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Gene Review

Nfe2  -  nuclear factor, erythroid derived 2

Mus musculus

Synonyms: Leucine zipper protein NF-E2, NF-E2, Nuclear factor, erythroid-derived 2 45 kDa subunit, Transcription factor NF-E2 45 kDa subunit, p45, ...
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Disease relevance of Nfe2

  • Dependence of globin gene expression in mouse erythroleukemia cells on the NF-E2 heterodimer [1].
  • Results of DNase I hypersensitivity mapping and in vivo footprinting assays showed no detectable chromatin alterations in beta-LCR HS-2 due to loss of NF-E2 [1].
  • While p45 gene knockout mice exhibit thrombocytopenia due to abnormal terminal differentiation of megakaryocytes, and the mutant mice die of massive bleeding within a week after birth, anemia is not apparent in these animals [2].
  • Unexpectedly, NF-E2-/- mice lack circulating platelets and die of hemorrhage; their megakaryocytes show no cytoplasmic platelet formation [3].
  • Although neonates exhibited severe anemia and dysmorphic red-cell changes, probably compounded by concomitant bleeding, surviving adults exhibited only mild changes consistent with a small decrease in the hemoglobin content per cell. p45 NF-E2-null mice responded to anemia with compensatory reticulocytosis and splenomegaly [4].

High impact information on Nfe2

  • Thus, as an essential factor for megakaryocyte maturation and platelet production, NF-E2 must regulate critical target genes independent of the action of thrombopoietin [3].
  • Whereas homodimers of the small Maf proteins act as negative regulators, heterodimers composed of Maf and p45 support active transcription in vivo [5].
  • Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins [5].
  • The mk allele carries a missense mutation that causes substitution of valine by alanine at amino acid 173 of the p45 NF-E2 protein [6].
  • Expression of p45 NF-E2 messenger RNA was detected in erythroid tissues of normal mice and in the duodenum of normal and severely anaemic beta-thalassaemic (Hbbd-th3/Hbbd-th3) mice [6].

Chemical compound and disease context of Nfe2


Biological context of Nfe2

  • These findings suggest that the beta-globin gene locus exists in a constitutively open chromatin conformation before terminal differentiation, and we speculate that recruitment of NF-E2 complex to the LCR and active promoters may be a rate-limiting step in the activation of beta-globin gene expression [9].
  • This differentiation-coupled recruitment of NF-E2 complex correlates with a greater than 100-fold increase in beta-major globin transcription, but is not associated with a significant change in locus-wide histone H3 acetylation [9].
  • NF-E2 binding sites, located in distant regulatory sequences, may be important for high level alpha- and beta-globin gene expression [10].
  • In addition, no evidence was found for reciprocal upregulation of NF-E2 or Nrf-2 protein in fetal liver cells deficient for either factor [10].
  • Cotransfection assays using HDC-luciferase reporter and p45 and/or mafK expression constructs showed that NF-E2 affects the transactivation of HDC gene [11].

Anatomical context of Nfe2

  • This subunit of NF-E2 is specifically expressed in haematopoietic progenitor cells and differentiated cells of the erythroid, megakaryocyte and mast cell lineages [6].
  • Reduced levels of both alpha- and beta-globin were associated with the lower levels of NF-E2 activity in this cell line [1].
  • Fetal liver cells deficient for both NF-E2 and Nrf-2 expressed normal levels of alpha- and beta-globin [10].
  • Northern blotting has shown that mouse small intestine contains relatively large amounts of the nuclear factor-E2 p45-related factor (Nrf) 2 transcription factor but relatively little Nrf1 [12].
  • These results suggest that NF-E2 is also an important transcription factor in mast cell differentiation [11].

Associations of Nfe2 with chemical compounds

  • The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes [12].
  • Domain analysis revealed an activation domain in the NH2-terminal region of p45 and a suppression domain in the basic region-leucine zipper of MafK [7].
  • Next, we removed the neo gene by Cre-mediated recombination, leaving a single LoxP site in place of the AP1/NFE2 sites [13].
  • Transcription of the p45 target genes was down-regulated and we indeed found that BACH1 binds to the thromboxane synthase gene, one of the target genes for p45 in megakaryocytes [14].
  • Other proline-rich sequences were dispensable, indicating that proline content per se does not determine NF-E2 activity [15].

Regulatory relationships of Nfe2

  • Caspase-12 is the most down-regulated gene we identified in NF-E2(-/-) megakaryocytes [16].
  • Our findings demonstrate marked induction of NF-E2 mRNA in control megakaryocytes in response to Mpl ligand, but no NF-E2 increase in transgenic cells, potentially explaining the lack of platelet increase in these transgenic mice [17].
  • In contrast to MEL cells, CB3 cells are null for p45 and thus express only extremely low levels of adult globin transcripts upon induction by agents promoting erythroid differentiation [18].

Other interactions of Nfe2


Analytical, diagnostic and therapeutic context of Nfe2


  1. Dependence of globin gene expression in mouse erythroleukemia cells on the NF-E2 heterodimer. Kotkow, K.J., Orkin, S.H. Mol. Cell. Biol. (1995) [Pubmed]
  2. Ablation of Nrf2 function does not increase the erythroid or megakaryocytic cell lineage dysfunction caused by p45 NF-E2 gene disruption. Kuroha, T., Takahashi, S., Komeno, T., Itoh, K., Nagasawa, T., Yamamoto, M. J. Biochem. (1998) [Pubmed]
  3. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Shivdasani, R.A., Rosenblatt, M.F., Zucker-Franklin, D., Jackson, C.W., Hunt, P., Saris, C.J., Orkin, S.H. Cell (1995) [Pubmed]
  4. Erythropoiesis and globin gene expression in mice lacking the transcription factor NF-E2. Shivdasani, R.A., Orkin, S.H. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  5. Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins. Igarashi, K., Kataoka, K., Itoh, K., Hayashi, N., Nishizawa, M., Yamamoto, M. Nature (1994) [Pubmed]
  6. Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2. Peters, L.L., Andrews, N.C., Eicher, E.M., Davidson, M.B., Orkin, S.H., Lux, S.E. Nature (1993) [Pubmed]
  7. Regulation of NF-E2 activity in erythroleukemia cell differentiation. Nagai, T., Igarashi, K., Akasaka, J., Furuyama, K., Fujita, H., Hayashi, N., Yamamoto, M., Sassa, S. J. Biol. Chem. (1998) [Pubmed]
  8. NF-E2p18/mafK is required in DMSO-induced differentiation of Friend erythroleukemia cells by enhancing NF-E2 activity. Francastel, C., Poindessous-Jazat, V., Augery-Bourget, Y., Robert-Lézénès, J. Leukemia (1997) [Pubmed]
  9. Activation of beta-major globin gene transcription is associated with recruitment of NF-E2 to the beta-globin LCR and gene promoter. Sawado, T., Igarashi, K., Groudine, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  10. 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]
  11. Histidine decarboxylase expression in mouse mast cell line P815 is induced by mouse peritoneal cavity incubation. Ohtsu, H., Kuramasu, A., Suzuki, S., Igarashi, K., Ohuchi, Y., Sato, M., Tanaka, S., Nakagawa, S., Shirato, K., Yamamoto, M., Ichikawa, A., Watanabe, T. J. Biol. Chem. (1996) [Pubmed]
  12. The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. McMahon, M., Itoh, K., Yamamoto, M., Chanas, S.A., Henderson, C.J., McLellan, L.I., Wolf, C.R., Cavin, C., Hayes, J.D. Cancer Res. (2001) [Pubmed]
  13. Role of AP1/NFE2 binding sites in endogenous alpha-globin gene transcription. Loyd, M.R., Okamoto, Y., Randall, M.S., Ney, P.A. Blood (2003) [Pubmed]
  14. Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment. Toki, T., Katsuoka, F., Kanezaki, R., Xu, G., Kurotaki, H., Sun, J., Kamio, T., Watanabe, S., Tandai, S., Terui, K., Yagihashi, S., Komatsu, N., Igarashi, K., Yamamoto, M., Ito, E. Blood (2005) [Pubmed]
  15. Multiple regions of p45 NF-E2 are required for beta-globin gene expression in erythroid cells. Bean, T.L., Ney, P.A. Nucleic Acids Res. (1997) [Pubmed]
  16. Caspase-12: a developmental link between G-protein-coupled receptors and integrin alphaIIbbeta3 activation. Kerrigan, S.W., Gaur, M., Murphy, R.P., Shattil, S.J., Leavitt, A.D. Blood (2004) [Pubmed]
  17. Cyclin D3 and megakaryocyte development: exploration of a transgenic phenotype. Zimmet, J.M., Toselli, P., Ravid, K. Stem Cells (1998) [Pubmed]
  18. Regulation of globin gene transcription by heme in erythroleukemia cells: analysis of putative heme regulatory motifs in the p45 NF-E2 transcription factor. Moore, A., Boudia, M.M., Lehalle, D., Massrieh, W., Derjuga, A., Blank, V. Antioxid. Redox Signal. (2006) [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. A role for Rab27b in NF-E2-dependent pathways of platelet formation. Tiwari, S., Italiano, J.E., Barral, D.C., Mules, E.H., Novak, E.K., Swank, R.T., Seabra, M.C., Shivdasani, R.A. Blood (2003) [Pubmed]
  21. Nitric oxide-releasing agents and cGMP analogues inhibit murine erythroleukemia cell differentiation and suppress erythroid-specific gene expression: correlation with decreased DNA binding of NF-E2 and altered c-myb mRNA expression. Suhasini, M., Boss, G.R., Pascual, F.E., Pilz, R.B. Cell Growth Differ. (1995) [Pubmed]
  22. Contiguous arrangement of p45 NFE2, HnRNP A1, and HP1 alpha on mouse chromosome 15 and human chromosome 12: evidence for suppression of these genes due to retroviral integration within the Fli-2 locus. Li, Y.J., Pak, B.J., Higgins, R.R., Lu, S.J., Ben-David, Y. Genes Chromosomes Cancer (2001) [Pubmed]
  23. Expression analysis of primary mouse megakaryocyte differentiation and its application in identifying stage-specific molecular markers and a novel transcriptional target of NF-E2. Chen, Z., Hu, M., Shivdasani, R.A. Blood (2007) [Pubmed]
  24. Nuclear relocation of a transactivator subunit precedes target gene activation. Francastel, C., Magis, W., Groudine, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  25. Pathophysiology of thrombocytopenia and anemia in mice lacking transcription factor NF-E2. Levin, J., Peng, J.P., Baker, G.R., Villeval, J.L., Lecine, P., Burstein, S.A., Shivdasani, R.A. Blood (1999) [Pubmed]
  26. Erythroid expression of the human alpha-spectrin gene promoter is mediated by GATA-1- and NF-E2-binding proteins. Boulanger, L., Sabatino, D.E., Wong, E.Y., Cline, A.P., Garrett, L.J., Garbarz, M., Dhermy, D., Bodine, D.M., Gallagher, P.G. J. Biol. Chem. (2002) [Pubmed]
  27. Thrombopoietin can influence mature megakaryocytes to undergo further nuclear and cytoplasmic maturation. Tajika, K., Nakamura, H., Nakayama, K., Dan, K. Exp. Hematol. (2000) [Pubmed]
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