DDIT3 (DNA damage inducible transcript 3)

2004-07-01 Pedro A Pérez-Mancera , Isidro Sánchez-García Affiliation

Laboratorio 13, Instituto de Biologia Molecular y Celular del Cancer (IBMCC), Centro de Investigacion del Cancer, Campus Unamuno, 37.007-Salamanca, Spain

Identity

HGNC

DDIT3

LOCATION

12q13.3

LOCUSID

1649

ALIAS

AltDDIT3,C/EBPzeta,CEBPZ,CHOP,CHOP-10,CHOP10,GADD153

FUSION GENES

Show Gene Fusions

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.

Proteins

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 name

t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/DDIT3.

Disease

Myxoid liposarcoma (MLS).

Hybrid 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 name

t(12;22)(q13;q12) chromosomal translocation. It produces the fusion protein EWS/DDIT3.

Disease

Myxoid liposarcoma (MLS).

Hybrid 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

Bibliography

Pubmed ID	Last Year	Title	Authors

Other Information

Locus ID:

NCBI: 1649
MIM: 126337
HGNC: 2726
Ensembl: ENSG00000175197

Variants:

dbSNP: 1649
ClinVar: 1649
TCGA: ENSG00000175197
COSMIC: DDIT3

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000175197	ENST00000346473	P35638
ENSG00000175197	ENST00000346473	Q53YD1
ENSG00000175197	ENST00000547303	P35638
ENSG00000175197	ENST00000547303	Q53YD1
ENSG00000175197	ENST00000547526	F8W133
ENSG00000175197	ENST00000551116	P35638
ENSG00000175197	ENST00000552740	P35638
ENSG00000175197	ENST00000623876	P35638
ENSG00000175197	ENST00000623876	Q53YD1

Expression (GTEx)

100

150

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

Pathway	Source	External ID
MAPK signaling pathway	KEGG	ko04010
Apoptosis	KEGG	ko04210
MAPK signaling pathway	KEGG	hsa04010
Apoptosis	KEGG	hsa04210
Protein processing in endoplasmic reticulum	KEGG	ko04141
Protein processing in endoplasmic reticulum	KEGG	hsa04141
Transcriptional misregulation in cancer	KEGG	ko05202
Transcriptional misregulation in cancer	KEGG	hsa05202
Non-alcoholic fatty liver disease (NAFLD)	KEGG	hsa04932
Non-alcoholic fatty liver disease (NAFLD)	KEGG	ko04932
Metabolism of proteins	REACTOME	R-HSA-392499
Unfolded Protein Response (UPR)	REACTOME	R-HSA-381119
ATF6 (ATF6-alpha) activates chaperones	REACTOME	R-HSA-381033
ATF6 (ATF6-alpha) activates chaperone genes	REACTOME	R-HSA-381183
PERK regulates gene expression	REACTOME	R-HSA-381042
ATF4 activates genes	REACTOME	R-HSA-380994

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA448871	celecoxib	Chemical	Pathway	associated			22336956

References

Pubmed ID	Year	Title	Citations
14685163	2004	Roles of CHOP/GADD153 in endoplasmic reticulum stress.	814
19855386	2009	Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.	117
17686866	2007	West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis.	112
19723703	2010	Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways.	103
20876114	2010	Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression.	99
14630918	2004	Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation.	94
27211800	2016	The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress.	91
20430872	2010	CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis.	72
11805088	2002	Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP.	66
18940792	2008	C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.	61

Citation

Pedro A Pérez-Mancera ; Isidro Sánchez-García

DDIT3 (DNA damage inducible transcript 3)

Atlas Genet Cytogenet Oncol Haematol. 2004-07-01

Online version: http://atlasgeneticsoncology.org/gene/80/tumors-explorer/