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P35639

- DDIT3_MOUSE

UniProt

P35639 - DDIT3_MOUSE

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Protein

DNA damage-inducible transcript 3 protein

Gene

Ddit3

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- 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. Acts as a major regulator of postnatal neovascularization through regulation of endothelial nitric oxide synthase (NOS3)-related signaling.11 Publications

GO - Molecular functioni

  1. DNA binding Source: MGI
  2. sequence-specific DNA binding Source: InterPro
  3. sequence-specific DNA binding transcription factor activity Source: MGI

GO - Biological processi

  1. apoptotic process Source: UniProtKB
  2. blood vessel maturation Source: UniProtKB
  3. cell cycle arrest Source: UniProtKB-KW
  4. cell redox homeostasis Source: Ensembl
  5. endoplasmic reticulum unfolded protein response Source: MGI
  6. ER overload response Source: MGI
  7. intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: UniProtKB
  8. mRNA transcription from RNA polymerase II promoter Source: Ensembl
  9. negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
  10. negative regulation of determination of dorsal identity Source: BHF-UCL
  11. negative regulation of myoblast differentiation Source: UniProtKB
  12. negative regulation of sequence-specific DNA binding transcription factor activity Source: Ensembl
  13. negative regulation of transcription, DNA-templated Source: UniProtKB
  14. positive regulation of interleukin-8 production Source: Ensembl
  15. positive regulation of neuron apoptotic process Source: UniProtKB
  16. positive regulation of transcription, DNA-templated Source: UniProtKB
  17. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
  18. proteasome-mediated ubiquitin-dependent protein catabolic process Source: Ensembl
  19. regulation of transcription, DNA-templated Source: UniProtKB
  20. regulation of transcription involved in anterior/posterior axis specification Source: BHF-UCL
  21. release of sequestered calcium ion into cytosol Source: UniProtKB
  22. response to endoplasmic reticulum stress Source: UniProtKB
  23. response to starvation Source: UniProtKB
  24. Wnt signaling pathway Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator, Repressor

Keywords - Biological processi

Apoptosis, Cell cycle, Growth arrest, Stress response, Transcription, Transcription regulation, Unfolded protein response, Wnt signaling pathway

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiREACT_32838. ATF6-alpha activates chaperone genes.
REACT_90370. ATF4 activates genes.

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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 10

Organism-specific databases

MGIiMGI:109247. Ddit3.

Subcellular locationi

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

GO - Cellular componenti

  1. late endosome Source: MGI
  2. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi14 – 141S → A: Loss of phosphorylation. 1 Publication
Mutagenesisi15 – 151S → A: Loss of phosphorylation. 1 Publication
Mutagenesisi30 – 301S → A: Loss of phosphorylation. 1 Publication
Mutagenesisi31 – 311S → A: Loss of phosphorylation. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 168168DNA damage-inducible transcript 3 proteinPRO_0000076643Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei14 – 141Phosphoserine; by CK21 Publication
Modified residuei15 – 151Phosphoserine; by CK21 Publication
Modified residuei30 – 301Phosphoserine; by CK21 Publication
Modified residuei31 – 311Phosphoserine; by CK21 Publication
Modified residuei78 – 781Phosphoserine; by MAPK141 Publication
Modified residuei81 – 811Phosphoserine; by MAPK141 Publication

Post-translational modificationi

Ubiquitinated, leading to its degradation by the proteasome.By similarity
Phosphorylation at serine residues by MAPK14 enhances its transcriptional activation activity while phosphorylation at serine residues by CK2 inhibits its transcriptional activation activity.2 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP35639.
PRIDEiP35639.

PTM databases

PhosphoSiteiP35639.

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.6 Publications

Gene expression databases

BgeeiP35639.
CleanExiMM_DDIT3.
ExpressionAtlasiP35639. baseline and differential.
GenevestigatoriP35639.

Interactioni

Subunit structurei

Heterodimer. Interacts with TCF7L2/TCF4, EP300/P300, HDAC5 and HDAC6. Interacts with TRIB3 which blocks its association with EP300/P300. Interacts with FOXO3, CEBPB and ATF4 (By similarity). Interacts with HDAC1.By similarity1 Publication

Protein-protein interaction databases

BioGridi199078. 2 interactions.
DIPiDIP-60705N.

Structurei

3D structure databases

ProteinModelPortaliP35639.
SMRiP35639. Positions 93-156.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini98 – 16164bZIPPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni10 – 2617N-terminalBy similarityAdd
BLAST
Regioni10 – 189Interaction with TRIB3By similarity
Regioni100 – 12930Basic motifPROSITE-ProRule annotationAdd
BLAST
Regioni133 – 14715Leucine-zipperPROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi92 – 976Poly-Glu

Domaini

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

Sequence similaritiesi

Belongs to the bZIP family.Curated
Contains 1 bZIP (basic-leucine zipper) domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiNOG279524.
GeneTreeiENSGT00390000006305.
HOGENOMiHOG000089934.
HOVERGENiHBG051328.
InParanoidiP35639.
KOiK04452.
OMAiDRMVNLH.
OrthoDBiEOG7QC7Z1.
PhylomeDBiP35639.
TreeFamiTF105006.

Family and domain databases

InterProiIPR004827. bZIP.
IPR016670. DNA_damage_induc_transcript_3.
[Graphical view]
PANTHERiPTHR16833. PTHR16833. 1 hit.
PIRSFiPIRSF016571. C/EBPzeta_CHOP_DDIT3. 1 hit.
SMARTiSM00338. BRLZ. 1 hit.
[Graphical view]
PROSITEiPS50217. BZIP. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P35639-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MAAESLPFTL ETVSSWELEA WYEDLQEVLS SDEIGGTYIS SPGNEEEESK
60 70 80 90 100
TFTTLDPASL AWLTEEPGPT EVTRTSQSPR SPDSSQSSMA QEEEEEEQGR
110 120 130 140 150
TRKRKQSGQC PARPGKQRMK EKEQENERKV AQLAEENERL KQEIERLTRE
160
VETTRRALID RMVSLHQA
Length:168
Mass (Da):19,189
Last modified:June 1, 1994 - v1
Checksum:iCA423B79512F33AB
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti34 – 341I → N in AAH13718. (PubMed:15489334)Curated

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X67083 mRNA. Translation: CAA47465.1.
BC013718 mRNA. Translation: AAH13718.1.
CCDSiCCDS24236.1.
PIRiS26148.
RefSeqiNP_001277112.1. NM_001290183.1.
NP_031863.3. NM_007837.4.
XP_006513260.1. XM_006513197.1.
XP_006513261.1. XM_006513198.1.
UniGeneiMm.110220.

Genome annotation databases

EnsembliENSMUST00000026475; ENSMUSP00000026475; ENSMUSG00000025408.
GeneIDi13198.
KEGGimmu:13198.
UCSCiuc007hiy.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X67083 mRNA. Translation: CAA47465.1 .
BC013718 mRNA. Translation: AAH13718.1 .
CCDSi CCDS24236.1.
PIRi S26148.
RefSeqi NP_001277112.1. NM_001290183.1.
NP_031863.3. NM_007837.4.
XP_006513260.1. XM_006513197.1.
XP_006513261.1. XM_006513198.1.
UniGenei Mm.110220.

3D structure databases

ProteinModelPortali P35639.
SMRi P35639. Positions 93-156.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 199078. 2 interactions.
DIPi DIP-60705N.

Chemistry

BindingDBi P35639.
ChEMBLi CHEMBL2146304.

PTM databases

PhosphoSitei P35639.

Proteomic databases

MaxQBi P35639.
PRIDEi P35639.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000026475 ; ENSMUSP00000026475 ; ENSMUSG00000025408 .
GeneIDi 13198.
KEGGi mmu:13198.
UCSCi uc007hiy.2. mouse.

Organism-specific databases

CTDi 1649.
MGIi MGI:109247. Ddit3.

Phylogenomic databases

eggNOGi NOG279524.
GeneTreei ENSGT00390000006305.
HOGENOMi HOG000089934.
HOVERGENi HBG051328.
InParanoidi P35639.
KOi K04452.
OMAi DRMVNLH.
OrthoDBi EOG7QC7Z1.
PhylomeDBi P35639.
TreeFami TF105006.

Enzyme and pathway databases

Reactomei REACT_32838. ATF6-alpha activates chaperone genes.
REACT_90370. ATF4 activates genes.

Miscellaneous databases

NextBioi 283336.
PROi P35639.
SOURCEi Search...

Gene expression databases

Bgeei P35639.
CleanExi MM_DDIT3.
ExpressionAtlasi P35639. baseline and differential.
Genevestigatori P35639.

Family and domain databases

InterProi IPR004827. bZIP.
IPR016670. DNA_damage_induc_transcript_3.
[Graphical view ]
PANTHERi PTHR16833. PTHR16833. 1 hit.
PIRSFi PIRSF016571. C/EBPzeta_CHOP_DDIT3. 1 hit.
SMARTi SM00338. BRLZ. 1 hit.
[Graphical view ]
PROSITEi PS50217. BZIP. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "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., Habener J.F.
    Genes Dev. 6:439-453(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION.
    Strain: Swiss.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: Czech II.
    Tissue: Mammary tumor.
  3. "Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase."
    Wang X.Z., Ron D.
    Science 272:1347-1349(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-78 AND SER-81.
  4. "C/EBP homologous protein (CHOP) up-regulates IL-6 transcription by trapping negative regulating NF-IL6 isoform."
    Hattori T., Ohoka N., Hayashi H., Onozaki K.
    FEBS Lett. 541:33-39(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  5. "CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation."
    Ubeda M., Habener J.F.
    J. Biol. Chem. 278:40514-40520(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-14; SER-15; SER-30 AND SER-31, MUTAGENESIS OF SER-14; SER-15; SER-30 AND SER-31.
  6. "CCAAT/enhancer binding protein homologous protein (DDIT3) induces osteoblastic cell differentiation."
    Pereira R.C., Delany A.M., Canalis E.
    Endocrinology 145:1952-1960(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  7. "CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum."
    Marciniak S.J., Yun C.Y., Oyadomari S., Novoa I., Zhang Y., Jungreis R., Nagata K., Harding H.P., Ron D.
    Genes Dev. 18:3066-3077(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. "TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death."
    Ohoka N., Yoshii S., Hattori T., Onozaki K., Hayashi H.
    EMBO J. 24:1243-1255(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  9. "C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation."
    Endo M., Mori M., Akira S., Gotoh T.
    J. Immunol. 176:6245-6253(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.
  10. "Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis."
    Li G., Mongillo M., Chin K.T., Harding H., Ron D., Marks A.R., Tabas I.
    J. Cell Biol. 186:783-792(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.
  11. "Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling."
    Woo C.W., Cui D., Arellano J., Dorweiler B., Harding H., Fitzgerald K.A., Ron D., Tabas I.
    Nat. Cell Biol. 11:1473-1480(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  12. "Molecular mechanisms of the LPS-induced non-apoptotic ER stress-CHOP pathway."
    Nakayama Y., Endo M., Tsukano H., Mori M., Oike Y., Gotoh T.
    J. Biochem. 147:471-483(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.
  13. "Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA."
    Galehdar Z., Swan P., Fuerth B., Callaghan S.M., Park D.S., Cregan S.P.
    J. Neurosci. 30:16938-16948(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.
  14. "Stress-induced C/EBP homology protein (CHOP) represses MyoD transcription to delay myoblast differentiation."
    Alter J., Bengal E.
    PLoS ONE 6:E29498-E29498(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, INDUCTION, INTERACTION WITH HDAC1.
  15. "C/EBP homologous protein-10 (CHOP-10) limits postnatal neovascularization through control of endothelial nitric oxide synthase gene expression."
    Loinard C., Zouggari Y., Rueda P., Ramkhelawon B., Cochain C., Vilar J., Recalde A., Richart A., Charue D., Duriez M., Mori M., Arenzana-Seisdedos F., Levy B.I., Heymes C., Silvestre J.S.
    Circulation 125:1014-1026(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.

Entry informationi

Entry nameiDDIT3_MOUSE
AccessioniPrimary (citable) accession number: P35639
Secondary accession number(s): Q91YW9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: October 29, 2014
This is version 119 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3