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Gene Review

Nfe2l2  -  nuclear factor, erythroid derived 2, like 2

Mus musculus

Synonyms: AI194320, NF-E2-related factor 2, NFE2-related factor 2, Nrf-2, Nrf2, ...
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Disease relevance of Nfe2l2

  • In summary, we show for the first time that mice lacking Nrf2 are more susceptible to DSS-induced colitis [1].
  • Treatment of mouse hepatoma (Hepa) cells with 50 microm CdCl(2) increased the amount of Nrf2 protein in a time-dependent manner; induction was observed within 30 min, prior to the accumulation of HO-1 mRNA [2].
  • We previously reported that Nrf2-deficient female mice develop lupus-like autoimmune nephritis (Kidney Int 60:1343-1353, 2001) [3].
  • METHODS: To investigate the mechanism whereby Nrf2 contributes to the susceptibility to autoimmune diseases, we generated nrf2-/-lpr/lpr mice [3].
  • Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates [4].

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 [6].
  • We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism [7].
  • Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain [7].
  • Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction [8].
  • We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2 [8].

Chemical compound and disease context of Nfe2l2


Biological context of Nfe2l2


Anatomical context of Nfe2l2


Associations of Nfe2l2 with chemical compounds


Physical interactions of Nfe2l2

  • Inducers disrupt the Keap1-Nrf2 complex by modifying two (C273 and C288) of the 25 cysteine residues of Keap1 [22].
  • In this study we sought to determine the identity of the specific constituent that collaboratively interacts with Nrf2 to bind to the Maf recognition element in vivo [23].
  • Alternatively, Nrf2 bound to antioxidant-responsive element-like-2 sequence of osteocalcin promoter [24].

Regulatory relationships of Nfe2l2

  • Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair [15].
  • These results suggest that PI3K/Akt signaling regulates Nrf2 activation by hyperoxia [25].
  • We demonstrate that Cul3-Keap1 complexes regulate Nrf2 polyubiquitination both in vitro and in vivo [26].
  • Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation [24].
  • Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization [11].

Other interactions of Nfe2l2


Analytical, diagnostic and therapeutic context of Nfe2l2


  1. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Khor, T.O., Huang, M.T., Kwon, K.H., Chan, J.Y., Reddy, B.S., Kong, A.N. Cancer Res. (2006) [Pubmed]
  2. Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. Stewart, D., Killeen, E., Naquin, R., Alam, S., Alam, J. J. Biol. Chem. (2003) [Pubmed]
  3. Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr. Morito, N., Yoh, K., Hirayama, A., Itoh, K., Nose, M., Koyama, A., Yamamoto, M., Takahashi, S. Kidney Int. (2004) [Pubmed]
  4. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. Rangasamy, T., Guo, J., Mitzner, W.A., Roman, J., Singh, A., Fryer, A.D., Yamamoto, M., Kensler, T.W., Tuder, R.M., Georas, S.N., Biswal, S. J. Exp. Med. (2005) [Pubmed]
  5. Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Calkins, M.J., Jakel, R.J., Johnson, D.A., Chan, K., Kan, Y.W., Johnson, J.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. 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]
  7. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J.D., Yamamoto, M. Genes Dev. (1999) [Pubmed]
  8. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Padmanabhan, B., Tong, K.I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.I., Kobayashi, A., Yokoyama, S., Yamamoto, M. Mol. Cell (2006) [Pubmed]
  9. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. Rangasamy, T., Cho, C.Y., Thimmulappa, R.K., Zhen, L., Srisuma, S.S., Kensler, T.W., Yamamoto, M., Petrache, I., Tuder, R.M., Biswal, S. J. Clin. Invest. (2004) [Pubmed]
  10. Nrf2 is essential for protection against acute pulmonary injury in mice. Chan, K., Kan, Y.W. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  11. Accelerated ovarian failure induced by 4-vinyl cyclohexene diepoxide in Nrf2 null mice. Hu, X., Roberts, J.R., Apopa, P.L., Kan, Y.W., Ma, Q. Mol. Cell. Biol. (2006) [Pubmed]
  12. Transcription factor Nrf2 protects HepG2 cells against CYP2E1 plus arachidonic acid-dependent toxicity. Gong, P., Cederbaum, A.I. J. Biol. Chem. (2006) [Pubmed]
  13. Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene. Rim, J.S., Kozak, L.P. J. Biol. Chem. (2002) [Pubmed]
  14. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Chan, K., Lu, R., Chang, J.C., Kan, Y.W. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  15. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Braun, S., Hanselmann, C., Gassmann, M.G., auf dem Keller, U., Born-Berclaz, C., Chan, K., Kan, Y.W., Werner, S. Mol. Cell. Biol. (2002) [Pubmed]
  16. Erythroid maturation and globin gene expression in mice with combined deficiency of NF-E2 and nrf-2. Martin, F., van Deursen, J.M., Shivdasani, R.A., Jackson, C.W., Troutman, A.G., Ney, P.A. Blood (1998) [Pubmed]
  17. Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Sun, J., Brand, M., Zenke, Y., Tashiro, S., Groudine, M., Igarashi, K. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A.M., Cook, J.L. J. Biol. Chem. (1999) [Pubmed]
  19. cDNA cloning of murine Nrf 2 gene, coding for a p45 NF-E2 related transcription factor. Chui, D.H., Tang, W., Orkin, S.H. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  20. Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Goldring, C.E., Kitteringham, N.R., Elsby, R., Randle, L.E., Clement, Y.N., Williams, D.P., McMahon, M., Hayes, J.D., Itoh, K., Yamamoto, M., Park, B.K. Hepatology (2004) [Pubmed]
  21. Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Cho, H.Y., Jedlicka, A.E., Reddy, S.P., Zhang, L.Y., Kensler, T.W., Kleeberger, S.R. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
  22. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Wakabayashi, N., Dinkova-Kostova, A.T., Holtzclaw, W.D., Kang, M.I., Kobayashi, A., Yamamoto, M., Kensler, T.W., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  23. Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway. Motohashi, H., Katsuoka, F., Engel, J.D., Yamamoto, M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  24. Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation. Hinoi, E., Fujimori, S., Wang, L., Hojo, H., Uno, K., Yoneda, Y. J. Biol. Chem. (2006) [Pubmed]
  25. Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Papaiahgari, S., Zhang, Q., Kleeberger, S.R., Cho, H.Y., Reddy, S.P. Antioxid. Redox Signal. (2006) [Pubmed]
  26. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Cullinan, S.B., Gordan, J.D., Jin, J., Harper, J.W., Diehl, J.A. Mol. Cell. Biol. (2004) [Pubmed]
  27. Activation of the mouse heme oxygenase-1 gene by 15-deoxy-Delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2. Gong, P., Stewart, D., Hu, B., Li, N., Cook, J., Nel, A., Alam, J. Antioxid. Redox Signal. (2002) [Pubmed]
  28. Role of Galpha12 and Galpha13 as novel switches for the activity of Nrf2, a key antioxidative transcription factor. Cho, M.K., Kim, W.D., Ki, S.H., Hwang, J.I., Choi, S., Lee, C.H., Kim, S.G. Mol. Cell. Biol. (2007) [Pubmed]
  29. Analysis of the interactions of Nrf-2, PMF-1, and CSN-7 with the 5'-flanking sequence of the mouse 4E-BP1 gene. Stephenson, A.H., Seidel, E.R. Life Sci. (2006) [Pubmed]
  30. 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]
  31. Response of the brain to oligemia: gene expression, c-Fos, and Nrf2 localization. Liverman, C.S., Cui, L., Yong, C., Choudhuri, R., Klein, R.M., Welch, K.M., Berman, N.E. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  32. Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Chan, J.Y., Kwong, M. Biochim. Biophys. Acta (2000) [Pubmed]
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