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FLASH GENE
Symbol ATF3 contributors: mct/shn - updated : 11-04-2015
HGNC name activating transcription factor 3
HGNC id 785
Location 1q32.3      Physical location : 212.738.696 - 212.794.114
Synonym name
  • liver generation factor 1
  • cAMP-dependent transcription factor ATF-3
  • Synonym symbol(s) LRFI, LRF1, ATF3deltaZip2, ATF3deltaZip2c, ATF3deltaZip3
    DNA
    TYPE functioning gene
    STRUCTURE 55.44 kb     4 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter (TATA box)
    Binding site   transcription factor
    text structure
  • ATF/CRE site, AP1, Mycmax, E2F, three putative EGR1 binding sites and others
  • P1 promoter contains multiple transcriptional start sites, and the different 5prime-UTRs markedly affected their translation in response to stress
  • P1 promoter was dominantly induced by serum and the P2 promoter was more efficiently activated in response to TGF-beta and oncogenic HRAS
  • MAPPING cloned Y linked N status provisional
    Map cen - D1S505 - D1S1667 - ATF3 - D1S217 - D1S2703 - qter
    Physical map
    LOC388733 1 similar to 40S ribosomal protein S25 LOC388734 1 similar to Px19-like protein (25 kDa protein of relevant evolutionary and lymphoid interest) (PRELI) (CGI-106) (SBBI12) FLJ10876 1q32.3 hypothetical protein FLJ10876 TRAF5 1q32 TNF receptor-associated factor 5 MGC14801 1q32.3 hypothetical protein MGC14801 LOC391160 1 similar to ARP2/3 complex 21 kDa subunit (p21-ARC) (Actin-related protein 2/3 complex subunit 3) C1orf36 1q32.3 chromosome 1 open reading frame 36 SLC30A1 1q32-q41 solute carrier family 30 (zinc transporter), member 1 LOC127184 1q32.3 similar to Farnesyl pyrophosphate synthetase (FPP synthetase) (FPS) (Farnesyl diphosphate synthetase) NEK2 1q32.2-q41 NIMA (never in mitosis gene a)-related kinase 2 KIAA0205 1p36.13-q42.3 NIMA (never in mitosis gene a)-related kinase 2 DKFZP434B168 1p36.13-q42.3 DKFZP434B168 protein RAMP 1q32.1-q32.2 DKFZP434B168 protein PPP2R5A 1q41 protein phosphatase 2, regulatory subunit B (B56), alpha isoform FLJ10874 1q32.3 hypothetical protein FLJ10874 SPUF 1q32.3 secreted protein of unknown function ATF3 1q32.3 activating transcription factor 3 FLJ32796 1q32.3 hypothetical protein FLJ32796 LOC388735 1 LOC388735 SNFT 1q32.3 Jun dimerization protein p21SNFT DC8 1q41 DKFZP566O1646 protein LOC388736 1 similar to ribosomal protein S5; 40S ribosomal protein S5 LOC149643 1q32.3 hypothetical LOC149643 FLVCR 1q32.1-q32.2 hypothetical LOC149643 FLJ12505 1q32.3 hypothetical protein FLJ12505 LOC90806 1q32.3 similar to RIKEN cDNA 2610307I21 RPS6KC1 1q41 ribosomal protein S6 kinase, 52kDa, polypeptide 1 LOC391161 1 similar to ribosomal protein L31 PROX1 1q32.2-q32.3 prospero-related homeobox 1 SMYD2 1q32.3 SET and MYND domain containing 2 PTPN14 1q32.2 protein tyrosine phosphatase, non-receptor type 14
    RNA
    TRANSCRIPTS type messenger
    text alternative ATF3 delta zip 2 and 2c
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 splicing 2088 20.4 181 - 2002 12034827
  • isoform 1, the longest
  • repressing rather than activating transcription from promoters with ATF binding elements
  • 4 splicing 1935 20 181 - - 12034827
  • differing in the 5'UTR
  • isoform 1, or deltaZip2c, deltaZip3
  • repressing rather than activating transcription from promoters with ATF binding elements
  • 4 splicing 2400 15 135 - 2002 12034827
  • isoform 2, deltaZip2a
  • lacked the leucine zipper domain and was incapable of binding to the ATF/CRE motif
  • induced by various stress signals and may modulate the activity of the full-length ATF3 protein during stress response
  • localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3
  • stimulating transcription presumably by sequestering inhibitory co-factors away from the promoter
  • 4 splicing 2010
    4 splicing 2048 - 124 - -
    4 splicing 2065 - 124 - -
    3 splicing 3187 - 120 - -
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrinepancreas     Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier/liningendothelium  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Endocrineislet cell (alpha,beta...) Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a basic region
  • mono polymer homomer , heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Atf3, Rattus norvegicus
    ortholog to Atf3, Mus musculus
    ortholog to ATF3, Pan troglodytes
    Homologene
    FAMILY
  • ATF/CREB family of transcription factors
  • CATEGORY chaperone/stress , regulatory , DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    intracellular,nucleus,nucleolus
    basic FUNCTION
  • may be playing a role in the endothelial cell death associated with atherogenesis
  • repressing MMP2 expression by antagonizing TP53 dependent transactivation of the collagenase promoter
  • negative regulator of IL6 and IL12b transcription by altering chromatin structure, thereby restricting access to transcription factors
  • seems to regulate TLR4-stimulated inflammatory responses as part of a negative-feedback loop
  • stress-activated regulator of TP53 protein stability/function providing the cell with a means of responding to a wide range of environmental insult, thus maintaining DNA integrity and protecting against cell transformation
  • repressor of the NFE2L2-directed stress response pathway (
  • acts within natural killer cells to regulate antiviral responses (
  • plays a pleiotropic role in determining cell fate in response to mitogenic or stress stimuli
  • ATF3 and OEATC1 are potentially novel gatekeepers of genomic integrity after UV exposure (Pubmed 19219066)
  • adaptive-response gene, induced by various stress signals relevant to T2D, such as high glucose and high fatty acid and proapoptotic in beta-cells
  • regulates proliferation or apoptosis under stress conditions by down or upregulation of related genes
  • promotes human Th1 differentiation
  • key role for ATF3 in regulating mast cell survival and mediator release
  • plays a key role in a mechanism defending against human papillomavirus-induced carcinogenesis
  • negatively regulates the expression of adiponectin and ADIPOR2, and downregulates ADIPOR1 expression
  • negatively regulates ADIPOR1 expression via binding to an ATF3-responsive region in the promoter, which plays an important role in attenuation of adiponectin signaling and induction of insulin resistance
  • plays a critical role in the development of insulin resistance in obesity and type 2 diabetes
  • negatively regulates the expression of both adiponectin and ADIPOR2, and may contribute to the development of insulin resistance or type 2 diabetes through attenuation of adiponectin signaling
  • protects cultured hippocampal neurons from apoptosis and extrasynaptic NMDA receptor-induced cell death triggered by bath application of NMDA or oxygen-glucose deprivation
  • plays a role in hyperglycemia or hyperlipidemia-mediated downregulation of PDX1 expression
  • can contribute to hyperglycemia or hyperlipidemia-mediated suppression of PDX1, lead to impaired insulin biosynthesis
  • role of ATF3 as an essential co-transcription factor for TP53 upon DNA damage
  • plays an important role in the dysfunction of beta-cells induced by chronic ER stress
  • inhibits PDX1-mediated transactivation through the inhibition of EP300-stimulated coactivation, which may lead to beta-cell dysfunction by ER stress
  • stress-adaptive gene that regulates proliferation or apoptosis under stress conditions
  • may contribute to the inhibition of adipocyte differentiation in hypoxia through downregulation of CEBPA expression
  • stress-induced ATF3 acts as a crucial inhibitor of adipocyte differentiation
  • is a novel repressor of androgen signaling that can inhibit AR functions, allowing prostate cells to restore homeostasis and maintain integrity in the face of a broad spectrum of intrinsic and environmental insults
  • ATF3 may play a role in adipocyte hypoxia-mediated mitochondrial dysfunction in obesity
  • hypoxia-inducible transcription factor that contributes to repression of adiponectin expression and inhibition of adipocyte differentiation, which are adipocyte dysfunctions induced by adipocyte hypoxia in obesity
  • may be involve in adipocyte hypoxia-mediated mitochondria dysfunction
  • ATF3 plays an important role in the control of glucose and energy metabolism by regulating AGRP
  • regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes
  • dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production but promotion of neutrophil chemotaxis
  • has neuroprotective action against cerebral ischemia, which may involve caspase 3
  • ATF3-mediated inhibition of PPARG expression may contribute to inhibition of adipocyte differentiation during cellular stress including ER stress
  • CELLULAR PROCESS cell life, proliferation/growth
    cell life, cell death/apoptosis
    nucleotide, transcription, regulation
    protein, post translation, targeting
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • heterodimerizing with Jvn proteins transcriptional activator
  • INTERACTION
    DNA
  • binding the cAMP response element (CRE)
  • cis-regulatory element of the IFN-gamma gene in natural killer cells (
  • NOXA promoter (
  • ADIPOR1 promoter
  • RNA
    small molecule
    protein
  • NF-kappa B (
  • gadd153/Chop10 (
  • TP53 (
  • KLF6 (
  • ATF4 (
  • histone deacetylase 1, HDAC1 (
  • MDM2 (
  • ATF3 modulated CD82 transcription through cooperation with other endogenous transcription factor as co-activator (ATF3-JunB) or co-repressor (ATF3-NFKB)
  • loss of EIF2AK4 ablated urea-induced phosphorylation of EIF2S1 and reduced the expression of ATF3
  • represses PDX1 expression via binding to an ATF3-responsive element in its promoter, which plays an important role in suppression of pancreatic beta-cells function
  • interacted with PDX1, and effectively inhibited EP300-mediated transcriptional coactivation of the PBE-containing promoter, whereas C-terminal domain-deleted ATF3 did not inhibit the transcoactivation of EP300
  • can inhibit PDX1-transactivation in a manner that is dependent on the C-terminal domain of ATF3
  • decreases the interaction of EP300 with PDX1
  • can directly bind the androgen receptor (AR) and consequently repress AR-mediated gene expression
  • association of HDAC3 and HDAC6 with JDP2 and ATF3 occurs via direct protein-protein interactions
  • SENP2 and SENP7 (two SUMOylation proteases) decreased SUMOylation of ATF3
  • ATF3 was an inhibitor of neutrophil differentiation and JDP2 directly suppresses its expression via inhibition of histone acetylation
  • NFKB1 inhibits NOD2-induced cytokine secretion through ATF3-dependent mechanisms
  • downregulated the mRNA and protein levels of THEM4, and protective effect of ATF3 against cerebral ischemia was mediated by downregulation of CTMP, a pro-apoptotic factor that inhibits the anti-apoptotic Akt/PKB cascade
  • downregulates peroxisome proliferator activated receptor (PPARG) gene expression and inhibits adipocyte differentiation
  • cell & other
    REGULATION
    activated by physiological stresses,serum stimulation in culture cells
    anisomycin at low concentration and stabilized
    homocysteine with JNK and inducing apoptosis through the IRE1/TRAF2 pathway,in endothelial cells
    induced by lipopolysaccharides
    EGR1
    its expression is induced by low glucose in pancreatic alpha and beta cells and regulates glucagon but not insulin gene transcription
    Other estrogen-responsive
    up-regulated during sexual differentiation
    regulated by a posttranslational mechanism (
    inducted by cAMP response element binding protein, CREB (
    induced by TGF&
    946; in the MCF10CA1a breast cancer cells (
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    ATF3 is up-regulated in the penile skin tissues of boys with hypospadias
    tumoral   amplification --over  
    amplified and overexpressed in esophageal squamous cell carcinomas activated during liver regeneration
    tumoral     --low  
    in esophageal squamous cell carcinoma
    Susceptibility to hypospadias
    Variant & Polymorphism other variants influencing the risk of hypospadias
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductiveuterus
    could serve as a novel therapeutic target for human papillomavirus-positive cancers
    neurologyneurodegenerative 
    ATF3 supplementation may counteract age- and disease-related neuronal cell loss caused by a reduction in synaptic activity, malfunctioning of calcium signaling toward and within the nucleus, or increases in death signaling by extrasynaptic NMDA receptor
    cancerdigestiveoesophagus
    targeting ATF3 might be a potential therapeutic strategy
    ANIMAL & CELL MODELS
  • ATF3-deficient mice are more susceptible to endotoxic shock (
  • ATF3null natural killer cells show increased transcription and secretion of IFN-gamma (
  • ATF3-deficient mice had higher renal I/R-induced mortality, kidney dysfunction, inflammation, and apoptosis compared with wild-type mice (
  • ATF3 were increased in white adipose tissue of high fat diet (HFD) obese mice compared with control lean mice(pMID: 23333392)