free Radic Biol Med 51: 88–96.  
  34. ^ "RTA 408 Lotion in Patients at Risk for Radiation Dermatitis (PRIMROSE)". 6 October 2014. 
  35. ^ "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. 
  36. ^ DeNicola, Gina M; et al (July 7, 2011). "Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis".  
  37. ^ "Natural antioxidants could scupper tumour's detox".  
  38. ^ a b Barajas, B (Jan 2011). "NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection". Arterioscler Thromb Vasc Biol 31 (1): 58–66.  
  39. ^ Araujo, Jesus A (2012). "Nrf2 and the promotion of atherosclerosis: lessons to be learned". Clin. Lipidol 7 (2): 123–126.  
  40. ^ Venugopal R, Jaiswal AK (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.  
  41. ^ Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (2001). "Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription". Genes Cells 6 (10): 857–68.  
  42. ^ a b Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Mol. Cell. Biol. 23 (20): 7198–209.  
  43. ^ a b Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proc. Natl. Acad. Sci. U.S.A. 105 (36): 13568–73.  
  44. ^ Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicol. Appl. Pharmacol. 230 (3): 383–9.  
  45. ^ Patel R, Maru G (2008). "Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs". Free Radic. Biol. Med. 44 (11): 1897–911.  

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