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P35639

- DDIT3_MOUSE

UniProt

P35639 - DDIT3_MOUSE

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
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    • History
      Entry version 118 (01 Oct 2014)
      Sequence version 1 (01 Jun 1994)
      Previous versions | rss
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    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. protein binding Source: UniProtKB
    3. sequence-specific DNA binding Source: InterPro
    4. 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

    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

    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

    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

    ArrayExpressiP35639.
    BgeeiP35639.
    CleanExiMM_DDIT3.
    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 104-152.
    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

    MAAESLPFTL ETVSSWELEA WYEDLQEVLS SDEIGGTYIS SPGNEEEESK    50
    TFTTLDPASL AWLTEEPGPT EVTRTSQSPR SPDSSQSSMA QEEEEEEQGR 100
    TRKRKQSGQC PARPGKQRMK EKEQENERKV AQLAEENERL KQEIERLTRE 150
    VETTRRALID RMVSLHQA 168
    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 104-152.
    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

    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

    ArrayExpressi P35639.
    Bgeei P35639.
    CleanExi MM_DDIT3.
    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

    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 1, 2014
    This is version 118 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