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DDIT3 (DNA damage inducible transcript 3)

Identity

Other namesCHOP (C/EBP homologous protein)
CHOP-10 (C/EBP homologous protein 10)
GADD153 (Growth arrest and DNA damage inducible gene 153)
C/EBP zeta (CCAAT/enhancer binding protein zeta)
HGNC (Hugo) DDIT3
LocusID (NCBI) 1649
Location 12q13.3
Location_base_pair Starts at 57910371 and ends at 57914300 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The gene has 4 exons (94 bp, 48 bp, 167 bp and 586 bp). The start codon is in the exon 3. The total genomic sequence spanning the DDIT3 gene is approx. 3 Kb.
Transcription Transcript lenght: 1,1 Kb.

Protein

 
Description 169 amino acids, 29 Kda. DDIT3 contains a carboxy-terminal region (bZIP) formed by a DNA-binding basic domain and a leucine zipper dimerization domain.
Expression DDIT3 is expressed ubiquitously. It is usually expressed at undetectable levels and its expression is induced by cellular stress.
Localisation Nuclear.
Function DDIT3 does not form homodimers and it functions as a dominant negative C/EBP forming heterodimers with other C/EBP members and preventing their binding to C/EBP sequences in the DNA. DDIT3 is implicated in adipogenesis, erythropoiesis, in the induction of growth arrest and in the endoplasmic reticulum stress response.
Homology DDIT3 belongs to the CCAAT/enhancer binding protein (C/EBP) family of transcription factors and it has been found to have high homology in hamster, rat and mouse.

Mutations

Germinal In the mouse, germine mutation in the ddit3 gene produces a decrease in the programmed cell death induced by perturbation in the endoplasmic reticulum function. On the other hand, while DDIT3 inhibits adipogenesis in 3T3-L1 preadipocytes, transgenic mice expressing DDIT3 from a housekeeping promoter display normal adipogenesis.

Implicated in

Note The DDIT3 gene is implicated in two chromosomal translocations associated to the myxoid liposarcoma (MLS). These fusion proteins generated as a result of chromosomal rearragements are used to monitor diagnosis and treatment.
 
  
Entity t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/DDIT3.
Disease Myxoid liposarcoma (MLS).
Hybrid/Mutated Gene 9 different types of fusions between the genes FUS and DDIT3 have been reported. The most frequent rearragements join the exons 5, 7 or 8 of FUS with the exon 2 of DDIT3.
Oncogenesis The unequivocally relation between FUS/DDIT3 and the MLS was shown by the generation of a transgenic mouse model expressing FUS/DDIT3 from a housekeeping promoter.
  
Entity t(12;22)(q13;q12) chromosomal translocation. It produces the fusion protein EWS/DDIT3.
Disease Myxoid liposarcoma (MLS).
Hybrid/Mutated Gene 2 different types of fusions between the genes EWS and DDIT3 have been reported. The first one joins the exon 7 of EWS with the exon 2 of DDIT3, while the second one joins the exon 10 of EWS with the exon 2 of DDIT3.
  

Breakpoints

 

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004 rhabID5004 blad5001

External links

Nomenclature
HGNC (Hugo)DDIT3   2726
Cards
AtlasDDIT3ID80
Entrez_Gene (NCBI)DDIT3  1649  DNA-damage-inducible transcript 3
GeneCards (Weizmann)DDIT3
Ensembl (Hinxton)ENSG00000175197 [Gene_View]  chr12:57910371-57914300 [Contig_View]  DDIT3 [Vega]
ICGC DataPortalENSG00000175197
cBioPortalDDIT3
AceView (NCBI)DDIT3
Genatlas (Paris)DDIT3
WikiGenes1649
SOURCE (Princeton)NM_001195053 NM_001195054 NM_001195055 NM_001195056 NM_001195057 NM_004083
Genomic and cartography
GoldenPath (UCSC)DDIT3  -  12q13.3   chr12:57910371-57914300 -  12q13.1-q13.2   [Description]    (hg19-Feb_2009)
EnsemblDDIT3 - 12q13.1-q13.2 [CytoView]
Mapping of homologs : NCBIDDIT3 [Mapview]
OMIM126337   613488   
Gene and transcription
Genbank (Entrez)AA054097 AA476561 AI658803 AK316581 AV729744
RefSeq transcript (Entrez)NM_001195053 NM_001195054 NM_001195055 NM_001195056 NM_001195057 NM_004083
RefSeq genomic (Entrez)AC_000144 NC_000012 NC_018923 NG_027674 NT_029419 NW_001838060 NW_004929384
Consensus coding sequences : CCDS (NCBI)DDIT3
Cluster EST : UnigeneHs.505777 [ NCBI ]
CGAP (NCI)Hs.505777
Alternative Splicing : Fast-db (Paris)GSHG0007572
Alternative Splicing GalleryENSG00000175197
Gene ExpressionDDIT3 [ NCBI-GEO ]     DDIT3 [ SEEK ]   DDIT3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP35638 (Uniprot)
NextProtP35638  [Medical]
With graphics : InterProP35638
Splice isoforms : SwissVarP35638 (Swissvar)
Domaine pattern : Prosite (Expaxy)BZIP (PS50217)   
Domains : Interpro (EBI)bZIP [organisation]   DNA_damage_induc_transcript_3 [organisation]  
Related proteins : CluSTrP35638
Domain families : Pfam (Sanger)bZIP_2 (PF07716)   
Domain families : Pfam (NCBI)pfam07716   
Domain families : Smart (EMBL)BRLZ (SM00338)  
DMDM Disease mutations1649
Blocks (Seattle)P35638
Human Protein AtlasENSG00000175197 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP35638
HPRD00529
IPIIPI00019956   IPI01021592   IPI00798213   
Protein Interaction databases
DIP (DOE-UCLA)P35638
IntAct (EBI)P35638
FunCoupENSG00000175197
BioGRIDDDIT3
InParanoidP35638
Interologous Interaction database P35638
IntegromeDBDDIT3
STRING (EMBL)DDIT3
Ontologies - Pathways
Ontology : AmiGOblood vessel maturation  DNA binding  sequence-specific DNA binding transcription factor activity  transcription corepressor activity  protein binding  nucleus  nucleoplasm  late endosome  regulation of transcription, DNA-templated  cellular response to DNA damage stimulus  ER overload response  response to unfolded protein  activation of signaling protein activity involved in unfolded protein response  cell cycle arrest  transcription factor binding  Wnt signaling pathway  endoplasmic reticulum unfolded protein response  positive regulation of interleukin-8 production  response to endoplasmic reticulum stress  response to starvation  mRNA transcription from RNA polymerase II promoter  proteasome-mediated ubiquitin-dependent protein catabolic process  negative regulation of sequence-specific DNA binding transcription factor activity  positive regulation of neuron apoptotic process  sequence-specific DNA binding  regulation of DNA-templated transcription in response to stress  cellular protein metabolic process  regulation of transcription involved in anterior/posterior axis specification  cell redox homeostasis  negative regulation of myoblast differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  release of sequestered calcium ion into cytosol  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  negative regulation of canonical Wnt signaling pathway  negative regulation of determination of dorsal identity  
Ontology : EGO-EBIblood vessel maturation  DNA binding  sequence-specific DNA binding transcription factor activity  transcription corepressor activity  protein binding  nucleus  nucleoplasm  late endosome  regulation of transcription, DNA-templated  cellular response to DNA damage stimulus  ER overload response  response to unfolded protein  activation of signaling protein activity involved in unfolded protein response  cell cycle arrest  transcription factor binding  Wnt signaling pathway  endoplasmic reticulum unfolded protein response  positive regulation of interleukin-8 production  response to endoplasmic reticulum stress  response to starvation  mRNA transcription from RNA polymerase II promoter  proteasome-mediated ubiquitin-dependent protein catabolic process  negative regulation of sequence-specific DNA binding transcription factor activity  positive regulation of neuron apoptotic process  sequence-specific DNA binding  regulation of DNA-templated transcription in response to stress  cellular protein metabolic process  regulation of transcription involved in anterior/posterior axis specification  cell redox homeostasis  negative regulation of myoblast differentiation  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  release of sequestered calcium ion into cytosol  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress  negative regulation of canonical Wnt signaling pathway  negative regulation of determination of dorsal identity  
Pathways : BIOCARTAp38 MAPK Signaling Pathway [Genes]   
Pathways : KEGGMAPK signaling pathway    Protein processing in endoplasmic reticulum    Non-alcoholic fatty liver disease (NAFLD)    Transcriptional misregulation in cancer   
Protein Interaction DatabaseDDIT3
Wikipedia pathwaysDDIT3
Gene fusion - rearrangments
Rearrangement : COSMICDDIT3 [12q13.3]  -  FUS [16p11.2]  
  [COSF831] 
Rearrangement : COSMICEWSR1 [22q12.2]  -  DDIT3 [12q13.3]  
  [COSF269] [COSF270] [COSF271] [COSF272] [COSF273] [COSF274] [COSF281] [COSF282] [COSF284] 
  [COSF328] [COSF837] 
Rearrangement : COSMICFUS [16p11.2]  -  DDIT3 [12q13.3]  
  [COSF1018] [COSF1019] [COSF291] [COSF292] [COSF293] [COSF294] [COSF297] [COSF298] [COSF300] 
  [COSF301] [COSF302] [COSF303] [COSF304] [COSF342] [COSF832] [COSF833] [COSF834] 
  [COSF835] [COSF836] [COSF867] [COSF868] 
Rearrangement : TICdbEWSR1 [22q12.2]  -  DDIT3 [17q21.2]
Rearrangement : TICdbFUS [16p11.2]  -  DDIT3 [7p21.2]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)DDIT3
snp3D : Map Gene to Disease1649
SNP (GeneSNP Utah)DDIT3
SNP : HGBaseDDIT3
Genetic variants : HAPMAPDDIT3
Exome VariantDDIT3
1000_GenomesDDIT3 
ICGC programENSG00000175197 
Cancer Gene: CensusDDIT3 
Somatic Mutations in Cancer : COSMICDDIT3 
CONAN: Copy Number AnalysisDDIT3 
Mutations and Diseases : HGMDDDIT3
Genomic VariantsDDIT3  DDIT3 [DGVbeta]
dbVarDDIT3
ClinVarDDIT3
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM126337    613488   
MedgenDDIT3
GENETestsDDIT3
Disease Genetic AssociationDDIT3
Huge Navigator DDIT3 [HugePedia]  DDIT3 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneDDIT3
Homology/Alignments : Family Browser (UCSC)DDIT3
Phylogenetic Trees/Animal Genes : TreeFamDDIT3
Chemical/Protein Interactions : CTD1649
Chemical/Pharm GKB GenePA27193
Clinical trialDDIT3
Cancer Resource (Charite)ENSG00000175197
Other databases
Probes
Litterature
PubMed166 Pubmed reference(s) in Entrez
CoreMineDDIT3
iHOPDDIT3
OncoSearchDDIT3

Bibliography

-
 
Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).
Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Willn H, Rydholm A, Mitelman F
Genes, chromosomes & cancer. 1992 ; 5 (4) : 278-285.
PMID 1283316
 
CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest.
Barone MV, Crozat A, Tabaee A, Philipson L, Ron D
Genes & development. 1994 ; 8 (4) : 453-464.
PMID 8125258
 
Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153).
Batchvarova N, Wang XZ, Ron D
The EMBO journal. 1995 ; 14 (19) : 4654-4661.
PMID 7588595
 
Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells.
Cao Z, Umek RM, McKnight SL
Genes & development. 1991 ; 5 (9) : 1538-1552.
PMID 1840554
 
Regulation of the C/EBP-related gene gadd153 by glucose deprivation.
Carlson SG, Fawcett TW, Bartlett JD, Bernier M, Holbrook NJ
Molecular and cellular biology. 1993 ; 13 (8) : 4736-4744.
PMID 8336711
 
Regulated expression and functional role of the transcription factor CHOP (GADD153) in erythroid growth and differentiation.
Coutts M, Cui K, Davis KL, Keutzer JC, Sytkowski AJ
Blood. 1999 ; 93 (10) : 3369-3378.
PMID 10233889
 
Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.
Crozat A, Aman P, Mandahl N, Ron D
Nature. 1993 ; 363 (6430) : 640-644.
PMID 8510758
 
Novel interaction between the transcription factor CHOP (GADD153) and the ribosomal protein FTE/S3a modulates erythropoiesis.
Cui K, Coutts M, Stahl J, Sytkowski AJ
The Journal of biological chemistry. 2000 ; 275 (11) : 7591-7596.
PMID 10713066
 
The role of C/EBP genes in adipocyte differentiation.
Darlington GJ, Ross SE, MacDougald OA
The Journal of biological chemistry. 1998 ; 273 (46) : 30057-30060.
PMID 9804754
 
Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents.
Fornace AJ Jr, Nebert DW, Hollander MC, Luethy JD, Papathanasiou M, Fargnoli J, Holbrook NJ
Molecular and cellular biology. 1989 ; 9 (10) : 4196-4203.
PMID 2573827
 
A novel type of EWS-CHOP fusion gene in two cases of myxoid liposarcoma.
Hosaka T, Nakashima Y, Kusuzaki K, Murata H, Nakayama T, Nakamata T, Aoyama T, Okamoto T, Nishijo K, Araki N, Tsuboyama T, Nakamura T, Toguchida J
The Journal of molecular diagnostics : JMD. 2002 ; 4 (3) : 164-171.
PMID 12169678
 
Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.
Knight JC, Renwick PJ, Cin PD, Van den Berghe H, Fletcher CD
Cancer research. 1995 ; 55 (1) : 24-27.
PMID 7805034
 
Biological role of the CCAAT/enhancer-binding protein family of transcription factors.
Lekstrom-Himes J, Xanthopoulos KG
The Journal of biological chemistry. 1998 ; 273 (44) : 28545-28548.
PMID 9786841
 
Fusion of the EWS and CHOP genes in myxoid liposarcoma.
Panagopoulos I, Hglund M, Mertens F, Mandahl N, Mitelman F, Aman P
Oncogene. 1996 ; 12 (3) : 489-494.
PMID 8637704
 
Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia.
Panagopoulos I, Lassen C, Isaksson M, Mitelman F, Mandahl N, Aman P
Oncogene. 1997 ; 15 (11) : 1357-1362.
PMID 9315104
 
A novel FUS/CHOP chimera in myxoid liposarcoma.
Panagopoulos I, Mertens F, Isaksson M, Mandahl N
Biochemical and biophysical research communications. 2000 ; 279 (3) : 838-845.
PMID 11162437
 
Isolation, characterization and chromosomal localization of the human GADD153 gene.
Park JS, Luethy JD, Wang MG, Fargnoli J, Fornace AJ Jr, McBride OW, Holbrook NJ
Gene. 1992 ; 116 (2) : 259-267.
PMID 1339368
 
The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice.
Prez-Losada J, Pintado B, Gutirrez-Adn A, Flores T, Baares-Gonzlez B, del Campo JC, Martn-Martn JF, Battaner E, Snchez-Garca I
Oncogene. 2000 ; 19 (20) : 2413-2422.
PMID 10828883
 
Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma.
Prez-Losada J, Snchez-Martn M, Rodrguez-Garca MA, Prez-Mancera PA, Pintado B, Flores T, Battaner E, Snchez-Garia I
Oncogene. 2000 ; 19 (52) : 6015-6022.
PMID 11146553
 
Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice.
Prez-Mancera PA, Prez-Losada J, Snchez-Martn M, Rodrguez-Garca MA, Flores T, Battaner E, Gutirrez-Adn A, Pintado B, Snchez-Garca I
Oncogene. 2002 ; 21 (11) : 1679-1684.
PMID 11896599
 
Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose-regulated proteins.
Price BD, Calderwood SK
Cancer research. 1992 ; 52 (13) : 3814-3817.
PMID 1617653
 
Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.
Rabbitts TH, Forster A, Larson R, Nathan P
Nature genetics. 1993 ; 4 (2) : 175-180.
PMID 7503811
 
CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription.
Ron D, Habener JF
Genes & development. 1992 ; 6 (3) : 439-453.
PMID 1547942
 
Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element.
Ubeda M, Wang XZ, Zinszner H, Wu I, Habener JF, Ron D
Molecular and cellular biology. 1996 ; 16 (4) : 1479-1489.
PMID 8657121
 
Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).
Wang XZ, Lawson B, Brewer JW, Zinszner H, Sanjay A, Mi LJ, Boorstein R, Kreibich G, Hendershot LM, Ron D
Molecular and cellular biology. 1996 ; 16 (8) : 4273-4280.
PMID 8754828
 
Identification of novel stress-induced genes downstream of chop.
Wang XZ, Kuroda M, Sok J, Batchvarova N, Kimmel R, Chung P, Zinszner H, Ron D
The EMBO journal. 1998 ; 17 (13) : 3619-3630.
PMID 9649432
 
Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins.
Yeh WC, Cao Z, Classon M, McKnight SL
Genes & development. 1995 ; 9 (2) : 168-181.
PMID 7531665
 
CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.
Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D
Genes & development. 1998 ; 12 (7) : 982-995.
PMID 9531536
 
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Contributor(s)

Written07-2004Pedro A Pérez-Mancera, Isidro Sánchez-Garcìa
Laboratorio 13, Instituto de Biologia Molecular y Celular del Cancer (IBMCC), Centro de Investigacion del Cancer, Campus Unamuno, 37.007-Salamanca, Spain

Citation

This paper should be referenced as such :
Pérez-Mancera, PA ; Sanchez-Garcia, I
DDIT3 (DNA damage inducible transcript 3)
Atlas Genet Cytogenet Oncol Haematol. 2004;8(3):232-235.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/DDIT3ID80.html

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