NRF1 (nuclear respiratory factor 1)

2008-12-01   Deodutta Roy  , Ranjan Tamuli  

Department of Environmental, Occupational Health, Florida International University, 11200 SW 8th Street, Miami, FL 33199-0001, USA

Identity

HGNC
NRF1
LOCATION
7q32.2
LOCUSID
4899
ALIAS
ALPHA-PAL
FUSION GENES
Show Gene Fusions

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).
Atlas Image

Description

DNA size 144.26 kb; mRNA size 2578 bp 12 exons.

Proteins

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

Description

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.

    • 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 name
    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 name
    Breast cancer
    Disease
    Motifs bound by ELK1, E2F, NRF1 and NFY positively correlate with malignant progression of breast cancer.
    Entity name
    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 name
    Hepatoma and thyroid oncocytoma
    Note
    NRF-1 overexpression has been observed in hepatoma and thyroid oncocytoma.
    Entity name
    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 name
    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.

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    113401672001Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells.Andersson U et al
    182344542008NRF-1, and AP-1 regulate the promoter of the human calpain small subunit 1 (CAPNS1) gene.Asangani IA et al
    183647452008NRF-1 is the major transcription factor regulating the expression of the human TOMM34 gene.Blesa JR et al
    82482561993Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast.Chan JY et al
    160825292005Association between polymorphisms in the nuclear respiratory factor 1 gene and type 2 diabetes mellitus in the Korean population.Cho YM et al
    180774502008Nuclear respiratory factor 1 regulates all ten nuclear-encoded subunits of cytochrome c oxidase in neurons.Dhar SS et al
    121981312002Mitochondrial transcription factor A and its downstream targets are up-regulated in a rat hepatoma.Dong X et al
    80346491994A 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 et al
    25477961989Interaction 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 et al
    158978992005Estrogen-induced G1/S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling.Felty Q et al
    158654352005Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers.Felty Q et al
    76291101995Structure, expression, and chromosomal assignment of the human gene encoding nuclear respiratory factor 1.Gopalakrishnan L et al
    92280451997Serine phosphorylation within a concise amino-terminal domain in nuclear respiratory factor 1 enhances DNA binding.Gugneja S et al
    181847512008NRF-1 genotypes and endurance exercise capacity in young Chinese men.He Z et al
    180710272008Genetic variation and association analyses of the nuclear respiratory factor 1 (nRF1) gene in Chinese patients with type 2 diabetes.Liu Y et al
    188235352008Integrative bioinformatics analysis of transcriptional regulatory programs in breast cancer cells.Niida A et al
    145502712003PGC-1-related coactivator and targets are upregulated in thyroid oncocytoma.Savagner F et al
    85418441995The pre-mRNA of nuclear respiratory factor 1, a regulator of mitochondrial biogenesis, is alternatively spliced in human tissues and cell lines.Spelbrink JN et al
    75580441995The gene (NFE2L1) for human NRF-1, an activator involved in nuclear-mitochondrial interactions, maps to 7q32.Tiranti V et al
    169085422006PGC-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 et al
    82533881993NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators.Virbasius CA et al

    Other Information

    Locus ID:

    NCBI: 4899
    MIM: 600879
    HGNC: 7996
    Ensembl: ENSG00000106459

    Variants:

    dbSNP: 4899
    ClinVar: 4899
    TCGA: ENSG00000106459
    COSMIC: NRF1

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000106459ENST00000223190Q16656
    ENSG00000106459ENST00000223190A0A024R770
    ENSG00000106459ENST00000311967Q16656
    ENSG00000106459ENST00000311967A0A024R774
    ENSG00000106459ENST00000353868Q16656
    ENSG00000106459ENST00000353868A0A024R774
    ENSG00000106459ENST00000393230Q16656
    ENSG00000106459ENST00000393230A0A024R770
    ENSG00000106459ENST00000393232Q16656
    ENSG00000106459ENST00000393232A0A024R770
    ENSG00000106459ENST00000454688C9JP85

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    Adipose - Subcutaneous
    Adipose - Visceral
    Adrenal Gland
    Artery - Aorta
    Artery - Tibial
    Bladder
    Brain - Amygdala
    Brain - Anterior cingulate cortex
    Brain - Caudate
    Brain - Cerebellar Hemisphere
    Brain - Cerebellum
    Brain - Cortex
    Brain - Frontal Cortex
    Brain - Hippocampus
    Brain - Hypothalamus
    Brain - Nucleus accumbens
    Brain - Putamen
    Brain - Spinal cord
    Brain - Substantia nigra
    Breast - Mammary Tissue
    Cells - Cultured fibroblasts
    Cells - EBV - transformed lymphocytes
    Cervix - Ectocervix
    Cervix - Endocervix
    Colon - Sigmoid
    Colon - Transverse
    Esophagus - Gastroesophageal Junction
    Esophagus - Mucosa
    Esophagus - Muscularis
    Fallopian Tube
    Heart - Atrial Appendage
    Heart - Left Ventricle
    Kidney - Cortex
    Kidney - Medulla
    Liver
    Lung
    Minor Salivary Gland
    Muscle - Skeletal
    Nerve - Tibial
    Ovary
    Pancreas
    Pituitary
    Prostate
    Skin - Not Sun Exposed
    Skin - Sun Exposed
    Small Intestine - Terminal Ileum
    Spleen
    Stomach
    Testis
    Thyroid
    Uterus
    Vagina
    Whole Blood

    Pathways

    PathwaySourceExternal ID
    Huntington's diseaseKEGGko05016
    Huntington's diseaseKEGGhsa05016
    Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
    Mitochondrial biogenesisREACTOMER-HSA-1592230
    Transcriptional activation of mitochondrial biogenesisREACTOMER-HSA-2151201
    MetabolismREACTOMER-HSA-1430728
    Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
    Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
    Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
    PPARA activates gene expressionREACTOMER-HSA-1989781
    Apelin signaling pathwayKEGGhsa04371

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High
    cerebral cortex
    cerebellum
    hippocampus
    caudate
    thyroid gland
    parathyroid gland
    adrenal gland
    nasopharynx
    bronchus
    lung
    oral mucosa
    salivary gland
    esophagus
    stomach 1
    stomach 2
    duodenum
    small intestine
    colon
    rectum
    liver
    gallbladder
    pancreas
    kidney
    urinary bladder
    testis
    epididymis
    seminal vesicle
    prostate
    vagina
    ovary
    fallopian tube
    endometrium 1
    endometrium 2
    cervix, uterine
    placenta
    breast
    heart muscle
    smooth muscle
    skeletal muscle
    soft tissue 1
    soft tissue 2
    adipose tissue
    skin 1
    skin 2
    appendix
    spleen
    lymph node
    tonsil
    bone marrow

    References

    Pubmed IDYearTitleCitations
    375396372024NRF1 promotes primordial germ cell development, proliferation and survival.3
    376689612024Inhibitor of DNA Binding Protein 3 (ID3) and Nuclear Respiratory Factor 1 (NRF1) Mediated Transcriptional Gene Signatures are Associated with the Severity of Cerebral Amyloid Angiopathy.1
    380558352024Molecular mechanism of specific DNA sequence recognition by NRF1.0
    375396372024NRF1 promotes primordial germ cell development, proliferation and survival.3
    376689612024Inhibitor of DNA Binding Protein 3 (ID3) and Nuclear Respiratory Factor 1 (NRF1) Mediated Transcriptional Gene Signatures are Associated with the Severity of Cerebral Amyloid Angiopathy.1
    380558352024Molecular mechanism of specific DNA sequence recognition by NRF1.0
    367383782023Nuclear respiratory factor 1 promotes the progression of EBV-associated gastric cancer and maintains EBV latent infection.1
    369604922023NRF1 Regulates the Epithelial Mesenchymal Transition of Breast Cancer by Modulating ROS Homeostasis.0
    369748122023The Regulatory Role of Nuclear Respiratory Factor 1 in Bladder Cancer Cells.1
    369891112023The N(6)-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis by disrupting NRF1 binding capacity.8
    370848172023UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage.1
    374023162023NRF1 knockdown alleviates lipopolysaccharide-induced pulmonary inflammatory injury by upregulating DKK3 and inhibiting the GSK-3β/β-catenin pathway.1
    378759672023Nuclear respiratory factor 1 drives hepatocellular carcinoma progression by activating LPCAT1-ERK1/2-CREB axis.0
    379620272023NRF1 Alleviated Oxidative Stress of Glioblastoma Cells by Regulating NOR1.0
    367383782023Nuclear respiratory factor 1 promotes the progression of EBV-associated gastric cancer and maintains EBV latent infection.1

    Citation

    Deodutta Roy ; Ranjan Tamuli

    NRF1 (nuclear respiratory factor 1)

    Atlas Genet Cytogenet Oncol Haematol. 2008-12-01

    Online version: http://atlasgeneticsoncology.org/gene/44233/nrf1id44233ch7q32