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FLASH GENE
Symbol ATF4 contributors: mct/shn - updated : 21-09-2019
HGNC name activating transcription factor 4 (tax-responsive enhancer element B67)
HGNC id 786
Location 22q13.1      Physical location : 39.916.568 - 39.918.690
Synonym name
  • cyclic AMP-responsive element-binding protein 2
  • cAMP-dependent transcription factor ATF-4
  • DNA-binding protein TAXREB67
  • cAMP-responsive element-binding protein 2
  • response element-binding protein 2
  • cyclic AMP-dependent transcription factor ATF-4
  • tax-responsive enhancer element-binding protein 67
    • Synonym symbol(s) TAXREB67, CREB2, TXREB, CREB-2, cAMP
    DNA
    TYPE functioning gene
    STRUCTURE 2.12 kb     3 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D22S272 - D22S1155 - ATF4 - D22S428 - D22S284 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 2022 - 351 - 2000 10486212
    3 - 1420 - 351 - 2000 10486212
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
     stomach   highly
    Reproductivefemale systemuteruscervix highly
    Respiratoryrespiratory tractlarynx  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Skeletonosteoblast Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text later stages of lens fiber cell differentiation
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a C terminal leucine zipper motif
  • a central region of ATF4 including the Zipper II domain, ODD domain and beta-TrCP recognition motif were involved in the interaction with EGLN2
  • an adjacent basic domain
    • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Atf4, Mus musculus
    ortholog to Atf4, Rattus norvegicus
    ortholog to ATF4, Pan troglodytes
    Homologene
    FAMILY
  • activating transcription factor/cAMP-responsive element-binding protein (ATF/CREB) family
    • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • activation transcription factor 4, cAMP dependent
  • negatively regulating transcription from the cAMP response element
  • involved in heme oxygenase 1 gene regulation
  • transcriptional activator of aspargine synthetase gene (ASNS) in response to nutrient deprivation
  • may regulate myeloid gene expression differentially by potentiating CEBPE but inhibiting CEBPA-mediated transcriptional activation
  • has an important function in tumour progression
  • required for ER stress and hypoxia-induced expansion of autophagy
  • facilitates autophagy through direct binding to a cyclic AMP response element binding site in the MAP1LC3B promoter, resulting in MAP1LC3B upregulation
  • has a key role in the regulation of autophagy in response to ER stress and provide a direct mechanistic link between the UPR and the autophagic machinery
  • major role of ATF4 in regulating the gene expression programme after hypoxia, although ATF6 and XBP1 are also induced by this pathway
  • transcriptional activator of the integrated stress response, a program of gene expression involved in metabolism, nutrient uptake, anti-oxidation, and the activation of additional transcription factors, such as DDIT3, that can induce apoptosis
  • its expression is subject to both transcriptional regulation and translational control
  • transcriptional activator required for osteoblast terminal differentiation and osteocalcin expression
  • master role of ATF4 in the regulation of the AARE-dependent transcription
  • ATF4, FOXO1 synergize to regulate glucose metabolism, insulin production, and insulin sensitivity
  • new role of ATF4 in controlling the CTNNB1 protein levels and MSC differentiation towards the osteoblast lineage
  • is a new key regulator of the HIF/VEGFA axis in osteoblasts in response to hypoxia and of VEGFA release from bone matrix, two critical steps for bone angiogenesis
  • is a critical transcription factor in osteoblastogenesis and endoplasmic reticulum stress (ERS)-induced apoptosis
  • ATF4 was involved at least in part in the process of ERS-mediated apoptosis contributing to vascular calcification (VC)
  • ATF4 is involved in the regulation of oxidative stress in fibroblasts and neurons
  • ATF4 is a novel regulator of oxidative stress as well as accumulation of triglyceride in response to high-fat diet (HFD)
  • ATF4-mediated repression of APLN contributes substantially to the pro-apoptotic effects of MAPK14
  • dual kinase function of the RET proto-oncogene negatively regulates ATF4-mediated apoptosis
  • is a key regulator of the physiological state necessary for neuronal plasticity and memory
  • directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver
  • ATF4 may exert various physiological roles in lipid metabolism depending on the nutrient composition
  • is essential for adipocytes differentiation, and also plays a vital role in regulating fatty acids biosynthesis
    • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • component of the PERK pathway involved in the unfolded protein response (UPR), a process that protects cells from the negative consequences of endoplasmic reticulum (ER) stress
  • EIF2AK4-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches
  • EIF2AK4/ATF4 pathway is involved in this regulation through the presence of an AARE in NUPR1 promoter
  • cell-autonomous role of ATF4 in chondrocytes dominates the role of ATF4 in osteoblasts during development for the control of early osteogenesis and skeletal growth
  • new cellular pathway in which ATF4 regulates the expression of ARHGDIA that in turn affects Rho GTPase protein levels, and thereby, controls cellular functions as diverse as memory and cell motility
    • a component
  • heterodimer with C/EBP, AP-1 and MAF family and NFE2L2/ATF4
    • INTERACTION
    DNA
  • tax-responsive enhancer element within the LTR of HTLV-1 cAMP response element (CRE) consensus
  • nutrient-sensing response elements (NSRE) 1 (
    • RNA
    small molecule metal binding,
  • cAMP
    • protein
  • GPE1-binding protein, GPE1-BP (
  • TATA-binding protein, TFIIB, the RAP30 subunit of TFIIF and the coactivator CREB-binding protein (
  • ZIP kinase
  • forms a heterodimer with the bZIP domain of C/EBP beta (
  • transcription factor 11 (basic leucine zipper type), TCF11 (
  • GABAB receptor (
  • SKP1 interacting partner 3, SKIP3 (
  • Disrupted-In-Schizophrenia 1, DISC1 (
  • subunit 3 of RNA polymerase II, RPB3 (
  • Zhangfei, ZF (
  • p300/CBP-associated factor, PCAF (
  • activating transcription factor 3, ATF3 (
  • transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin (PARK2)promoter
  • interaction with PTH (bone formation stimulated by PTH is in part mediated by ATF4)
  • may be a down stream target of FGF2 signaling in osteoblasts
  • necessary for the regulation of NUPR1 expression during leucine starvation
  • TWIST1, TWIST2 are novel inhibitory binding partners of ATF4
  • is a protein interacting with EGLN2 as well as EGLN3, but not with EGLN1
  • functional interaction between ATF4, TXLNG, and NACA, three proteins that have been previously shown to associate using various protein-protein interaction assays
  • FOXO1 physically interacts with and promotes the transcriptional activity of ATF4 (FOXO1 and ATF4 cooperate to increase glucose levels and decrease glucose tolerance)
  • ATF4 activates BGLAP in osteoblasts and indian hedgehog (IHH) in chondrocytes
  • transcriptional repressor of ATF4 during UV stress (binds to critical elements in the ATF4 promoter, resulting in its transcriptional repression)
  • VIM, a leucine zipper-containing intermediate filament protein, suppresses ATF4-dependent osteocalcin (OCN) transcription and osteoblast differentiation
  • FAM175B interaction with ATF4 is necessary and essential for the cytoprotective function of FAM175B following oxidative stress
  • APLN is down-regulated by ATF4 via the pro-apoptotic MAPK14 pathway under endoplasmic reticulum (ER) stress
  • TBL2 interacts with PKR-like ER-resident kinase (EIF2AK3), and under ER stress, it mediates protein expression of activating transcription factor 4 (ATF4)
  • under ER stress, TBL2 participates in ATF4 translation through its association with the mRNA
  • role of ATF4 in the SESN2 gene upregulation induced by mitochondrial dysfunction
  • ATF4 could maintain SREBF1 protein stability by directly activating the expression of USP7 which deubiquitinates SREBF1 and increases its protein content in cell
  • chenodeoxycholic acid (CDCA) regulation of FGF21 transcription is mediated at least partially by an EIF2A-dependent increase in ATF4 expression
  • beneficial role of hypothalamic ATF4/ATG5 axis in the regulation of energy expenditure, obesity, and obesity-related metabolic disorders
  • among UPR-related transcription factors, XBP1 upregulated ACTN2, whereas XBP1, ATF4 and ATF6 downregulated ACTN3 promoter activity
    • cell & other
  • activation for a tax responsive enhancer element B67 in the long terminal repeat of human T cell leukemia virus type I
    • REGULATION
    Other transcriptionally regulated in response to UV-C and ER stress, suggesting that there is a transcriptional repressor(s) and activator(s) that contributes to ATF4 expression
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in gastric cancer
    constitutional     --over  
    increased ATF4 expression is both necessary for upregulation of DDIT4 expression in response to ER stress and sufficient to upregulate expression of the protein
    constitutional     --low  
    loss of ATF4 delays skeletal muscle atrophy induced by fasting or immobilization
    constitutional     --low  
    resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera
    Susceptibility to schizophrenia in male patients
    Variant & Polymorphism SNP increasing the risk of schizophrenia in male patients
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    abrogation of ATF4 expression significantly inhibited tumour growth
    cancer  
    ATF4 antagonists would be worth investigating for anti-tumour effects
    cancer  
    ATF4 and HMOX1 are potential targets for therapeutic intervention in solid tumors
    obesity  
    ATF4/ATG5 axis in the hypothalamus may be a new potential therapeutic target for treating obesity and obesity-related metabolic diseases
    digestiveliver 
    may be considered a therapeutic target for non-alcoholic fatty liver disease (NAFLD)
    ANIMAL & CELL MODELS
  • Atf4 knockout mice exhibit severe microphthalmia
  • ATF4-deficient mouse neurons exhibit markedly reduced levels of PUMA expression and cell death (