Disease relevance of NFE2

• Single-copy transduction and expression of human gamma-globin in K562 erythroleukemia cells using recombinant adeno-associated virus vectors: the effect of mutations in NF-E2 and GATA-1 binding motifs within the hypersensitivity site 2 enhancer [1].
• Recently, we reported that the NF-E2 p45-related factor 2 (Nrf2)/MafK heterodimer binds to GST-P enhancer 1 (GPE1), a strong enhancer of the GST-P gene, and activates this gene in preneoplastic lesions and hepatomas [2].
• Nuclear PLCbeta(1) acts as a negative regulator of p45/NF-E2 expression levels in Friend erythroleukemia cells [3].
• This study suggests that elevated levels of zinc protoporphyrin IX found in the anemia of chronic disease, iron deficiency, and lead poisoning may contribute to a decrease in globin gene expression by interfering with the transcriptional activity of enhancer elements containing binding sites for NF-E2 [4].
• These 14 markers, as well as the previously described PRV1 and NF-E2, exhibited the same gene expression alterations also in patients with exogenously activated granulocytes due to sepsis or granulocyte colony-stimulating factor (G-CSF) treatment [5].

High impact information on NFE2

• We also find that NF-E2, another trans-acting factor of the erythrocytic lineage, is present in megakaryocytes [6].
• We have explored the expression of the transcription factors GATA-1, GATA-2, and NF-E2 in purified early hematopoietic progenitor cells (HPCs) induced to gradual unilineage erythroid or granulocytic differentiation by growth factor stimulus [7].
• Differential expression and functional role of GATA-2, NF-E2, and GATA-1 in normal adult hematopoiesis [7].
• One antibody reacts with a mitochondrially located 45 kDa polypeptide (p45) which contains a conserved repetitive amino acid domain. p45 co-purifies with RNA ligase and Tutase in a large ( approximately 700 kDa) RNP, and anti-p45 antibody inhibits in vitro RNA editing [8].
• To find target genes for p45 NF-E2 in megakaryopoiesis, we used an in vivo immunoselection assay: genomic fragments bound to p45 NF-E2 in the chromatin of a megakaryocytic cell line were immunoprecipitated with an anti-p45 antiserum and cloned [9].

Biological context of NFE2

• A 1.6-kilobase pair full-length cDNA encoding a transcription factor homologous to the Maf family of proteins was isolated by screening a K562 cDNA library with the NFE2 tandem repeat probe derived from the globin locus control region [10].
• Expressed in vitro, the hMAF protein is able to homodimerize in solution and band-shift the NFE2 tandem repeat probe [10].
• Chromosomal localization by fluorescence in situ hybridization demonstrates that these genes are non-syntenic. p45-NF-E2 mapped to chromosome 12q13.1-13.3, whereas Nrf1 and 2 mapped to 17q21.3 and 2q31, respectively [11].
• The transcription factor NF-E2 (nuclear factor erythroid 2), interacting via DNA motifs within regulatory regions of several hematopoietic genes, is thought to mediate the enhancer activity of the globin locus control regions [12].
• By screening a human fetal liver cDNA library with probes derived from mouse NF-E2, we have isolated a splicing variant of the NF-E2 gene (fNF-E2) that differs in the 5' untranslated region from the previously reported cDNA (aNF-E2) [12].

Anatomical context of NFE2

• Time-course of butyric acid-induced differentiation in human K562 leukemic cell line: rapid increase in gamma-globin, porphobilinogen deaminase and NF-E2 mRNA levels [13].
• Expression in the colon and testis suggests that NF-E2 may participate in the regulation of genes other than globin [14].
• Thus, p18 appears to be the sole specific partner of p45 NF-E2 in erythroid cells [15].
• Furthermore, the motif was recognized by the exogenous NF-E2 protein expressed in HeLa cells, which have a repressive state of chromatin at the beta-globin locus, as shown by ligation-mediated PCR and chromatin immunoprecipitation assay [16].
• OBJECTIVE: The transcription factor NF-E2, a heterodimeric protein complex composed of p45 and small Maf family proteins, is considered crucial for the proper differentiation of erythrocytes and megakaryocytes in vivo [17].

Associations of NFE2 with chemical compounds

• By in vitro sumoylation reaction and DNA transfection experiments, we show that the sumoylation occurs at lysine 368 (K368) of human p45/NF-E2 [18].
• Increased expression of GATA-1 and NFE-2 erythroid-specific transcription factors during aclacinomycin-mediated differentiation of human erythroleukemic cells [19].
• Différentiation of the erythroleukemic cell line K562 is stimulated by butyric acid with a increased expression of GATA-1 and NF-E2 transcription factors as well as PBGD and gamma-globin genes

  Transcriptional response of stress-regulated genes to cadmium exposure in the cockle Cerastoderma glaucum from the gulfof Gabès area (Tunisia)

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• Twenty percent O2 supported higher expression of the Mk-early and -late-maturation-specific transcription factors GATA-1 (1.2- to 2.2-fold higher) and NF-E2 (1.1- to 2.8-fold higher) [20].
• As shown by Northern blotting, high concentrations of SNP (1 mM) reduced the expression of gamma-globin and porphobilinogen deaminase, but did not change GATA-1 and NF-E2 mRNA levels in ACLA- and Butyric acid-treated cells [21].
• Furthermore, gene expression of megakaryocytopoietic transcriptional factors, GATA-1 and NF-E2, and several megakaryocytic markers such as glycoprotein (GP)IIb and thromboxane synthase was observed in the individual differentiation stage [22].

Physical interactions of NFE2

• Nrf1, Nrf2 and c-Jun binding to these NFE2 sites under basal conditions was demonstrated using chromatin immunoprecipitation assays [23].
• We provide evidence that the erythroid-specific enhancer- binding protein NF-E2 interacts with the cognate motif at DNase I-hypersensitive site 2 of the human beta-globin locus control region in a repressive state [16].
• Using antibodies, TCF11 isoforms bound to the single NF-E2 site were detected in K562 erythroid cell nuclear extracts [24].
• Band shifting and chromatin immunoprecipitation assays indicated that p45 NF-E2 was bound to the TXAS promoter in vitro and in vivo [25].

Regulatory relationships of NFE2

• We previously showed that p45 NF-E2 activated the TXAS promoter in hematopoietic cells via binding to the nucleotides -86/-77 from the transcriptional start site [Yaekashiwa and Wang (2002) J. Biol. Chem. 277, 22497-22508] [26].
• The abolishment of NF-E2 p45 with NF-E2 antisense oligomers inhibited TPO plus K252a-induced polyploidization [27].
• 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 [24].
• Requirement of GATA-1 and p45 NF-E2 expression in butyric acid-induced erythroid differentiation [28].
• Interleukin-4 downregulates nuclear factor-erythroid 2 (NF-E2) expression in primary megakaryocytes and in megakaryoblastic cell lines [29].

Other interactions of NFE2

• Analysis of erythroid transcription factor mRNA levels during the time course of BA treatment showed, for the first time, an early and marked (up to three-fold) increase in p45 NF-E2 mRNA, contrasting with that of GATA-1 mRNA (<1.5-fold) [13].
• Mutation of the NF-E2 site greatly reduced TXAS promoter activity in these two types of cells [26].
• Two regions homologous to the NFE2 motif are demonstrated to be important for basal expression of human GSS, as mutation of these sites reduced the promoter activity by 66% [23].
• An analysis of the sauternes mutant, which carries a mutation in the ALAS-2 gene and thus has defective heme synthesis, demonstrates higher levels of NFE2 expression than normal [30].
• The human homolog of mouse NF-E2 was isolated from the K562 cell line and found to encode a member of the basic leucine-zipper family of DNA-binding regulatory proteins [14].

Analytical, diagnostic and therapeutic context of NFE2

• Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization [11].
• Immunoprecipitation experiments demonstrated that p45 NF-E2 is associated in vivo with an 18-kDa protein (p18) [15].
• The human p45 NF-E2 gene was localized to chromosome 12q13 by fluorescent in situ hybridization [15].
• Gel mobility shift assays indicate that the region can interact in vitro with GATA-1 and AP-1/NF-E2, and functional studies show that the region serves as a scaffold attachment region in both erythroid and nonerythroid cell lines [31].
• Using site-directed mutagenesis of human HSs 2 and 3 we have tested the hypothesis that these NF-E2 and GATA sites are common requirements for the formation of all LCR HSs [32].

References