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FLASH GENE
Symbol DDIT3 contributors: npt/shn - updated : 08-06-2015
HGNC name DNA-damage-inducible transcript 3
HGNC id 2726
Corresponding disease
DDIT3 myxoid liposarcoma
Location 12q13.3      Physical location : 57.910.372 - 57.914.300
Synonym name
  • C/EBP homologous protein
  • c/EBP-homologous protein 10
  • DNA damage-inducible transcript 3 protein
  • growth arrest and DNA-damage-inducible protein GADD153
  • CCAAT/enhancer-binding protein homologous protein
  • C/EBP zeta
  • Synonym symbol(s) CHOP, GADD153, D12S1943, CHOP10, CEBPZ, MGC4154, C/EBP zeta, DDIT-3
    DNA
    TYPE functioning gene
    STRUCTURE 3.93 kb     4 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • NR1H4/RXRA-binding site in the human DDIT3 promoter, demonstrating a highly conserved regulatory pathway
  • MAPPING cloned Y linked N status confirmed
    Map cen - D12S1644 - D12S1691 - DDIT3 DDIT3 - DD12S90 - D12S305 - qter
    Physical map
    NAB2 12q13.3-q14.1 NGFI-A binding protein 2 (EGR1 binding protein 2) STAT6 12q13.3-q14.1 signal transducer and activator of transcription 6, interleukin-4 induced LRP1 12q13.3 low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor) SHMT2 12q13.2 serine hydroxymethyltransferase 2 (mitochondrial) NXPH4 12q13.2 neurexophilin 4 LOC56901 12q13.2 NADH:ubiquinone oxidoreductase MLRQ subunit homolog MGC2793 12q13.2 hypothetical protein MGC2793 KIAA1002 12q13.2 Homo sapiens KIAA1002 protein (KIAA1002), mRNA. LOC338803 12q13.2 similar to RIKEN cDNA 1300003K24 INHBC 12q13.1 inhibin, beta C INHBE 12q13.2 inhibin, beta E GLI 12q13.3-q14.1 glioma-associated oncogene homolog (zinc finger protein) ARHGAP9 12q14 Rho GTPase activating protein 9 MARS 12q13.11-q14.3 methionine-tRNA synthetase DDIT3 12q13.1-q13.2 DNA-damage-inducible transcript 3 MBD6 12q13.2 methyl-CpG binding domain protein 6 DCTN2 12q13.2-q13.3 dynactin 2 (p50) KIF5A 12q13 kinesin family member 5A PIP5K2C 12q13.2 phosphatidylinositol-4-phosphate 5-kinase, type II, gamma FLJ34766 GEFT 12q13.2 RAC/CDC42 exchange factor SLC26A10 12q13 solute carrier family 26, member 10 GALGT 12q13.3 UDP-N-acetyl-alpha-D-galactosamine:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase (GalNAc-T) LOC390333 12 similar to ribosomal protein L13a; 60S ribosomal protein L13a; 23 kD highly basic protein OS-9 12q13 amplified in osteosarcoma CENTG1 12q13.3 centaurin, gamma 1 SAS 12q13-q14 sarcoma amplified sequence CDK4 12q14 cyclin-dependent kinase 4 LOC92979 12q13.2 hypothetical protein BC009489 CYP27B1 12q13-q14 cytochrome P450, family 27, subfamily B, polypeptide 1 METTL1 12q13 methyltransferase-like 1
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 splicing 924 - 169 - -
    4 splicing 910 - 169 - -
    also called variant 5/isoform 2
    3 splicing 1191 - 192 - -
    also called variant 4/isoform 1
    4 splicing 1005 - 192 - -
    also called variant 3/isoform 1
    4 splicing 1028 - 192 - -
    also called variant 2/isoform 1
    4 splicing 1081 - 192 - -
    also called variant 1/isoform 1
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus   highly
    Digestivestomach   highly
    Visualeye   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  highly
    Connectivebone   
    Lymphoid    
    Muscularstriatumskeletal highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • basic leucine zipper (bZIP) protein
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Ddit3, Mus musculus
    ortholog to Ddit3, Rattus norvegicus
    ortholog to ddit3, Danio rerio
    ortholog to DDIT3, Pan troglodytes
    Homologene
    FAMILY
  • CCAAT/enhancer-binding protein (C/EBP) family of transcription factors
  • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • dominant negative regulator of several C/EBP transcription factors, involved in erythroid growth and differentiation possibly through interaction with both C/EBP and non C/EBP family members
  • playing a role in the regulation of AKR1A1 expression in the liver
  • blocking adipogenesis, and inducing osteoblastogenesis
  • stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration
  • ER stress-DDIT3 pathway plays a role in neuronal apoptosis during the development of the brain
  • involved in DNA damage, growth arrest, and the induction of apoptosis after endoplasmic reticulum stress and nutrient deprivation
  • apoptosis-regulated gene, increasing during endoplasmic reticulum (ER) stress
  • plays a role in stretch-induced vascular smooth muscle cells apoptosis
  • functions as a dimer to inhibit the DNA-binding activity of C/EBP and liver-enriched activator protein
  • the elevated cellular DDIT3 levels could contribute to ER stress-mediated apoptosis after change of BRSK2 protein
  • role in the transcriptional regulation of metabolism
  • is not strictly an apoptotic regulator but carries out non-apoptotic physiological functions as well
  • is an important regulator of hepatic hepcidin expression in chronic liver disease
  • regulated expression of DDIT3 during obesity is critical for adaptation to chronic caloric excess and maintenance of energy homeostasis via integration of metabolic and immune systems
  • plays a crucial role in the pathogenesis of chronic kidney disease (CKD)-dependent vascular calcification
  • promotes liver damage during acute liver failure (ALF) through activation of ERO1A, a key mediator to link ER stress and ROS
  • induces cell death and inflammatory responses following saturated free fatty acid exposure by activating NFKB1 through a pathway involving IRAK2 expression
  • plays a vital role in the pathophysiology of nonalcoholic steatohepatitis (NASH) through induction of secreted factors that trigger inflammation and hepatocellular death via a signaling pathway specific to human hepatocytes
  • is the key signal for myocyte apoptosis and cardiac dysfunction induced by methylglyoxal (MGO)
  • NR1H4 and DDIT3 have critical functions in hepatic lipid metabolism
  • CELLULAR PROCESS cell life, cell death/apoptosis
    nucleotide, repair
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA PUMA promoter during endoplasmic reticulum stress (
    RNA
    small molecule
    protein
  • CCAAT/enhancer-binding protein beta, CEBPB (
  • activating transcription factor 3, ATF3 (
  • growth-promoting AP-1 transcription factor family, JunD, c-Jun, and c-Fos, to activate promoter elements in the somatostatin, JunD, and collagenase genes (
  • casein kinase II, CK2 (
  • CCAAT/enhancer binding protein (C/EBP), epsilon, CEBPE (
  • tribbles homolog 3 (Drosophila), TRB3 (
  • hypusination by DHPS is required for the ongoing production of proteins, particularly DDIT3, in response to ER stress in the beta cell
  • DDIT3 is a specific RNASEL target, and RNASEL is an essential regulator of adipogenesis via the regulation of DDIT3 mRNA
  • DDIT3, a protein known to regulate Ca2+ release from the ER during ER stress, amplifies NLRP3 inflammasome activation
  • LCN2 is a new DDIT3 target gene that mediates ER stress-induced apoptosis
  • PARM1 may regulate EIF2AK3, ATF6, and DDIT3 expression through BMP2 expression
  • necessary for suppression of genes encoding the transcriptional master regulators of lipid metabolism: CEBPA, PPARA, and SREBF1
  • induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis, and both ATF5 and DDIT3 have proapoptotic functions
  • FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (DDIT3)
  • BCL2L1 protein protects from DDIT3-dependent apoptosis during plasma cell differentiation
  • ERO1A, a target of DDIT3, is an important oxidizing enzyme that regulates reactive oxygen species (ROS), which play a prominent role in hepatocellular death during acute liver failure (ALF)
  • protects pancreatic beta-cells against ER stress-mediated apoptosis by up-regulating BIRC5 expression and down-regulating DDIT3 expression, which we termed as "positive and negative regulation
  • ELANE induces endothelial cell apoptosis by activating the EIF2AK3/DDIT3 branch of the unfolded protein response
  • NR1H4 controls DDIT3 expression in steatohepatitis
  • cell & other
    REGULATION
    induced by DNA -damage
    repressed by JDP2 functionally associated with HDAC3
    ASSOCIATED DISORDERS
    corresponding disease(s) DDIT3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    translocated with FUS in t(12;16)(q13;p11) and with ESWR1 in t(12;22)(q13;q12) in myxoid liposarcoma
    constitutional       loss of function
    in conjunction with a COMP mutation, may lead to aggravation of the skeletal phenotype via a potentially synergistic effect on endochondral ossification
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    diabete  
    therapeutic potential of CHOP inhibition in the management of diabetic cardiovascular complications including diabetic cardiomyopathy
    digestiveliver 
    targeting DDIT3/ERO1A signalling could be a novel therapeutic approach during acute liver failure (ALF)
    ANIMAL & CELL MODELS
  • Chop-null mice are resistant to fibrosis, which is a key risk factor for hepatocellular carcinoma (HCC)