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Gene Review

NFE2L1  -  nuclear factor, erythroid 2-like 1

Homo sapiens

Synonyms: FLJ00380, HBZ17, LCR-F1, Locus control region-factor 1, NF-E2-related factor 1, ...
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Disease relevance of NFE2L1

  • Differences in the percentage of alternatively spliced NRF-1 pre-mRNA may influence mitochondrial biogenesis under variable physiological conditions and could play a role in distinct mitochondrial diseases [1].
  • Nrf2 determines the susceptibility of lungs to cigarette smoke-induced emphysema in mice through the transcriptional induction of numerous antioxidant genes [2].
  • The mRNA expression of both mtTFA and NRF-1 was upregulated at nephrosis phase, but mtTFA was downregulated at FSGS phase [3].
  • In this study we have demonstrated that Tax trans-activates the promoter for CXCR4, a coreceptor for T cell-tropic HIV-1 through its association with nuclear respiratory factor 1 (NRF1) [4].
  • The mRNA levels of the regulatory factors for mitochondrial gene (NRF-1 and mtTFA) and cytochrome b were significantly increased by chronic hepatitis (160, 280, and 175%, respectively) compared with those in normal livers, but were not different between cirrhotic and normal livers [5].

High impact information on NFE2L1

  • The synthesis of normal hemoglobin levels in erythroid cells of chimeras derived from Lcrf1 null cells suggests that LCR-F1 is not essential for globin gene expression [6].
  • The bZIP transcription factor LCR-F1 is essential for mesoderm formation in mouse development [6].
  • Interestingly, Lcrf1 null ES cells injected into wild-type blastocysts contributed to all mesodermally derived tissues examined, including erythroid cells producing hemoglobin [6].
  • Functional NRF-1 sites are now observed in several other recently isolated nuclear genes whose products function in the mitochondria [7].
  • The presence of NRF-1-binding sites in nuclear genes encoding structural components of the mammalian electron transport chain, as well as the mitochondrial DNA replication machinery, suggests a mechanism for coordination of nuclear and mitochondrial genetic systems through the concerted modulation of nuclear genes [7].

Biological context of NFE2L1

  • Nrf1 activates transcription via NF-E2 binding sites in yeast cells [8].
  • When co-expressed, MafG interferes with TCF11 transactivation in a dose dependent manner [9].
  • Nrf2 containing one mutated leucine in its leucine zipper region was more efficient in upregulation of ARE-mediated gene expression, as compared to Nrf1 with two mutated leucines [10].
  • To investigate the activity of TCF11 through this selected site, both alone and in the presence of MafG, we have used a transient transfection assay [9].
  • We have now determined the complete genomic organization of the TCF11 gene, which consists of 9 exons distributed over 15 kb of genomic DNA [11].

Anatomical context of NFE2L1

  • Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury [12].
  • Activation of ARE-driven genes by Nrf1 was negatively controlled by the NTD (N-terminal domain) through its ability to direct Nrf1 to the endoplasmic reticulum [13].
  • Using overexpression of the transcription factor in COS-1 cells we show that TCF11/Nrf1 stimulates GSH accumulation [14].
  • In studies of the expression of the NRF-1 gene in cultured human fibroblasts, using RT-PCR, we identified two distinct transcripts, one of which contained an in-frame deletion of 198 bp [1].
  • This dependence on NRF-1 activation is confirmed by in vitro transcription using highly purified recombinant proteins that display the same binding specificities as the HeLa cell factors [15].

Associations of NFE2L1 with chemical compounds


Physical interactions of NFE2L1

  • Using antibodies, TCF11 isoforms bound to the single NF-E2 site were detected in K562 erythroid cell nuclear extracts [20].
  • ATF4 shows evidence of complex regulation during development and shows elevated expression in many of the same sites as TCF11 [21].

Regulatory relationships of NFE2L1

  • These findings place TCF11 as a good candidate for the proposed widely expressed factor(s) known to interact with small Maf proteins and bind NF-E2 sites in a sequence-specific manner resembling NF-E2 [20].

Other interactions of NFE2L1

  • We show here that the TCF11 protein interacts to form heterodimers with small Maf proteins, previously shown to dimerize with p45 NF-E2, ECH and Fos [20].
  • We therefore carried out expression analysis of four candidate partner molecules; the three small Maf genes and another bZIP transcription factor found to bind to TCF11 in a two-hybrid screen, ATF4 [21].
  • The murine homologue of the human NFE2L1 basic leucine-zipper gene was isolated from an early embryo library [22].
  • This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses [23].

Analytical, diagnostic and therapeutic context of NFE2L1


  1. The pre-mRNA of nuclear respiratory factor 1, a regulator of mitochondrial biogenesis, is alternatively spliced in human tissues and cell lines. Spelbrink, J.N., Van den Bogert, C. Hum. Mol. Genet. (1995) [Pubmed]
  2. Glutathione Peroxidase 2, the Major Cigarette Smoke-Inducible Isoform of GPX in Lungs, Is Regulated by Nrf2. Singh, A., Rangasamy, T., Thimmulappa, R.K., Lee, H., Osburn, W.O., Brigelius-Floh??, R., Kensler, T.W., Yamamoto, M., Biswal, S. Am. J. Respir. Cell Mol. Biol. (2006) [Pubmed]
  3. Mitochondrial dysfunction in focal segmental glomerulosclerosis of puromycin aminonucleoside nephrosis. Hagiwara, M., Yamagata, K., Capaldi, R.A., Koyama, A. Kidney Int. (2006) [Pubmed]
  4. HTLV type I Tax activation of the CXCR4 promoter by association with nuclear respiratory factor 1. Moriuchi, M., Moriuchi, H., Fauci, A.S. AIDS Res. Hum. Retroviruses (1999) [Pubmed]
  5. Effects of chronic liver diseases on mitochondrial DNA transcription and replication in human liver. Kotake, K., Nonami, T., Kurokawa, T., Nakao, A., Murakami, T., Shimomura, Y. Life Sci. (1999) [Pubmed]
  6. The bZIP transcription factor LCR-F1 is essential for mesoderm formation in mouse development. Farmer, S.C., Sun, C.W., Winnier, G.E., Hogan, B.L., Townes, T.M. Genes Dev. (1997) [Pubmed]
  7. NRF-1: a trans-activator of nuclear-encoded respiratory genes in animal cells. Evans, M.J., Scarpulla, R.C. Genes Dev. (1990) [Pubmed]
  8. Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Chan, J.Y., Han, X.L., Kan, Y.W. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  9. Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription. Johnsen, O., Murphy, P., Prydz, H., Kolsto, A.B. Nucleic Acids Res. (1998) [Pubmed]
  10. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Venugopal, R., Jaiswal, A.K. Oncogene (1998) [Pubmed]
  11. Structural organization and mapping of the human TCF11 gene. Luna, L., Skammelsrud, N., Johnsen, O., Abel, K.J., Weber, B.L., Prydz, H., Kolstø, A.B. Genomics (1995) [Pubmed]
  12. Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury. Hernandez-Montes, E., Pollard, S.E., Vauzour, D., Jofre-Montseny, L., Rota, C., Rimbach, G., Weinberg, P.D., Spencer, J.P. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  13. Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum. Zhang, Y., Crouch, D.H., Yamamoto, M., Hayes, J.D. Biochem. J. (2006) [Pubmed]
  14. TCF11/Nrf1 overexpression increases the intracellular glutathione level and can transactivate the gamma-glutamylcysteine synthetase (GCS) heavy subunit promoter. Myhrstad, M.C., Husberg, C., Murphy, P., Nordström, O., Blomhoff, R., Moskaug, J.O., Kolstø, A.B. Biochim. Biophys. Acta (2001) [Pubmed]
  15. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Virbasius, J.V., Scarpulla, R.C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  16. Identification of regulatory sequences in the gene for 5-aminolevulinate synthase from rat. Braidotti, G., Borthwick, I.A., May, B.K. J. Biol. Chem. (1993) [Pubmed]
  17. Nuclear respiratory factor 1 activation sites in genes encoding the gamma-subunit of ATP synthase, eukaryotic initiation factor 2 alpha, and tyrosine aminotransferase. Specific interaction of purified NRF-1 with multiple target genes. Chau, C.M., Evans, M.J., Scarpulla, R.C. J. Biol. Chem. (1992) [Pubmed]
  18. Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response. Kim, Y.C., Yamaguchi, Y., Kondo, N., Masutani, H., Yodoi, J. Oncogene (2003) [Pubmed]
  19. Expression of the Avirulence gene Avr9 of the fungal tomato pathogen Cladosporium fulvum is regulated by the global nitrogen response factor NRF1. Pérez-García, A., Snoeijers, S.S., Joosten, M.H., Goosen, T., De Wit, P.J. Mol. Plant Microbe Interact. (2001) [Pubmed]
  20. Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1. Johnsen, O., Skammelsrud, N., Luna, L., Nishizawa, M., Prydz, H., Kolstø, A.B. Nucleic Acids Res. (1996) [Pubmed]
  21. Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development. Murphy, P., Kolstø, A. Mech. Dev. (2000) [Pubmed]
  22. Cloning and mapping of murine Nfe2l1. McKie, J., Johnstone, K., Mattei, M.G., Scambler, P. Genomics (1995) [Pubmed]
  23. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Clements, C.M., McNally, R.S., Conti, B.J., Mak, T.W., Ting, J.P. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  24. Genomic organization and functional characterization of the chemokine receptor CXCR4, a major entry co-receptor for human immunodeficiency virus type 1. Wegner, S.A., Ehrenberg, P.K., Chang, G., Dayhoff, D.E., Sleeker, A.L., Michael, N.L. J. Biol. Chem. (1998) [Pubmed]
  25. Hepatocyte growth factor protects RPE cells from apoptosis induced by glutathione depletion. Jin, M., Yaung, J., Kannan, R., He, S., Ryan, S.J., Hinton, D.R. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
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