P35638 (DDIT3_HUMAN) 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

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	169 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. Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.14 Ref.15 Ref.16 Ref.18
Subunit structure	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. Ref.8 Ref.9 Ref.10 Ref.12 Ref.15 Ref.18
Subcellular location	Cytoplasm. Nucleus. Note: Present in the cytoplasm under non-stressed conditions and ER stress leads to its nuclear accumulation. Ref.10 Ref.15 Ref.18
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.13 Ref.15
Domain	The N-terminal region is necessary for its proteasomal degradation, transcriptional activity and interaction with EP300/P300.
Post-translational modification	Ubiquitinated, leading to its degradation by the proteasome. Ref.10 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.
Involvement in disease	A chromosomal aberration involving DDIT3 is found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with FUS.
Sequence similarities	Belongs to the bZIP family. Contains 1 bZIP (basic-leucine zipper) domain.
Sequence caution	The sequence AAB27103.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Growth arrest Stress response Transcription Transcription regulation Unfolded protein response Wnt signaling pathway
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Disease	Proto-oncogene
Ligand	DNA-binding
Molecular function	Activator Repressor
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW activation of signaling protein activity involved in unfolded protein response Traceable author statement. Source: Reactome cell cycle arrest Inferred from electronic annotation. Source: UniProtKB-KW cell redox homeostasis Inferred from direct assay PubMed 14667815. Source: MGI intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Inferred from direct assay Ref.12Ref.15. Source: UniProtKB mRNA transcription from RNA polymerase II promoter Inferred from direct assay PubMed 14667815. Source: MGI negative regulation of canonical Wnt receptor signaling pathway Inferred from sequence or structural similarity Ref.9. Source: BHF-UCL negative regulation of determination of dorsal identity Inferred from direct assay Ref.9. Source: BHF-UCL negative regulation of sequence-specific DNA binding transcription factor activity Inferred from direct assay Ref.9. Source: BHF-UCL negative regulation of transcription, DNA-dependent Inferred from direct assay Ref.12. Source: UniProtKB positive regulation of interleukin-8 production Inferred from mutant phenotype Ref.15. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype PubMed 22065586. Source: BHF-UCL proteasomal ubiquitin-dependent protein catabolic process Inferred from direct assay Ref.10. Source: UniProtKB regulation of DNA-dependent transcription in response to stress Traceable author statement PubMed 19816510. Source: BHF-UCL regulation of transcription involved in anterior/posterior axis specification Inferred from sequence or structural similarity Ref.9. Source: BHF-UCL response to DNA damage stimulus Traceable author statement Ref.1. Source: ProtInc
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	DNA binding Inferred from direct assay Ref.12. Source: UniProtKB sequence-specific DNA binding Inferred from electronic annotation. Source: InterPro sequence-specific DNA binding transcription factor activity Non-traceable author statement Ref.2. Source: ProtInc transcription corepressor activity Traceable author statement Ref.3. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 169	169	DNA damage-inducible transcript 3 protein		PRO_0000076642
Regions
	Domain	99 – 162	64	bZIP
	Region	10 – 26	17	N-terminal
	Region	10 – 18	9	Interaction with TRIB3
	Region	101 – 130	30	Basic motif By similarity
	Region	134 – 148	15	Leucine-zipper By similarity
	Compositional bias	93 – 97	5	Poly-Glu
Amino acid modifications
	Modified residue	14	1	Phosphoserine; by CK2 By similarity
	Modified residue	15	1	Phosphoserine; by CK2 By similarity
	Modified residue	30	1	Phosphoserine; by CK2 By similarity
	Modified residue	31	1	Phosphoserine; by CK2 By similarity
	Modified residue	79	1	Phosphoserine; by MAPK14 By similarity
	Modified residue	82	1	Phosphoserine; by MAPK14 By similarity
Natural variations
	Natural variant	115	1	A → V in a colorectal cancer sample; somatic mutation. Ref.19		VAR_036000
Experimental info
	Sequence conflict	10 – 14	5	FGTLS → SDTV in AAB22646. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P35638 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: 31905293FB1FBBE2	FASTA	169	19,175
	10 20 30 40 50 60 MAAESLPFSF GTLSSWELEA WYEDLQEVLS SDENGGTYVS PPGNEEEESK IFTTLDPASL 70 80 90 100 110 120 AWLTEEEPEP AEVTSTSQSP HSPDSSQSSL AQEEEEEDQG RTRKRKQSGH SPARAGKQRM 130 140 150 160 KEKEQENERK VAQLAEENER LKQEIERLTR EVEATRRALI DRMVNLHQA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation, characterization and chromosomal localization of the human GADD153 gene." Park J.S., Luethy J.D., Wang M.G., Fargnoli J., Fornace A.J. Jr., McBride O.W., Holbrook N.J. Gene 116:259-267(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma." Crozat A., Aman P., Mandahl N., Ron D. Nature 363:640-644(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma." Rabbitts T.H., Forster A., Larson R., Nathan P. Nat. Genet. 4:175-180(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION WITH FUS.
[4]	NIEHS SNPs program Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"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]. Tissue: Muscle.
[6]	"Roles of CHOP/GADD153 in endoplasmic reticulum stress." Oyadomari S., Mori M. Cell Death Differ. 11:381-389(2004) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[7]	"CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells." Yamaguchi H., Wang H.G. J. Biol. Chem. 279:45495-45502(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, INTERACTION WITH TRIB3.
[9]	"The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals." Horndasch M., Lienkamp S., Springer E., Schmitt A., Pavenstaedt H., Walz G., Gloy J. Oncogene 25:3397-3407(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TCF7L2.
[10]	"Critical and functional regulation of CHOP (C/EBP homologous protein) through the N-terminal portion." Ohoka N., Hattori T., Kitagawa M., Onozaki K., Hayashi H. J. Biol. Chem. 282:35687-35694(2007) [PubMed] [Europe PMC] [Abstract] Cited for: N-TERMINAL REGION, SUBCELLULAR LOCATION, INTERACTION WITH TRIB3; EP300; HDAC1; HDAC5 AND HDAC6, UBIQUITINATION, PROTEASOMAL DEGRADATION.
[11]	"CHOP transcription factor mediates IL-8 signaling in cystic fibrosis bronchial epithelial cells." Vij N., Amoako M.O., Mazur S., Zeitlin P.L. Am. J. Respir. Cell Mol. Biol. 38:176-184(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." Su N., Kilberg M.S. J. Biol. Chem. 283:35106-35117(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ATF4.
[13]	"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.
[14]	"ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity." Oliveira S.J., Pinto J.P., Picarote G., Costa V.M., Carvalho F., Rangel M., de Sousa M., de Almeida S.F. PLoS ONE 4:E6618-E6618(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor gamma." Park S.H., Choi H.J., Yang H., Do K.H., Kim J., Lee D.W., Moon Y. J. Biol. Chem. 285:35330-35339(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CEBPB, INDUCTION.
[16]	"Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression." Goodall J.C., Wu C., Zhang Y., McNeill L., Ellis L., Saudek V., Gaston J.S. Proc. Natl. Acad. Sci. U.S.A. 107:17698-17703(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[17]	"CHOP is a multifunctional transcription factor in the ER stress response." Nishitoh H. J. Biochem. 151:217-219(2012) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[18]	"CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress." Ghosh A.P., Klocke B.J., Ballestas M.E., Roth K.A. PLoS ONE 7:E39586-E39586(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH FOXO3, SUBCELLULAR LOCATION.
[19]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] VAL-115.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Cross-references

Sequence databases
EMBL GenBank DDBJ	S40706 mRNA. Translation: AAB22646.1. S62138 mRNA. Translation: AAB27103.1. Sequence problems. AY880949 Genomic DNA. Translation: AAW56077.1. BC003637 mRNA. Translation: AAH03637.1.
IPI	IPI00019956.
PIR	JC1169. S33798.
RefSeq	NP_001181986.1. NM_001195057.1. NP_004074.2. NM_004083.5.
UniGene	Hs.505777.
3D structure databases
ProteinModelPortal	P35638.
ModBase	Search...
Protein-protein interaction databases
IntAct	P35638. 15 interactions.
MINT	MINT-1434413.
STRING	9606.ENSP00000340671.
PTM databases
PhosphoSite	P35638.
Polymorphism databases
DMDM	544022.
Proteomic databases
PaxDb	P35638.
PRIDE	P35638.
Protocols and materials databases
DNASU	1649.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000346473; ENSP00000340671; ENSG00000175197. ENST00000547303; ENSP00000447188; ENSG00000175197.
GeneID	1649.
KEGG	hsa:1649.
UCSC	uc001soi.3. human.
Organism-specific databases
CTD	1649.
GeneCards	GC12M057910.
HGNC	HGNC:2726. DDIT3.
MIM	126337. gene+phenotype.
neXtProt	NX_P35638.
PharmGKB	PA27193.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG279524.
HOGENOM	HOG000089934.
HOVERGEN	HBG051328.
InParanoid	P35638.
KO	K04452.
OrthoDB	EOG480HZ0.
PhylomeDB	P35638.
Enzyme and pathway databases
Pathway_Interaction_DB	p38alphabetadownstreampathway. Signaling mediated by p38-alpha and p38-beta.
Reactome	REACT_116125. Disease.
Gene expression databases
ArrayExpress	P35638.
Bgee	P35638.
CleanEx	HS_DDIT3.
Genevestigator	P35638.
GermOnline	ENSG00000175197. Homo sapiens.
Family and domain databases
InterPro	IPR004827. bZIP. IPR016670. DNA_damage_induc_transcript_3. [Graphical view]
PANTHER	PTHR16833. PTHR16833. 1 hit.
Pfam	PF07716. bZIP_2. 1 hit. [Graphical view]
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
ChiTaRS	DDIT3. human.
GenomeRNAi	1649.
NextBio	6792.
SOURCE	Search...

Entry information

Entry name

DDIT3_HUMAN

Accession

Primary (citable) accession number: P35638

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	May 1, 2013
This is version 128 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.