DDIT3

This gene encodes a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, such as C/EBP and LAP (liver activator protein), and preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis, is activated by endoplasmic reticulum stress, and promotes apoptosis. Fusion of this gene and FUS on chromosome 16 or EWSR1 on chromosome 22 induced by translocation generates chimeric proteins in myxoid liposarcomas or Ewing sarcoma. Multiple alternatively spliced transcript variants encoding two isoforms with different length have been identified. [provided by RefSeq, Aug 2010]

DNA Damage Inducible Transcript 3

Multifunctional transcription factor in endoplasmic reticulum (ER) stress response (PubMed:15322075, PubMed:15775988, PubMed:19672300).

Plays an essential role in the response to a wide variety of cell stresses and induces cell cycle arrest and apoptosis in response to ER stress (PubMed:15322075, PubMed:15775988).

Plays a dual role both as an inhibitor of CCAAT/enhancer-binding protein (C/EBP) function and as an activator of other genes (By similarity).

Acts as a dominant-negative regulator of C/EBP-induced transcription: dimerizes with members of the C/EBP family, impairs their association with C/EBP binding sites in the promoter regions, and inhibits the expression of C/EBP regulated genes (By similarity).

Positively regulates the transcription of TRIB3, IL6, IL8, IL23, TNFRSF10B/DR5, PPP1R15A/GADD34, BBC3/PUMA, BCL2L11/BIM and ERO1L (PubMed:15775988, PubMed:17709599, PubMed:22761832, PubMed:20876114).

Negatively regulates; expression of BCL2 and MYOD1, ATF4-dependent transcriptional activation of asparagine synthetase (ASNS), CEBPA-dependent transcriptional activation of hepcidin (HAMP) and CEBPB-mediated expression of peroxisome proliferator-activated receptor gamma (PPARG) (PubMed:18940792, PubMed:19672300, PubMed:20829347).

Together with ATF4, mediates ER-mediated cell death by promoting expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the unfolded protein response (UPR) in response to ER stress (By similarity).

Inhibits the canonical Wnt signaling pathway by binding to TCF7L2/TCF4, impairing its DNA-binding properties and repressing its transcriptional activity (PubMed:16434966).

Plays a regulatory role in the inflammatory response through the induction of caspase-11 (CASP4/CASP11) which induces the activation of caspase-1 (CASP1) and both these caspases increase the activation of pro-IL1B to mature IL1B which is involved in the inflammatory response (By similarity).

Acts as a major regulator of postnatal neovascularization through regulation of endothelial nitric oxide synthase (NOS3)-related signaling (By similarity).

Anterior/posterior axis specification Source: BHF-UCL
ATF6-mediated unfolded protein response Source: ParkinsonsUK-UCL
Blood vessel maturation Source: Ensembl
Cell cycle arrest Source: CACAO
Cell redox homeostasis Source: MGI
Cellular response to DNA damage stimulus Source: ProtInc
Endoplasmic reticulum unfolded protein response Source: UniProtKB
ER overload response Source: GO_Central
Establishment of protein localization to mitochondrion Source: Ensembl
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: UniProtKB
Intrinsic apoptotic signaling pathway in response to nitrosative stress Source: Ensembl
Negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
Negative regulation of cold-induced thermogenesis Source: YuBioLab
Negative regulation of CREB transcription factor activity Source: ParkinsonsUK-UCL
Negative regulation of determination of dorsal identity Source: BHF-UCL
Negative regulation of DNA-binding transcription factor activity Source: BHF-UCL
Negative regulation of fat cell differentiation Source: Ensembl
Negative regulation of interferon-gamma production Source: ARUK-UCL
Negative regulation of interleukin-17 production Source: ARUK-UCL
Negative regulation of interleukin-4 production Source: ARUK-UCL
Negative regulation of myoblast differentiation Source: Ensembl
Negative regulation of NF-kappaB transcription factor activity Source: ARUK-UCL
Negative regulation of protein kinase B signaling Source: ParkinsonsUK-UCL
Negative regulation of RNA polymerase II regulatory region sequence-specific DNA binding Source: ParkinsonsUK-UCL
Negative regulation of transcription, DNA-templated Source: UniProtKB
Negative regulation of transcription by RNA polymerase II Source: ParkinsonsUK-UCL
PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
Positive regulation of DNA-binding transcription factor activity Source: CAFA
Positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
Positive regulation of interleukin-8 production Source: UniProtKB
Positive regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
Positive regulation of neuron apoptotic process Source: UniProtKB
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: NTNU_SB
Positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
Proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
Regulation of autophagy Source: UniProtKB
Regulation of transcription, DNA-templated Source: UniProtKB
Regulation of transcription by RNA polymerase II Source: MGI
Regulation of transcription from RNA polymerase II promoter in response to stress Source: BHF-UCL
Release of sequestered calcium ion into cytosol Source: Ensembl
Response to endoplasmic reticulum stress Source: UniProtKB
Response to starvation Source: Ensembl
Response to unfolded protein Source: UniProtKB
Sensory perception of sound Source: Ensembl
Wnt signaling pathway Source: UniProtKB-KW

Cytoplasm; Nucleus. Present in the cytoplasm under non-stressed conditions and ER stress leads to its nuclear accumulation.

Myxoid liposarcoma (MXLIPO):
The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving DDIT3 has been found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with FUS (PubMed:7503811). A soft tissue tumor that tends to occur in the limbs (especially the thigh) of patients ranging in age from 35 to 55 years. It is defined by the presence of a hypocellular spindle cell proliferation set in a myxoid background, often with mucin pooling. Lipoblasts tend to be small and often monovacuolated and to cluster around vessels or at the periphery of the lesion.

Ubiquitinated, leading to its degradation by the proteasome.
Phosphorylation at serine residues by MAPK14 enhances its transcriptional activation activity while phosphorylation at serine residues by CK2 inhibits its transcriptional activation activity.