NFE2L2

NFE2L2
Nuclear factor (erythroid-derived 2)-like 2
Identifiers
Symbols NFE2L2; NRF2
External IDs OMIM600492 MGI108420 HomoloGene2412 GeneCards: NFE2L2 Gene
RNA expression pattern
PBB GE NFE2L2 201146 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4780 18024
Ensembl ENSG00000116044 ENSMUSG00000015839
UniProt Q16236 Q05DU7
RefSeq (mRNA) NM_001145412.1 NM_010902.3
RefSeq (protein) NP_001138884.1 NP_035032.1
Location (UCSC) Chr 2:
178.09 – 178.26 Mb
Chr 2:
75.51 – 75.54 Mb
PubMed search [1] [2]

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] NFE2L2 induces the expression of various genes including those that encode for several antioxidant enzymes, and it may play a physiological role in the regulation of oxidative stress. Investigational drugs that target NFE2L2 are of interest as potential therapeutic interventions for oxidative-stress related pathologies.

Contents

Function

NFE2, NFE2L1, and NFE2L2 (this protein) 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 and FOS, although remaining regions have diverged considerably from each other.[2][3]

Under normal or unstressed conditions, Nrf2 is tethered in the cytoplasm by another protein called Kelch like-ECH-associated protein 1 (Keap1).[4] Keap1 acts as a substrate adaptor protein for Cullin 3-based ubiquitination, which results in the proteasomal degradation of Nrf2, and under normal conditions Nrf2 has a half-life of only 20 minutes.[5] Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, resulting in a disruption of the Keap1-Cul3 ubiquitination system and a build-up of Nrf2 in the cytoplasm.[6][7] Unbound Nrf2 is then able to translocate into the nucleus, where it will heterodimerize with a small Maf protein and bind to the Antioxidant Response Element (ARE) in the upstream promoter region of many antioxidative genes, where it will initiate their transcription.[8]

Target Genes

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.[9]
  • 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.[10]
  • 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.[11]
  • 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 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.[12]
  • 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.[13]
  • 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 pharamacokinetics and toxicity of compounds.[14][15]

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.[16] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.[17] 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.[18] The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CBP), which possesses intrinsic histone acetyltransferase activity.[17] 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.[19]

Tissue distribution

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

Nrf2 as a drug target

Investigational drugs that target NFE2L2 have been evaluated in animal models as therapeutic interventions for oxidative-stress related pathologies. One such compound, bardoxolone methyl, is undergoing testing in human clinical trials.

The dithiolethiones are a class of organosulfur compounds, of which, oltipraz is the most well-studied. Oltipraz has been shown to inhibit cancer formation in a variety of rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[20] However, clinical trials involving oltipraz have demonstrated significant side-effects with no or questionable chemopreventive efficacy.[20] In one clinical study, side-effects after 8 weeks of treatment included numbness, tingling, and pain in the extremities. In another study, side-effects after 4 weeks included gastrointestinal toxicity. Oltipraz has also been shown to generate superoxide radical, which can be quite toxic.[21]

A series of synthetic oleane triterpenoid compounds that are Nrf2 activators and referred to as antioxidant inflammation modulators (AIMs), are in clinical development at Reata Pharmaceuticals. The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), has completed Phase 2 clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus. Data indicate that bardoxolone methyl improves markers of kidney function, including producing a significant increase in estimated glomerular filtration rate that correlates with changes in blood urea nitrogen, serum phosphorus, uric acid, and magnesium. Improvements were sustained over 6 months of therapy and remained significant compared to placebo.[citation needed]) A Phase 3 outcomes study (BEACON) is scheduled to begin in mid 2011.[citation needed]) Reata also indicates that it has other Nrf2 inducers in the same class that are in preclinical development for the treatment of CNS and respiratory diseases.[citation needed])

Interactions

NFE2L2 has been shown to interact with CREB-binding protein,[22] KEAP1,[23][24][25] C-jun,[26] EIF2AK3[23] and Ubiquitin C.[24][27]

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. doi:10.1073/pnas.91.21.9926. PMC 44930. PMID 7937919. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=44930. 
  2. ^ 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. doi:10.1007/BF00225191. PMID 7868116. 
  3. ^ "Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4780. 
  4. ^ 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. doi:10.1101/gad.13.1.76. PMC 316370. PMID 9887101. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316370. 
  5. ^ Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (August 2004). "Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2". Mol. Cell. Biol. 24 (16): 7130–9. doi:10.1128/MCB.24.16.7130-7139.2004. PMC 479737. PMID 15282312. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=479737. 
  6. ^ 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. doi:10.1128/MCB.01704-07. PMC 2293100. PMID 18268004. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2293100. 
  7. ^ Sekhar KR, Rachakonda G, Freeman ML (June 2009). "Cysteine-based Regulation of the CUL3 Adaptor Protein Keap1". Toxicol. Appl. Pharmacol. 244 (1): 21–6. doi:10.1016/j.taap.2009.06.016. PMC 2837771. PMID 19560482. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2837771. 
  8. ^ Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (July 1997). "An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements". Biochem. Biophys. Res. Commun. 236 (2): 313–22. doi:10.1006/bbrc.1997.6943. PMID 9240432. 
  9. ^ 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. doi:10.1073/pnas.93.25.14960. PMC 26245. PMID 8962164. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=26245. 
  10. ^ 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. doi:10.1016/S0006-2952(02)00897-3. PMID 12007577. 
  11. ^ Jarmi T, Agarwal A (February 2009). "Heme oxygenase and renal disease". Curr. Hypertens. Rep. 11 (1): 56–62. doi:10.1007/s11906-009-0011-z. PMID 19146802. 
  12. ^ 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. PMID 10816095. 
  13. ^ 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. doi:10.1074/jbc.M610790200. PMID 17259171. 
  14. ^ 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. doi:10.1002/hep.21831. PMID 17668877. 
  15. ^ 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. doi:10.1093/toxsci/kfp047. PMC 2675638. PMID 19246624. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2675638. 
  16. ^ 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. doi:10.1073/pnas.0305902101. PMC 404053. PMID 15087497. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=404053. 
  17. ^ a b Motohashi H, Yamamoto M (November 2004). "Nrf2-Keap1 defines a physiologically important stress response mechanism". Trends Mol Med 10 (11): 549–57. doi:10.1016/j.molmed.2004.09.003. PMID 15519281. 
  18. ^ 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. doi:10.1128/MCB.25.24.10895-10906.2005. PMC 1316965. PMID 16314513. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1316965. 
  19. ^ 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. doi:10.1074/jbc.M403061200. PMID 15143058. 
  20. ^ 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. PMID 15252150. 
  21. ^ Velayutham M, Villamena FA, Fishbein JC, Zweier JL (March 2005). "Cancer chemopreventive oltipraz generates superoxide anion radical". Arch. Biochem. Biophys. 435 (1): 83–8. doi:10.1016/j.abb.2004.11.028. PMID 15680910. 
  22. ^ 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 Cells (England) 6 (10): 857–68. doi:10.1046/j.1365-2443.2001.00469.x. ISSN 1356-9597. PMID 11683914. 
  23. ^ a b Cullinan, Sara B; Zhang Donna, Hannink Mark, Arvisais Edward, Kaufman Randal J, Diehl J Alan (Oct. 2003). "Nrf2 Is a Direct PERK Substrate and Effector of PERK-Dependent Cell Survival". Mol. Cell. Biol. (United States) 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. ISSN 0270-7306. PMC 230321. PMID 14517290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=230321. 
  24. ^ a b Shibata, Tatsuhiro; Ohta Tsutomu, Tong Kit I, Kokubu Akiko, Odogawa Reiko, Tsuta Koji, Asamura Hisao, Yamamoto Masayuki, Hirohashi Setsuo (Sep. 2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proc. Natl. Acad. Sci. U.S.A. (United States) 105 (36): 13568–73. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2533230. 
  25. ^ Wang, Xiao-Jun; Sun Zheng, Chen Weimin, Li Yanjie, Villeneuve Nicole F, Zhang Donna D (Aug. 2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicol. Appl. Pharmacol. (United States) 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. ISSN 0041-008X. PMC 2610481. PMID 18417180. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2610481. 
  26. ^ Venugopal, R; Jaiswal A K (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 (ENGLAND) 17 (24): 3145–56. doi:10.1038/sj.onc.1202237. ISSN 0950-9232. PMID 9872330. 
  27. ^ Patel, Rachana; Maru Girish (Jun. 2008). "Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs". Free Radic. Biol. Med. (United States) 44 (11): 1897–911. doi:10.1016/j.freeradbiomed.2008.02.006. ISSN 0891-5849. PMID 18358244. 

Further reading

External links

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