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

Article Bibliography

Pubmed ID	Last Year	Title	Authors
1283316	1992	Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).	Aman P et al
8125258	1994	CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest.	Barone MV et al
7588595	1995	Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153).	Batchvarova N et al
1840554	1991	Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells.	Cao Z et al
8336711	1993	Regulation of the C/EBP-related gene gadd153 by glucose deprivation.	Carlson SG et al
10233889	1999	Regulated expression and functional role of the transcription factor CHOP (GADD153) in erythroid growth and differentiation.	Coutts M et al
8510758	1993	Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.	Crozat A et al
10713066	2000	Novel interaction between the transcription factor CHOP (GADD153) and the ribosomal protein FTE/S3a modulates erythropoiesis.	Cui K et al
9804754	1998	The role of C/EBP genes in adipocyte differentiation.	Darlington GJ et al
2573827	1989	Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents.	Fornace AJ Jr et al
12169678	2002	A novel type of EWS-CHOP fusion gene in two cases of myxoid liposarcoma.	Hosaka T et al
7805034	1995	Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.	Knight JC et al
9786841	1998	Biological role of the CCAAT/enhancer-binding protein family of transcription factors.	Lekstrom-Himes J et al
11896599	2002	Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice.	Pérez-Mancera PA et al
11162437	2000	A novel FUS/CHOP chimera in myxoid liposarcoma.	Panagopoulos I et al
1339368	1992	Isolation, characterization and chromosomal localization of the human GADD153 gene.	Park JS et al
1617653	1992	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 et al
7503811	1993	Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.	Rabbitts TH et al
1547942	1992	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 et al
8657121	1996	Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element.	Ubeda M et al
9649432	1998	Identification of novel stress-induced genes downstream of chop.	Wang XZ et al
8754828	1996	Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).	Wang XZ et al
7531665	1995	Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins.	Yeh WC et al
9531536	1998	CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.	Zinszner H et al

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
38474084	2024	Integrated Bioinformatics Analysis Identified ASNS and DDIT3 as the Therapeutic Target in Castrate-Resistant Prostate Cancer.	0
38475919	2024	C/EBPα-p30 confers AML cell susceptibility to the terminal unfolded protein response and resistance to Venetoclax by activating DDIT3 transcription.	0
38671504	2024	Deciphering the role of FUS::DDIT3 expression and tumor microenvironment in myxoid liposarcoma development.	0
38726820	2024	A study on expression of GRP78 and CHOP in neutrophil endoplasmic reticulum and their relationship with neutrophil apoptosis in the development of sepsis.	0
38474084	2024	Integrated Bioinformatics Analysis Identified ASNS and DDIT3 as the Therapeutic Target in Castrate-Resistant Prostate Cancer.	0
38475919	2024	C/EBPα-p30 confers AML cell susceptibility to the terminal unfolded protein response and resistance to Venetoclax by activating DDIT3 transcription.	0
38671504	2024	Deciphering the role of FUS::DDIT3 expression and tumor microenvironment in myxoid liposarcoma development.	0
38726820	2024	A study on expression of GRP78 and CHOP in neutrophil endoplasmic reticulum and their relationship with neutrophil apoptosis in the development of sepsis.	0
36946083	2023	Some Macrophages With High Expression of CHOP Undergo Necroptosis in Chronic Rhinosinusitis.	0
37894865	2023	Endoplasmic Reticulum Stress Promotes the Expression of TNF-α in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1α and MAPK/NF-κB Pathways.	3
37957724	2023	CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns.	0
36946083	2023	Some Macrophages With High Expression of CHOP Undergo Necroptosis in Chronic Rhinosinusitis.	0
37894865	2023	Endoplasmic Reticulum Stress Promotes the Expression of TNF-α in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1α and MAPK/NF-κB Pathways.	3
37957724	2023	CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns.	0
33856595	2022	CHOP Increases TRIB3-Dependent miR-208 Expression to Potentiate Vascular Smooth Muscle Cell Proliferation and Migration by Downregulating TIMP3 in Atherosclerosis.	3

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/ddit3-(dna-damage-inducible-transcript-3)