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NRF1 (nuclear respiratory factor 1)

Identity

Other namesALPHA-PAL (Alpha palindromic-binding protein)
EWG
HBZ17
OTTHUMP00000184912
TCF11
HGNC (Hugo) NRF1
LocusID (NCBI) 4899
Location 7q32.2
Location_base_pair Starts at 129269919 and ends at 129396922 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note NRF1 is located at contig NT 079596 of Genebank, 28668299-28812556 bp.
There is a confusion in bibliographic databases as well as among scientific communities due to following reasons: i) The shared symbol of NRF1 for nuclear respiratory factor 1 gene and for 'nuclear factor (erythroid-derived 2)-like 1' which has an official symbol of NFE2L1; ii) The nuclear respiratory factor 1 gene symbol for human is NRF1, where as the symbol of this same gene for rat and mice is Nrf1. Confusion between NRF1 and Nrf1 (NFE2Ll) started in early 1990s. Chan et al. (1993) identified a distinct human bZIP transcription factor, NFE2L1, which they designated NRF1 (NFE2-related factor-1). Later on Tiranti et al. (1995) mapped the NRF1 gene to 7q32 and referred to the gene as NFE2L1. The majority of the scientists working on NFE2L1or NFE2L1-regulatable proteins continue to use Nrf1 in their manuscripts instead of NFE2L1. The same is true for pharmaceutical firms who sell NFE2L products. This not only creates a major problem for new researchers in the field, but produces erroneous interpretation of the research findings.

DNA/RNA

Note NRF-1 / a-PAL (nuclear respiratory factor-1/a-palindrome-binding protein) is a transcription factor. It belongs to the NRF1/Ewg family. The optimal NRF-1 binding site is (T/C)GCGCA(C/T)GCGC(A/G).
 
Description DNA size 144.26 kb; mRNA size 2578 bp 12 exons.

Protein

Description 503 amino acids; 53.5 kDa protein.
Post translational modifications: Phosphorylation enhances DNA binding. DNA binding 109-305 (197), region 1-78 (78) is required for dimerization, region 301-476 (176) required for transcriptional activation, motif 88-116 (29) is nuclear localization signal, compositional bias 41-66 (26) Asp/Glu-rich (acidic), compositional bias 80-86 (7).

Isoforms:
Two isoforms have been identified.

  • Isoform Long (identifier: Q16656-1)
    This isoform has been chosen as the 'canonical' sequence.
  • Isoform Short (identifier: Q16656-2)
    The sequence of this isoform differs from the canonical sequence, amino acid residues from 256-321 are missing.
  • Expression It is widely expressed, and strongest expression is in skeletal muscle.
    Localisation Nucleus.
    Function NRF-1 was first discovered as an activator of the cytochrome c gene (Evans and Scarpulla, 1989). Now we know that this transcription factor activates the expression of several key genes regulating cell growth and development, nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication.
    A genome-wide analysis has revealed that NRF-1 binding elements are present in genes involved in DNA replication, mitosis, and cytokinesis, suggesting that NRF-1 plays an important role in cell cycle regulation. Similarly, computation analysis of NRF-1 gene regulation by querying the TRANSFAC database revealed that the TGCGCATGCGCA motif of the consensus NRF1 binding site is present in genes encoding proteins regulating cell growth (CKS2, CDC6, CDC7, CDC25C, NPAT), replication (ORC6L, FEN1), and DNA repair (DNA polymerase alpha, MLH1, MSH2, PCNA, Prim2A, TOP1, ATM, XRCC2, GTSE, SMC4L1, KIF22, PP5C, cyclin B1, cyclin G2, RAD54B, PRC1, CBX5). NRF-1 and CREB elements significantly co-occur on promoters of cell cycle-regulated genes. NRF-1 also binds to the gene promoters of cysteine proteases (CAPNS1 and CASP2), chemokines (CXR5, CKLF), the putative breast adenocarcinoma marker BC2, BRCA2, BCCIP, tumor suppressors (putative tumor suppressor, 101F6 and tumor suppressor deleted in oral cancer-related 1). These NRF-1 target genes control cell adhesion, cell spreading, migration, proliferation, apoptosis, and tumor invasion. NRF-1 responds to redox signaling pathways through post-translational modifications and through its specific interaction with transcriptional co-activators.
    Homology The percent Identity below represents identity of NRF-1 over an aligned region in UniGene.
    M. musculus : 99.8 (Percentage Identity)
    M. domestica : 99.8
    E. caballus : 99.8
    B. taurus : 99.8
    C. lupus familiaris : 99.6
    G. gallus : 99.6
    D. rerio : 93.7
    X. laevis : 92.9
    D. melanogaster : 51.5

    Mutations

    Note Two novel single nucleotide polymorphisms (SNPs) in the NRF1 gene SNPs are found to be associated with type 2 diabetes in a Han Chinese population.

    Implicated in

    Entity Estrogen-dependent breast cancer
    Note NRF-1 is a redox sensitive transcription factor. Some of the same mitogenic pathways that are sensitive to oxidant levels and estrogen are also directly regulated by NRF-1. For example, the expression of CDC25C, which is required for progression of the cell cycle, is regulated by both E2 and reactive oxygen species ( ROS ) and its promoter contains NRF-1 binding motif. The expression of cyclin D1 is also regulated by both E2 and ROS. There are several estrogen-regulatable genes, which are also regulated by ROS. Cell cycle regulation by the cdks and cyclins is dependent upon cell adhesion mediated by integrins, which control expression of cell cycle genes via ROS. Many of the genes associated with high-risk breast tumors appear to participate in cell cycle regulation, including those encoding CDC2 and PRC1. As noted above, both genes are NRF-1 regulatable. Importantly, in human breast cancer cells, the expression of almost 15% of the genes significantly affected by E2 contain the NRF-1 binding element, and the NRF-1 binding signature is significantly enriched in the promoters of genes induced by estrogen treatment. We have recently shown that inhibitors of mitochondrial oxidant production prevent E2-induced expression of cell cycle genes containing NRF-1 binding sites (cyclin B1, PCNA, and PRC1), decrease E2-induced NRF-1 expression, and delay growth. These findings show that E2 stimulates NRF-1 expression and cell cycle progression of breast cancer cells through ROS, possibly by altering NRF-1 activity.
      
    Entity Breast cancer
    Disease Motifs bound by ELK1, E2F, NRF1 and NFY positively correlate with malignant progression of breast cancer.
      
    Entity Colorectal tumors
    Note NRF-1 is also the main transcription factor regulating the expression of human TOMM34 gene that encodes a cytosolic protein with chaperone-like activity. TOMM34 helps import some preproteins to the mitochondria by keeping them in an unfolded, import-compatible state. TOMM34 was found to be upregulated frequently in colorectal tumors, suggesting that it also has a role in the growth of cancer cells.
      
    Entity Hepatoma and thyroid oncocytoma
    Note NRF-1 overexpression has been observed in hepatoma and thyroid oncocytoma.
      
    Entity Diabetes Mellitus, Type 2
    Note Two novel single nucleotide polymorphisms (SNPs) in the NRF1 gene SNPs (-46127T>C and +98560A>G) are associated with type 2 diabetes in a Han Chinese population. NRF1 genetic polymorphisms may be a suspectibility factor for type 2 diabetes by conferring abnormalities in triglyceride metabolism.
    Two common haplotypes of NRF1 gene are found to be associated with type 2 diabetes in the Korean population. A haplotype (H2) is associated with a decreased risk of type 2 diabetes and another haplotype (H4) is associated with an increased risk of type 2 diabetes.
      
    Entity Endurance exercise capacity
    Note In young Chinese men of Han origin, two NRF1 genotypes have been found to be associated with the baseline and/or training response of human aerobic capacity. NRF1 is a critical component of the energy-sensing mechanism in mammalian cells, and translates physiological signals, including those induced by exercise, into increased capacity for mitochondrial biogenesis and oxidative phosphorylation.
      

    External links

    Nomenclature
    HGNC (Hugo)NRF1   7996
    Cards
    AtlasNRF1ID44233ch7q32
    Entrez_Gene (NCBI)NRF1  4899  nuclear respiratory factor 1
    GeneCards (Weizmann)NRF1
    Ensembl (Hinxton)ENSG00000106459 [Gene_View]  chr7:129269919-129396922 [Contig_View]  NRF1 [Vega]
    ICGC DataPortalENSG00000106459
    cBioPortalNRF1
    AceView (NCBI)NRF1
    Genatlas (Paris)NRF1
    WikiGenes4899
    SOURCE (Princeton)NM_001040110 NM_001293163 NM_001293164 NM_005011
    Genomic and cartography
    GoldenPath (UCSC)NRF1  -  7q32.2   chr7:129269919-129396922 +  7q32   [Description]    (hg19-Feb_2009)
    EnsemblNRF1 - 7q32 [CytoView]
    Mapping of homologs : NCBINRF1 [Mapview]
    OMIM600879   
    Gene and transcription
    Genbank (Entrez)AI816827 AK290891 AK293351 AL530274 BC016925
    RefSeq transcript (Entrez)NM_001040110 NM_001293163 NM_001293164 NM_005011
    RefSeq genomic (Entrez)AC_000139 NC_000007 NC_018918 NT_007933 NW_001839071 NW_004929332
    Consensus coding sequences : CCDS (NCBI)NRF1
    Cluster EST : UnigeneHs.654363 [ NCBI ]
    CGAP (NCI)Hs.654363
    Alternative Splicing : Fast-db (Paris)GSHG0027717
    Alternative Splicing GalleryENSG00000106459
    Gene ExpressionNRF1 [ NCBI-GEO ]     NRF1 [ SEEK ]   NRF1 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ16656 (Uniprot)
    NextProtQ16656  [Medical]
    With graphics : InterProQ16656
    Splice isoforms : SwissVarQ16656 (Swissvar)
    Domains : Interpro (EBI)Nrf1_activation-bd [organisation]   Nrf1_NLS/DNA-bd_dimer [organisation]  
    Related proteins : CluSTrQ16656
    Domain families : Pfam (Sanger)Nrf1_activ_bdg (PF10492)    Nrf1_DNA-bind (PF10491)   
    Domain families : Pfam (NCBI)pfam10492    pfam10491   
    DMDM Disease mutations4899
    Blocks (Seattle)Q16656
    Human Protein AtlasENSG00000106459 [gene] [tissue] [antibody] [cell] [cancer]
    Peptide AtlasQ16656
    HPRD02930
    IPIIPI00003428   IPI00219917   IPI01011429   IPI00165068   
    Protein Interaction databases
    DIP (DOE-UCLA)Q16656
    IntAct (EBI)Q16656
    FunCoupENSG00000106459
    BioGRIDNRF1
    InParanoidQ16656
    Interologous Interaction database Q16656
    IntegromeDBNRF1
    STRING (EMBL)NRF1
    Ontologies - Pathways
    Ontology : AmiGORNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  response to hypoxia  nucleoplasm  cytoplasm  generation of precursor metabolites and energy  transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  mitochondrion organization  organ regeneration  response to estradiol  response to lipopolysaccharide  cellular lipid metabolic process  small molecule metabolic process  positive regulation of transcription from RNA polymerase II promoter  response to folic acid  response to electrical stimulus  extracellular vesicular exosome  
    Ontology : EGO-EBIRNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  response to hypoxia  nucleoplasm  cytoplasm  generation of precursor metabolites and energy  transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  mitochondrion organization  organ regeneration  response to estradiol  response to lipopolysaccharide  cellular lipid metabolic process  small molecule metabolic process  positive regulation of transcription from RNA polymerase II promoter  response to folic acid  response to electrical stimulus  extracellular vesicular exosome  
    Pathways : KEGGHuntington's disease   
    Protein Interaction DatabaseNRF1
    Wikipedia pathwaysNRF1
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)NRF1
    snp3D : Map Gene to Disease4899
    SNP (GeneSNP Utah)NRF1
    SNP : HGBaseNRF1
    Genetic variants : HAPMAPNRF1
    Exome VariantNRF1
    1000_GenomesNRF1 
    ICGC programENSG00000106459 
    Somatic Mutations in Cancer : COSMICNRF1 
    CONAN: Copy Number AnalysisNRF1 
    Mutations and Diseases : HGMDNRF1
    Genomic VariantsNRF1  NRF1 [DGVbeta]
    dbVarNRF1
    ClinVarNRF1
    Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
    Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
    Diseases
    OMIM600879   
    MedgenNRF1
    GENETestsNRF1
    Disease Genetic AssociationNRF1
    Huge Navigator NRF1 [HugePedia]  NRF1 [HugeCancerGEM]
    General knowledge
    Homologs : HomoloGeneNRF1
    Homology/Alignments : Family Browser (UCSC)NRF1
    Phylogenetic Trees/Animal Genes : TreeFamNRF1
    Chemical/Protein Interactions : CTD4899
    Chemical/Pharm GKB GenePA31775
    Clinical trialNRF1
    Cancer Resource (Charite)ENSG00000106459
    Other databases
    Probes
    Litterature
    PubMed75 Pubmed reference(s) in Entrez
    CoreMineNRF1
    iHOPNRF1
    OncoSearchNRF1

    Bibliography

    Interaction of nuclear factors with multiple sites in the somatic cytochrome c promoter. Characterization of upstream NRF-1, ATF, and intron Sp1 recognition sequences.
    Evans MJ, Scarpulla RC.
    J Biol Chem. 1989 Aug 25;264(24):14361-8.
    PMID 2547796
     
    Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast.
    Chan JY, Han XL, Kan YW.
    Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11371-5.
    PMID 8248256
     
    NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators.
    Virbasius CA, Virbasius JV, Scarpulla RC.
    Genes Dev. 1993 Dec;7(12A):2431-45.
    PMID 8253388
     
    A key transcription factor for eukaryotic initiation factor-2 alpha is strongly homologous to developmental transcription factors and may link metabolic genes to cellular growth and development.
    Efiok BJ, Chiorini JA, Safer B.
    J Biol Chem. 1994 Jul 22;269(29):18921-30.
    PMID 8034649
     
    Structure, expression, and chromosomal assignment of the human gene encoding nuclear respiratory factor 1.
    Gopalakrishnan L, Scarpulla RC.
    J Biol Chem. 1995 Jul 28;270(30):18019-25.
    PMID 7629110
     
    The pre-mRNA of nuclear respiratory factor 1, a regulator of mitochondrial biogenesis, is alternatively spliced in human tissues and cell lines.
    Spelbrink JN, Van den Bogert C.
    Hum Mol Genet. 1995 Sep;4(9):1591-6.
    PMID 8541844
     
    The gene (NFE2L1) for human NRF-1, an activator involved in nuclear-mitochondrial interactions, maps to 7q32.
    Tiranti V, Rossi E, Rocchi M, DiDonato S, Zuffardi O, Zeviani M.
    Genomics. 1995 Jun 10;27(3):555-7.
    PMID 7558044
     
    Serine phosphorylation within a concise amino-terminal domain in nuclear respiratory factor 1 enhances DNA binding.
    Gugneja S, Scarpulla RC.
    J Biol Chem. 1997 Jul 25;272(30):18732-9.
    PMID 9228045
     
    Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells.
    Andersson U, Scarpulla RC.
    Mol Cell Biol. 2001 Jun;21(11):3738-49.
    PMID 11340167
     
    Mitochondrial transcription factor A and its downstream targets are up-regulated in a rat hepatoma.
    Dong X, Ghoshal K, Majumder S, Yadav SP, Jacob ST.
    J Biol Chem. 2002 Nov 8;277(45):43309-18. Epub 2002 Aug 26.
    PMID 12198131
     
    PGC-1-related coactivator and targets are upregulated in thyroid oncocytoma.
    Savagner F, Mirebeau D, Jacques C, Guyetant S, Morgan C, Franc B, Reynier P, Malthiery Y.
    Biochem Biophys Res Commun. 2003 Oct 24;310(3):779-84.
    PMID 14550271
     
    Association between polymorphisms in the nuclear respiratory factor 1 gene and type 2 diabetes mellitus in the Korean population.
    Cho YM, Shin HD, Park BL, Kim JH, Park KS, Kim SY, Lee HK.
    Diabetologia. 2005 Oct;48(10):2033-8. Epub 2005 Aug 5.
    PMID 16082529
     
    Estrogen-induced G1/S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling.
    Felty Q, Singh KP, Roy D.
    Oncogene. 2005 Jul 21;24(31):4883-93.
    PMID 15897899
     
    Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers.
    Felty Q, Xiong WC, Sun D, Sarkar S, Singh KP, Parkash J, Roy D.
    Biochemistry. 2005 May 10;44(18):6900-9.
    PMID 15865435
     
    PGC-1-related coactivator: immediate early expression and characterization of a CREB/NRF-1 binding domain associated with cytochrome c promoter occupancy and respiratory growth.
    Vercauteren K, Pasko RA, Gleyzer N, Marino VM, Scarpulla RC.
    Mol Cell Biol. 2006 Oct;26(20):7409-19. Epub 2006 Aug 14.
    PMID 16908542
     
    NRF-1, and AP-1 regulate the promoter of the human calpain small subunit 1 (CAPNS1) gene.
    Asangani IA, Rasheed SA, Leupold JH, Post S, Allgayer H.
    Gene. 2008 Feb 29;410(1):197-206. Epub 2007 Dec 23.
    PMID 18234454
     
    NRF-1 is the major transcription factor regulating the expression of the human TOMM34 gene.
    Blesa JR, Prieto-Ruiz JA, Abraham BA, Harrison BL, Hegde AA, Hernandez-Yago J.
    Biochem Cell Biol. 2008 Feb;86(1):46-56.
    PMID 18364745
     
    Nuclear respiratory factor 1 regulates all ten nuclear-encoded subunits of cytochrome c oxidase in neurons.
    Dhar SS, Ongwijitwat S, Wong-Riley MT.
    J Biol Chem. 2008 Feb 8;283(6):3120-9. Epub 2007 Dec 12.
    PMID 18077450
     
    NRF-1 genotypes and endurance exercise capacity in young Chinese men.
    He Z, Hu Y, Feng L, Li Y, Liu G, Xi Y, Wen L, Lucia A.
    Br J Sports Med. 2008 May;42(5):361-6. Epub 2008 Jan 9.
    PMID 18184751
     
    Genetic variation and association analyses of the nuclear respiratory factor 1 (nRF1) gene in Chinese patients with type 2 diabetes.
    Liu Y, Niu N, Zhu X, Du T, Wang X, Chen D, Wu X, Gu HF, Liu Y.
    Diabetes. 2008 Mar;57(3):777-82. Epub 2007 Dec 10.
    PMID 18071027
     
    Integrative bioinformatics analysis of transcriptional regulatory programs in breast cancer cells.
    Niida A, Smith AD, Imoto S, Tsutsumi S, Aburatani H, Zhang MQ, Akiyama T.
    BMC Bioinformatics. 2008 Sep 29;9:404.
    PMID 18823535
     
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    Contributor(s)

    Written12-2008Deodutta Roy, Ranjan Tamuli
    Department of Environmental and Occupational Health, Florida International University, 11200 SW 8th Street, Miami, FL 33199-0001, USA

    Citation

    This paper should be referenced as such :
    Roy, D ; Tamuli, R
    NRF1 (nuclear respiratory factor 1)
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):861-864.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/NRF1ID44233ch7q32.html

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    indexed on : Wed Jul 30 16:55:41 CEST 2014

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