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Protein

DNA damage-inducible transcript 3 protein

Gene

DDIT3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Multifunctional transcription factor in ER stress response. 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. Plays a dual role both as an inhibitor of CCAAT/enhancer-binding protein (C/EBP) function and as an activator of other genes. 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. Positively regulates the transcription of TRIB3, IL6, IL8, IL23, TNFRSF10B/DR5, PPP1R15A/GADD34, BBC3/PUMA, BCL2L11/BIM and ERO1L. 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). Inhibits the canonical Wnt signaling pathway by binding to TCF7L2/TCF4, impairing its DNA-binding properties and repressing its transcriptional activity. 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.9 Publications

GO - Molecular functioni

  • cAMP response element binding protein binding Source: ParkinsonsUK-UCL
  • DNA binding Source: UniProtKB
  • DNA binding transcription factor activity Source: ParkinsonsUK-UCL
  • leucine zipper domain binding Source: ParkinsonsUK-UCL
  • protein heterodimerization activity Source: ParkinsonsUK-UCL
  • protein homodimerization activity Source: CAFA
  • RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • RNA polymerase II transcription factor activity, sequence-specific DNA binding Source: NTNU_SB
  • transcriptional activator activity, RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • transcription corepressor activity Source: ProtInc
  • transcription factor binding Source: BHF-UCL
  • transcription regulatory region DNA binding Source: ParkinsonsUK-UCL
  • transcription regulatory region sequence-specific DNA binding Source: ParkinsonsUK-UCL

GO - Biological processi

  • 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
  • ER overload response Source: Ensembl
  • 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
  • mRNA transcription by RNA polymerase II Source: MGI
  • negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
  • 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 myoblast differentiation Source: Ensembl
  • 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 neuron apoptotic process Source: ParkinsonsUK-UCL
  • 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
  • protein oligomerization Source: CAFA
  • regulation of DNA-templated transcription in response to stress Source: BHF-UCL
  • regulation of transcription, DNA-templated Source: UniProtKB
  • regulation of transcription involved in anterior/posterior axis specification 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
  • Wnt signaling pathway Source: UniProtKB-KW

Keywordsi

Molecular functionActivator, DNA-binding, Repressor
Biological processApoptosis, Cell cycle, Growth arrest, Stress response, Transcription, Transcription regulation, Unfolded protein response, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-380994 ATF4 activates genes
R-HSA-381183 ATF6 (ATF6-alpha) activates chaperone genes
SignaLinkiP35638
SIGNORiP35638

Names & Taxonomyi

Protein namesi
Recommended name:
DNA damage-inducible transcript 3 protein
Short name:
DDIT-3
Alternative name(s):
C/EBP zeta
C/EBP-homologous protein
Short name:
CHOP
C/EBP-homologous protein 10
Short name:
CHOP-10
CCAAT/enhancer-binding protein homologous protein
Growth arrest and DNA damage-inducible protein GADD153
Gene namesi
Name:DDIT3
Synonyms:CHOP, CHOP10, GADD153
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000175197.10
HGNCiHGNC:2726 DDIT3
MIMi126337 gene
neXtProtiNX_P35638

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Myxoid liposarcoma (MXLIPO)1 Publication
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).1 Publication
Disease descriptionA 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.
See also OMIM:613488

Keywords - Diseasei

Proto-oncogene

Organism-specific databases

DisGeNETi1649
MalaCardsiDDIT3
MIMi613488 phenotype
OpenTargetsiENSG00000175197
Orphaneti99967 Myxoid/round cell liposarcoma
PharmGKBiPA27193

Chemistry databases

ChEMBLiCHEMBL3351207

Polymorphism and mutation databases

BioMutaiDDIT3
DMDMi544022

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000766421 – 169DNA damage-inducible transcript 3 proteinAdd BLAST169

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei14Phosphoserine; by CK2By similarity1
Modified residuei15Phosphoserine; by CK2By similarity1
Modified residuei30Phosphoserine; by CK2By similarity1
Modified residuei31Phosphoserine; by CK2By similarity1
Modified residuei79Phosphoserine; by MAPK14By similarity1
Modified residuei82Phosphoserine; by MAPK14By similarity1

Post-translational modificationi

Ubiquitinated, leading to its degradation by the proteasome.1 Publication
Phosphorylation at serine residues by MAPK14 enhances its transcriptional activation activity while phosphorylation at serine residues by CK2 inhibits its transcriptional activation activity.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP35638
PeptideAtlasiP35638
PRIDEiP35638

PTM databases

iPTMnetiP35638
PhosphoSitePlusiP35638

Expressioni

Inductioni

By oxidative stress, amino-acid deprivation, hypoxia and ER stress. During ER stress, induced by a EIF2AK3/ATF4 pathway and/or ERN1/ATF6 pathway. Expression is suppressed by TLR-TRIF signaling pathway during prolonged ER stress.2 Publications

Gene expression databases

BgeeiENSG00000175197
CleanExiHS_DDIT3
ExpressionAtlasiP35638 baseline and differential
GenevisibleiP35638 HS

Organism-specific databases

HPAiHPA058416
HPA068416

Interactioni

Subunit structurei

Heterodimer. Interacts with TCF7L2/TCF4, EP300/P300, HDAC1, HDAC5 and HDAC6. Interacts with TRIB3 which blocks its association with EP300/P300. Interacts with FOXO3, CEBPB and ATF4.6 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • cAMP response element binding protein binding Source: ParkinsonsUK-UCL
  • leucine zipper domain binding Source: ParkinsonsUK-UCL
  • protein heterodimerization activity Source: ParkinsonsUK-UCL
  • protein homodimerization activity Source: CAFA
  • transcription factor binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi108016, 75 interactors
CORUMiP35638
DIPiDIP-41589N
IntActiP35638, 52 interactors
STRINGi9606.ENSP00000447803

Structurei

3D structure databases

DisProtiDP00624
ProteinModelPortaliP35638
SMRiP35638
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini99 – 162bZIPPROSITE-ProRule annotationAdd BLAST64

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni10 – 26N-terminalAdd BLAST17
Regioni10 – 18Interaction with TRIB39
Regioni101 – 130Basic motifPROSITE-ProRule annotationAdd BLAST30
Regioni134 – 148Leucine-zipperPROSITE-ProRule annotationAdd BLAST15

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi93 – 97Poly-Glu5

Domaini

The N-terminal region is necessary for its proteasomal degradation, transcriptional activity and interaction with EP300/P300.

Sequence similaritiesi

Belongs to the bZIP family.Curated

Phylogenomic databases

eggNOGiENOG410ISXY Eukaryota
ENOG41127XB LUCA
GeneTreeiENSGT00390000006305
HOGENOMiHOG000089934
HOVERGENiHBG051328
InParanoidiP35638
KOiK04452
OMAiWELEAWY
OrthoDBiEOG091G0UKC
PhylomeDBiP35638
TreeFamiTF105006

Family and domain databases

InterProiView protein in InterPro
IPR004827 bZIP
IPR016670 DNA_damage_induc_transcript_3
PANTHERiPTHR16833 PTHR16833, 1 hit
PfamiView protein in Pfam
PF07716 bZIP_2, 1 hit
PIRSFiPIRSF016571 C/EBPzeta_CHOP_DDIT3, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P35638-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAAESLPFSF GTLSSWELEA WYEDLQEVLS SDENGGTYVS PPGNEEEESK
60 70 80 90 100
IFTTLDPASL AWLTEEEPEP AEVTSTSQSP HSPDSSQSSL AQEEEEEDQG
110 120 130 140 150
RTRKRKQSGH SPARAGKQRM KEKEQENERK VAQLAEENER LKQEIERLTR
160
EVEATRRALI DRMVNLHQA
Length:169
Mass (Da):19,175
Last modified:June 1, 1994 - v1
Checksum:i31905293FB1FBBE2
GO
Isoform 2 (identifier: P35638-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MELVPATPHYPADVLFQTDPTAEM

Show »
Length:192
Mass (Da):21,700
Checksum:i1C569DBC247612EB
GO

Sequence cautioni

The sequence AAB27103 differs from that shown. Contaminating sequence. Sequence of unknown origin in the N-terminal part.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti10 – 14FGTLS → SDTV in AAB22646 (PubMed:1339368).Curated5

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_036000115A → V in a colorectal cancer sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0472771M → MELVPATPHYPADVLFQTDP TAEM in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S40706 mRNA Translation: AAB22646.1
S62138 mRNA Translation: AAB27103.1 Sequence problems.
AY461580 mRNA No translation available.
AY880949 Genomic DNA Translation: AAW56077.1
AC022506 Genomic DNA No translation available.
BC003637 mRNA Translation: AAH03637.1
CCDSiCCDS55838.1 [P35638-2]
CCDS8943.1 [P35638-1]
PIRiJC1169
S33798
RefSeqiNP_001181982.1, NM_001195053.1 [P35638-2]
NP_001181983.1, NM_001195054.1 [P35638-2]
NP_001181984.1, NM_001195055.1 [P35638-2]
NP_001181986.1, NM_001195057.1 [P35638-1]
NP_004074.2, NM_004083.5 [P35638-1]
UniGeneiHs.505777

Genome annotation databases

EnsembliENST00000346473; ENSP00000340671; ENSG00000175197 [P35638-1]
ENST00000547303; ENSP00000447188; ENSG00000175197 [P35638-1]
ENST00000551116; ENSP00000448665; ENSG00000175197 [P35638-2]
ENST00000552740; ENSP00000447803; ENSG00000175197 [P35638-2]
GeneIDi1649
KEGGihsa:1649
UCSCiuc009zps.4 human [P35638-1]

Keywords - Coding sequence diversityi

Alternative splicing, Chromosomal rearrangement, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiDDIT3_HUMAN
AccessioniPrimary (citable) accession number: P35638
Secondary accession number(s): F8VS99
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: April 25, 2018
This is version 180 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health