P35639 (DDIT3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	Ddit3
Synonyms:	Chop, Chop10, Gadd153

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	168 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.1 Ref.4 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15
Subunit structure	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. Ref.14
Subcellular location	Cytoplasm. Nucleus. Note: Present in the cytoplasm under non-stressed conditions and ER stress leads to its nuclear accumulation. Ref.1 Ref.14
Induction	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. Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14
Domain	The N-terminal region is necessary for its proteasomal degradation, transcriptional activity and interaction with EP300/P300 By similarity.
Post-translational modification	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.
Sequence similarities	Belongs to the bZIP family. Contains 1 bZIP (basic-leucine zipper) domain.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Growth arrest Stress response Transcription Transcription regulation Unfolded protein response Wnt signaling pathway
Cellular component	Cytoplasm Nucleus
Ligand	DNA-binding
Molecular function	Activator Repressor
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ER overload response Inferred from mutant phenotype PubMed 11854325. Source: MGI Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW blood vessel maturation Inferred from mutant phenotype Ref.15. Source: UniProtKB cell cycle arrest Inferred from electronic annotation. Source: UniProtKB-KW cell redox homeostasis Inferred from electronic annotation. Source: Compara endoplasmic reticulum unfolded protein response Inferred from mutant phenotype Ref.7. Source: MGI intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Inferred from mutant phenotype Ref.13. Source: UniProtKB mRNA transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara negative regulation of canonical Wnt receptor signaling pathway Inferred from direct assay PubMed 16434966. Source: BHF-UCL negative regulation of determination of dorsal identity Inferred from direct assay PubMed 16434966. Source: BHF-UCL negative regulation of myoblast differentiation Inferred from mutant phenotype Ref.14. Source: UniProtKB negative regulation of sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara negative regulation of transcription, DNA-dependent Inferred from direct assay Ref.14. Source: UniProtKB positive regulation of interleukin-8 production Inferred from electronic annotation. Source: Compara positive regulation of neuron apoptotic process Inferred from mutant phenotype Ref.13. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara positive regulation of transcription, DNA-dependent Inferred from direct assay Ref.13. Source: UniProtKB proteasomal ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: Compara regulation of transcription involved in anterior/posterior axis specification Inferred from direct assay PubMed 16434966. Source: BHF-UCL release of sequestered calcium ion into cytosol Inferred from mutant phenotype Ref.10. Source: UniProtKB
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay Ref.14. Source: UniProtKB
Molecular_function	DNA binding Inferred from direct assay Ref.7. Source: MGI sequence-specific DNA binding Inferred from electronic annotation. Source: InterPro sequence-specific DNA binding transcription factor activity Inferred from mutant phenotype Ref.7. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 168	168	DNA damage-inducible transcript 3 protein		PRO_0000076643
Regions
	Domain	98 – 161	64	bZIP
	Region	10 – 26	17	N-terminal By similarity
	Region	10 – 18	9	Interaction with TRIB3 By similarity
	Region	100 – 129	30	Basic motif By similarity
	Region	133 – 147	15	Leucine-zipper By similarity
	Compositional bias	92 – 97	6	Poly-Glu
Amino acid modifications
	Modified residue	14	1	Phosphoserine; by CK2 Ref.5
	Modified residue	15	1	Phosphoserine; by CK2 Ref.5
	Modified residue	30	1	Phosphoserine; by CK2 Ref.5
	Modified residue	31	1	Phosphoserine; by CK2 Ref.5
	Modified residue	78	1	Phosphoserine; by MAPK14 Ref.3
	Modified residue	81	1	Phosphoserine; by MAPK14 Ref.3
Experimental info
	Mutagenesis	14	1	S → A: Loss of phosphorylation. Ref.5
	Mutagenesis	15	1	S → A: Loss of phosphorylation. Ref.5
	Mutagenesis	30	1	S → A: Loss of phosphorylation. Ref.5
	Mutagenesis	31	1	S → A: Loss of phosphorylation. Ref.5
	Sequence conflict	34	1	I → N in AAH13718. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P35639 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: CA423B79512F33AB	FASTA	168	19,189
	10 20 30 40 50 60 MAAESLPFTL ETVSSWELEA WYEDLQEVLS SDEIGGTYIS SPGNEEEESK TFTTLDPASL 70 80 90 100 110 120 AWLTEEPGPT EVTRTSQSPR SPDSSQSSMA QEEEEEEQGR TRKRKQSGQC PARPGKQRMK 130 140 150 160 EKEQENERKV AQLAEENERL KQEIERLTRE VETTRRALID RMVSLHQA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X67083 mRNA. Translation: CAA47465.1. BC013718 mRNA. Translation: AAH13718.1.
IPI	IPI00120656.
PIR	S26148.
RefSeq	NP_031863.3. NM_007837.3.
UniGene	Mm.110220.
3D structure databases
ProteinModelPortal	P35639.
SMR	P35639. Positions 104-149.
ModBase	Search...
PTM databases
PhosphoSite	P35639.
Proteomic databases
PRIDE	P35639.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000026475; ENSMUSP00000026475; ENSMUSG00000025408.
GeneID	13198.
KEGG	mmu:13198.
UCSC	uc007hiy.2. mouse.
Organism-specific databases
CTD	1649.
MGI	MGI:109247. Ddit3.
Phylogenomic databases
eggNOG	NOG279524.
GeneTree	ENSGT00390000006305.
HOGENOM	HOG000089934.
HOVERGEN	HBG051328.
InParanoid	P35639.
KO	K04452.
OMA	LPFSFGT.
OrthoDB	EOG480HZ0.
Gene expression databases
ArrayExpress	P35639.
Bgee	P35639.
CleanEx	MM_DDIT3.
Genevestigator	P35639.
GermOnline	ENSMUSG00000025408. Mus musculus.
Family and domain databases
InterPro	IPR004827. bZIP. IPR016670. DNA_damage_induc_transcript_3. [Graphical view]
PANTHER	PTHR16833. PTHR16833. 1 hit.
PIRSF	PIRSF016571. C/EBPzeta_CHOP_DDIT3. 1 hit.
SMART	SM00338. BRLZ. 1 hit. [Graphical view]
PROSITE	PS50217. BZIP. 1 hit. PS00036. BZIP_BASIC. False negative. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P35639.
NextBio	283336.
SOURCE	Search...

Entry information

Entry name

DDIT3_MOUSE

Accession

Primary (citable) accession number: P35639
Secondary accession number(s): Q91YW9

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	May 1, 2013
This is version 103 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program