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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic thymus       highly Digestive stomach       highly Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     highly Connective bone       Lymphoid         Muscular striatum skeletal   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)
	DDIT3 and KAT2A cooperatively up-regulate TNFRSF10A and TNFRSF10B
	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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed diabete     therapeutic potential of CHOP inhibition in the management of diabetic cardiovascular complications including diabetic cardiomyopathy digestive liver   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)