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Gene Review

NFE2L2  -  nuclear factor, erythroid 2-like 2

Homo sapiens

Synonyms: HEBP1, NF-E2-related factor 2, NFE2-related factor 2, NRF2, Nuclear factor erythroid 2-related factor 2, ...
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Disease relevance of NFE2L2

  • Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology [1].
  • Neuroblastoma cells were stably transfected with DN-Nrf2, which repressed both the expression of protective genes and their induction by NO [2].
  • In fact, the specific inhibitor of CBP, adenovirus E1A protein, significantly reduced Nrf2 activity [3].
  • Moreover, in contrast to AA, l-buthionine-(S,R)-sulfoximine toxicity is not prevented by plasmid Nrf2 probably because protective GSH cannot be synthesized [4].
  • We previously found that Nrf2(-/-) mice have increased sensitivity to in vivo mitochondrial stress and ischemia [5].
  • This study reveals that NRP/B enhances oxidative stress responses in breast cancer cells via the Nrf2 pathway, identifying a novel role of nuclear matrix protein(s) in oxidative stress responses [6].
  • Two NRF2 mutation 'hot-spots' were identified in approximately 10% of patients with lung cancer, enabling the transcription factor to evade KEAP1-mediated repression [7].
  • In univariate analysis, nuclear Nrf2 expression was associated with worse recurrence-free survival in squamous cell carcinoma patients who received adjuvant treatment (P = 0.0410; HR, 3.37) [8].

Psychiatry related information on NFE2L2


High impact information on NFE2L2

  • However, upon recognition of chemical signals imparted by oxidative and electrophilic molecules, Nrf2 is released from Keap1, escapes proteasomal degradation, translocates to the nucleus, and transactivates the expression of several dozen cytoprotective genes that enhance cell survival [10].
  • This review focuses on the molecular mechanisms whereby the transcriptional activation mediated by the interaction between the ARE and NF-E2-related factor 2 (Nrf2) is regulated [11].
  • Keap1 is a BTB-Kelch substrate adaptor protein that regulates steady-state levels of Nrf2, a bZIP transcription factor, in response to oxidative stress [12].
  • The Nrf2 peptide contains two short antiparallel beta-strands connected by two overlapping type I beta-turns stabilized by the aspartate and threonine residues [12].
  • Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2(-/-) and keap1(-/-) mouse embryonic fibroblasts [13].

Chemical compound and disease context of NFE2L2


Biological context of NFE2L2


Anatomical context of NFE2L2

  • Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells [20].
  • These results suggest that O-flow inhibits Nrf2 activity at the DNA binding step, thereby suppressing athero-protective gene expression and hence predisposing the blood vessels to the formation of atherosclerosis [20].
  • Deletion mapping of INrf2 revealed the requirement of KELCH domain (amino acid residues 361-597) and C-terminal region (amino acid residues 598-624) in retention of Nrf2 in the cytosol [21].
  • Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2 [22].
  • The levels of the transcription factor Nrf2 in the nuclei were maximal at 3 h, remained elevated at 6 h, and decreased to control values at 24 h in both cell lines [23].

Associations of NFE2L2 with chemical compounds

  • Immunocytochemistry and subcellular fractionation revealed that PMA, like tert-butylhydroquinone (tBHQ), promoted the nuclear localization of Nrf2, a process that was blocked by staurosporine or Ro-32-0432 [18].
  • Collectively, our results indicate that transcriptional activation of Nrf2/ARE is critical in sulforaphane-mediated induction of HO-1, which can be modulated in part by the blockade of p38 MAPK signaling pathway [24].
  • A dominant-negative mutant of Nrf2 (a CNC-bZIP member), but not of c-Jun or C/EBPbeta, inhibits pE1-luc activation by cadmium [25].
  • Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C [26].
  • Mutations of E1 that inhibit cadmium inducibility also suppress the trans-activation and DNA binding activities of Nrf2, and SB203580, but not PD098059, attenuates Nrf2-mediated trans-activation of pE1-luc [25].
  • These results demonstrate that stress-induced dephosphorylation of tyrosine 141 is a novel mechanism in Nrf2 activation and cellular protection [27].
  • The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA) [28].

Physical interactions of NFE2L2


Regulatory relationships of NFE2L2


Other interactions of NFE2L2

  • In contrast to Maf-Nrf2, the Maf-Nrf1 heterodimers failed to bind with the NQO1 gene ARE and did not demonstrate the repressive effect in transfection assays [29].
  • hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2 [38].
  • The dominant mechanism of Nrf2-mediated IL-8 induction is through mRNA stabilization [39].
  • CSN 7 and PMF-1 bind to each other, as well as compete with each other for binding to Nrf-2 [40].
  • A family of human genes encoding basic-leucine zipper (bZIP) transcription factors, p45-NF-E2, Nrf1 and Nrf2, have been isolated independently [41].
  • Hence, postinduction repression of the Nrf2-mediated antioxidant response is controlled by the nuclear export function of Keap1 in alliance with the cytoplasmic ubiquitination and degradation machinery [42].

Analytical, diagnostic and therapeutic context of NFE2L2


  1. Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Kim, Y.J., Ahn, J.Y., Liang, P., Ip, C., Zhang, Y., Park, Y.M. Cancer Res. (2007) [Pubmed]
  2. Nitric oxide-induced transcriptional up-regulation of protective genes by Nrf2 via the antioxidant response element counteracts apoptosis of neuroblastoma cells. Dhakshinamoorthy, S., Porter, A.G. J. Biol. Chem. (2004) [Pubmed]
  3. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Katoh, Y., Itoh, K., Yoshida, E., Miyagishi, M., Fukamizu, A., Yamamoto, M. Genes Cells (2001) [Pubmed]
  4. Transcription factor Nrf2 protects HepG2 cells against CYP2E1 plus arachidonic acid-dependent toxicity. Gong, P., Cederbaum, A.I. J. Biol. Chem. (2006) [Pubmed]
  5. Dopamine activates Nrf2-regulated neuroprotective pathways in astrocytes and meningeal cells. Shih, A.Y., Erb, H., Murphy, T.H. J. Neurochem. (2007) [Pubmed]
  6. The nuclear matrix protein, NRP/B, enhances Nrf2-mediated oxidative stress responses in breast cancer cells. Seng, S., Avraham, H.K., Jiang, S., Yang, S., Sekine, M., Kimelman, N., Li, H., Avraham, S. Cancer Res. (2007) [Pubmed]
  7. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Hayes, J.D., McMahon, M. Trends Biochem. Sci. (2009) [Pubmed]
  8. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Solis, L.M., Behrens, C., Dong, W., Suraokar, M., Ozburn, N.C., Moran, C.A., Corvalan, A.H., Biswal, S., Swisher, S.G., Bekele, B.N., Minna, J.D., Stewart, D.J., Wistuba, I.I. Clin. Cancer Res. (2010) [Pubmed]
  9. Mechanistic studies of the nrf2-keap1 signaling pathway*. Zhang, D.D. Drug Metab. Rev. (2006) [Pubmed]
  10. Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway. Kensler, T.W., Wakabayashi, N., Biswal, S. Annu. Rev. Pharmacol. Toxicol. (2007) [Pubmed]
  11. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Nguyen, T., Sherratt, P.J., Pickett, C.B. Annu. Rev. Pharmacol. Toxicol. (2003) [Pubmed]
  12. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. Lo, S.C., Li, X., Henzl, M.T., Beamer, L.J., Hannink, M. EMBO J. (2006) [Pubmed]
  13. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Dinkova-Kostova, A.T., Liby, K.T., Stephenson, K.K., Holtzclaw, W.D., Gao, X., Suh, N., Williams, C., Risingsong, R., Honda, T., Gribble, G.W., Sporn, M.B., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. Nrf2-dependent activation of the antioxidant responsive element by tert-butylhydroquinone is independent of oxidative stress in IMR-32 human neuroblastoma cells. Lee, J.M., Moehlenkamp, J.D., Hanson, J.M., Johnson, J.A. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  15. Carbon monoxide mediates heme oxygenase 1 induction via Nrf2 activation in hepatoma cells. Lee, B.S., Heo, J., Kim, Y.M., Shim, S.M., Pae, H.O., Kim, Y.M., Chung, H.T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  16. Effect of isothiocyanates on nuclear accumulation of NF-kappaB, Nrf2, and thioredoxin in caco-2 cells. Jakubíková, J., Sedlák, J., Bod'o, J., Bao, Y. J. Agric. Food Chem. (2006) [Pubmed]
  17. Neuronal sensitivity to kainic acid is dependent on the Nrf2-mediated actions of the antioxidant response element. Kraft, A.D., Lee, J.M., Johnson, D.A., Kan, Y.W., Johnson, J.A. J. Neurochem. (2006) [Pubmed]
  18. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Huang, H.C., Nguyen, T., Pickett, C.B. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. 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. Moi, P., Chan, K., Asunis, I., Cao, A., Kan, Y.W. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  20. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. Hosoya, T., Maruyama, A., Kang, M.I., Kawatani, Y., Shibata, T., Uchida, K., Warabi, E., Noguchi, N., Itoh, K., Yamamoto, M. J. Biol. Chem. (2005) [Pubmed]
  21. Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Dhakshinamoorthy, S., Jaiswal, A.K. Oncogene (2001) [Pubmed]
  22. Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2. Anwar, A.A., Li, F.Y., Leake, D.S., Ishii, T., Mann, G.E., Siow, R.C. Free Radic. Biol. Med. (2005) [Pubmed]
  23. Bucillamine induces glutathione biosynthesis via activation of the transcription factor Nrf2. Wielandt, A.M., Vollrath, V., Farias, M., Chianale, J. Biochem. Pharmacol. (2006) [Pubmed]
  24. Mechanism of Action of Sulforaphane: Inhibition of p38 Mitogen-Activated Protein Kinase Isoforms Contributing to the Induction of Antioxidant Response Element-Mediated Heme Oxygenase-1 in Human Hepatoma HepG2 Cells. Keum, Y.S., Yu, S., Chang, P.P., Yuan, X., Kim, J.H., Xu, C., Han, J., Agarwal, A., Kong, A.N. Cancer Res. (2006) [Pubmed]
  25. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. Alam, J., Wicks, C., Stewart, D., Gong, P., Touchard, C., Otterbein, S., Choi, A.M., Burow, M.E., Tou, J. J. Biol. Chem. (2000) [Pubmed]
  26. Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C. Rushworth, S.A., Chen, X.L., Mackman, N., Ogborne, R.M., O'Connell, M.A. J. Immunol. (2005) [Pubmed]
  27. Phosphorylation and dephosphorylation of tyrosine 141 regulate stability and degradation of INrf2: a novel mechanism in Nrf2 activation. Jain, A.K., Mahajan, S., Jaiswal, A.K. J. Biol. Chem. (2008) [Pubmed]
  28. Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Homma, S., Ishii, Y., Morishima, Y., Yamadori, T., Matsuno, Y., Haraguchi, N., Kikuchi, N., Satoh, H., Sakamoto, T., Hizawa, N., Itoh, K., Yamamoto, M. Clin. Cancer Res. (2009) [Pubmed]
  29. Small maf (MafG and MafK) proteins negatively regulate antioxidant response element-mediated expression and antioxidant induction of the NAD(P)H:Quinone oxidoreductase1 gene. Dhakshinamoorthy, S., Jaiswal, A.K. J. Biol. Chem. (2000) [Pubmed]
  30. Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins. Nakaso, K., Nakamura, C., Sato, H., Imamura, K., Takeshima, T., Nakashima, K. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  31. Alpha-lipoic acid-induced heme oxygenase-1 expression is mediated by nuclear factor erythroid 2-related factor 2 and p38 mitogen-activated protein kinase in human monocytic cells. Ogborne, R.M., Rushworth, S.A., O'Connell, M.A. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  32. Nrf2 regulates thromboxane synthase gene expression in human lung cells. Yaekashiwa, M., Wang, L.H. DNA Cell Biol. (2003) [Pubmed]
  33. Cloning and characterization of the human glutathione synthetase 5'-flanking region. Lee, T.D., Yang, H., Whang, J., Lu, S.C. Biochem. J. (2005) [Pubmed]
  34. 1,2,3,4,6-penta-O-galloyl-beta-D-glucose up-regulates heme oxygenase-1 expression by stimulating Nrf2 nuclear translocation in an extracellular signal-regulated kinase-dependent manner in HepG2 cells. Pae, H.O., Oh, G.S., Jeong, S.O., Jeong, G.S., Lee, B.S., Choi, B.M., Lee, H.S., Chung, H.T. World J. Gastroenterol. (2006) [Pubmed]
  35. 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. Wang, Y., Devereux, W., Stewart, T.M., Casero, R.A. Biochem. J. (2001) [Pubmed]
  36. Redox regulation of the transcriptional repressor Bach1. Ishikawa, M., Numazawa, S., Yoshida, T. Free Radic. Biol. Med. (2005) [Pubmed]
  37. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Chen, X.L., Dodd, G., Thomas, S., Zhang, X., Wasserman, M.A., Rovin, B.H., Kunsch, C. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  38. hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2. Marini, M.G., Chan, K., Casula, L., Kan, Y.W., Cao, A., Moi, P. J. Biol. Chem. (1997) [Pubmed]
  39. Activation of the Nrf2/antioxidant response pathway increases IL-8 expression. Zhang, X., Chen, X., Song, H., Chen, H.Z., Rovin, B.H. Eur. J. Immunol. (2005) [Pubmed]
  40. Polyamine-modulated factor 1 binds to the human homologue of the 7a subunit of the Arabidopsis COP9 signalosome: implications in gene expression. Wang, Y., Devereux, W., Stewart, T.M., Casero, R.A. Biochem. J. (2002) [Pubmed]
  41. Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. Chan, J.Y., Cheung, M.C., Moi, P., Chan, K., Kan, Y.W. Hum. Genet. (1995) [Pubmed]
  42. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Sun, Z., Zhang, S., Chan, J.Y., Zhang, D.D. Mol. Cell. Biol. (2007) [Pubmed]
  43. Nrf2-Keap1 Signaling Pathway Regulates Human UGT1A1 Expression in Vitro and in Transgenic UGT1 Mice. Yueh, M.F., Tukey, R.H. J. Biol. Chem. (2007) [Pubmed]
  44. Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Kwak, M.K., Itoh, K., Yamamoto, M., Sutter, T.R., Kensler, T.W. Mol. Med. (2001) [Pubmed]
  45. Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Jeong, W.S., Jun, M., Kong, A.N. Antioxid. Redox Signal. (2006) [Pubmed]
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