NFE2L2

Nuclear factor (erythroid-derived 2)-like 2
Identifiers
Symbols NFE2L2; NRF2
External IDs OMIM: 600492 MGI: 108420 HomoloGene: 2412 GeneCards: NFE2L2 Gene
RNA expression pattern
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:

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.) A Phase 3 outcomes study (BEACON) is scheduled to begin in mid 2011.) 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.)

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. 
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  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. 
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  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. 
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  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. 
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  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. 
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Further reading

External links

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