Alternative titles; symbols
HGNC Approved Gene Symbol: NFE2L1
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:48,048,359-48,061,545 (from NCBI)
The NFE2L1 gene encodes a transcription factor containing a basic leucine zipper (bZIP), a simple DNA-binding motif that has been identified in many different transcriptional regulatory proteins in diverse organisms. The bZIP motif is made up of 2 distinct but usually adjacent subdomains, a DNA-binding or basic domain that interacts with sequence-specific DNA and a dimerization or leucine zipper domain (summary by Luna et al., 1994).
Chan et al. (1993) devised a complementation assay in yeast to clone mammalian transcription activators and used it to identify a distinct human bZIP transcription factor, NFE2L1, which they designated NRF1 (NFE2-related factor-1) because of its similarities to NFE2 (601490). Chan et al. (1995) showed that the NFE2L1 gene encodes a 742-amino acid protein with a different molecular weight than either the p45 subunit (NFE2) or the Maf protein subunit (MafF, MafG (602020), or MafK (600197)) of nuclear factor erythroid-2. Chan et al. (1993) found that NFE2L1 activates transcription via NFE2-binding sites in yeast cells. The ubiquitous expression pattern of NFE2L1 and the range of promoters containing the NFE2-binding motif suggested that this gene may play a role in the regulation of heme synthesis and ferritin genes.
Luna et al. (1994) cloned and characterized cDNA clones and a genomic clone encoding the NFE2L1 protein, which they called TCF11. The structure of the derived protein and other evidence identified TCF11 as a member of the bZIP family of transcription factors. The predicted gene product showed a high degree of similarity to p45 NF-E2 (NFE2), the hematopoietic cell-specific 45-kD subunit of the human globin locus control region-binding protein NF-E2. These 2 proteins showed regions of remarkable homology to 2 invertebrate proteins, CNC and skn-1, postulated to regulate embryonic development in Drosophila melanogaster and Caenorhabditis elegans, respectively.
McKie et al. (1995) cloned the mouse homolog of NFE2L1. The deduced amino acid sequence was shown to have 97% homology to the human protein.
Zhang et al. (2014) showed that as well as increasing protein synthesis, mTORC1 (see 601231) activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor NRF1. Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumor suppressors TSC1 (605284) or TSC2 (191092), or physiologic activation of mTORC1 in response to growth factors or feeding, resulted in increased NRF1 expression in cells and tissues. Zhang et al. (2014) found that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. The authors therefore concluded that mTORC1 signaling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.
Luna et al. (1994) localized the human NFE2L1 gene to 17q22 by fluorescence in situ hybridization (FISH). Chan et al. (1995) localized NFE2L1 to chromosome 17q21.3 by FISH. By in situ hybridization, McKie et al. (1995) mapped the mouse Nfe2l1 gene to 11DE, but signals were also detected at 7D1-7F1 and 2E4-2G. McKie and Scambler (1996) also mapped the murine homolog to mouse chromosome 11, using haplotype analysis of an interspecific backcross.
To determine the function of Nrf1, Chan et al. (1998) disrupted the mouse gene by homologous recombination. Heterozygous Nfr1 mutant mice developed normally, were fertile, and showed no obvious abnormalities. Mice homozygous for the Nrf1 mutation suffered from anemia as a result of abnormal fetal liver erythropoiesis and died in utero at mid-late gestation. The authors did not detect defects in globin gene expression. Abnormal red cell production appeared to result from a defect in the fetal liver microenvironment specific for erythroid cells. Chan et al. (1998) suggested that target genes regulated by Nrf1 play an essential role during fetal liver hematopoiesis.
In adult mice with conditional deletion of hepatic Nrf1, Xu et al. (2005) observed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. Nrf1 -/- hepatocytes showed oxidative stress, and gene expression analysis revealed decreased expression of antioxidant response element-containing genes (e.g. Gstm3 138390) and upregulation of Cyp4a genes (see 601310). Xu et al. (2005) concluded that NRF1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver.
Chan, J. Y., Cheung, M.-C., Moi, P., Chan, K., Kan, Y. W. Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. Hum. Genet. 95: 265-269, 1995. [PubMed: 7868116] [Full Text: https://doi.org/10.1007/BF00225191]
Chan, J. Y., Han, X.-L., Kan, Y. W. Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc. Nat. Acad. Sci. 90: 11371-11375, 1993. [PubMed: 8248256] [Full Text: https://doi.org/10.1073/pnas.90.23.11371]
Chan, J. Y., Kwong, M., Lu, R., Chang, J., Wang, B., Yen, T. S. B., Kan, Y. W. Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice. EMBO J. 17: 1779-1787, 1998. [PubMed: 9501099] [Full Text: https://doi.org/10.1093/emboj/17.6.1779]
Luna, L., Johnsen, O., Skartlien, A. H., Pedeutour, F., Turc-Carel, C., Prydz, H., Kolsto, A.-B. Molecular cloning of a putative novel human bZIP transcription factor on chromosome 17q22. Genomics 22: 553-562, 1994. [PubMed: 8001966] [Full Text: https://doi.org/10.1006/geno.1994.1428]
McKie, J., Johnstone, K., Mattei, M.-G., Scambler, P. Cloning and mapping of murine Nfe2l1. Genomics 25: 716-719, 1995. [PubMed: 7759107] [Full Text: https://doi.org/10.1016/0888-7543(95)80015-e]
McKie, J., Scambler, P. J. The Nfe2l1 gene maps to distal mouse chromosome 11. Mammalian Genome 7: 89-90, 1996. [PubMed: 8903741] [Full Text: https://doi.org/10.1007/s003359900023]
Xu, Z., Chen, L., Leung, L., Yen, T. S. B., Lee, C., Chan, J. Y. Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc. Nat. Acad. Sci. 102: 4120-4125, 2005. [PubMed: 15738389] [Full Text: https://doi.org/10.1073/pnas.0500660102]
Zhang, Y., Nicholatos, J., Dreier, J. R., Ricoult, S. J. H., Widenmaier, S. B., Hotamisligil, G. S., Kwiatkowski, D. J., Manning, B. D. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513: 440-443, 2014. [PubMed: 25043031] [Full Text: https://doi.org/10.1038/nature13492]