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ATF3 (activating transcription factor 3)

Written2009-06Shigetaka Kitajima, Yujiro Tanaka, Junya Kawauchi
Biochemical Genetics, Medical Research Institute, Tokyo Medical, Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8510, Japan

(Note : for Links provided by Atlas : click)

Identity

Other aliasATF3deltaZip2
ATF3deltaZip2c
ATF3deltaZip3
HGNC (Hugo) ATF3
LocusID (NCBI) 467
Atlas_Id 719
Location 1q32.3  [Link to chromosome band 1q32]
Location_base_pair Starts at 212565334 and ends at 212620777 bp from pter ( according to hg19-Feb_2009)  [Mapping ATF3.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ATF3 (1q32.3) / CDH20 (18q21.33)ATF3 (1q32.3) / SNX1 (15q22.31)DAP3 (1q22) / ATF3 (1q32.3)
JAK1 (1p31.3) / ATF3 (1q32.3)NR6A1 (9q33.3) / ATF3 (1q32.3)RGS17 (6q25.2) / ATF3 (1q32.3)

DNA/RNA

 
Description The ATF3 gene spans a region of 55 Kb and has two major transcription start sites, each designated P1 and P2, respectively. The P1 and P2 transcripts differ in the first exon but share common exons 2, 3, and 4 encoding the same protein sequence.
Transcription Transcribed from centromere to telomere orientation. The P1 and P2 promoters are differentially activated by growth and stress stimuli.
Pseudogene Unknown.

Protein

Note atf3 protein represents one of the 53 basic leucine zipper (b-Zip) transcription factors in human and is composed of 181 amino acids with putative basic leucine zipper structure. The leucine zipper region is responsible for homo- or heterodimer formation with other member of bZip family proteins. One study reported that transcriptional activation or repression activity is located at both N- or C-terminal region, but the detailed mechanism of those activity remains elusive.
 
Description The P1 and P2 transcripts give rise to atf3 proteins of an identical sequence. These transcripts, however, are differentially spliced to give rise to full length and deltaZip or deltaZip2 proteins lacking the C-terminal dimerization domain.
Expression ATF3 is expressed ubiquitously but its level is maintained low in the absence of cellular stresses. Upon exposure to various conditions, such as hypoxia, DNA damaging agents (MMS, 5-FU, etoposide, ionizing radiation, UV irradiation), heat shock, cold shock, nutrient starvation, and serum stimulation, ATF3 is rapidly induced by transcriptional activation. Known upstream regulators of ATF3 include ATF4, HIF-1a, C/EBPb, and p53.
Localisation ATF3 proteins are localized in the nucleus.
Function ATF3 is a member of the CREB/ATF family of transcription factors and both homodimerize and heterodimerize with other members of CREB/ATF family, including C/EBPg, CHOP/DDIT3, ATF2, Jun, JunB, p21SNFT/JDP1, and Nrf2/NFE2L2.
ATF3 and various heterodimers containing ATF3 has been shown to bind to a consensus cAMP response element (5'-GTGACGT[AC][AG]-3') with varying affinities in vitro. ATF3 also interacts with other DNA binding proteins such as Elk1, Sp1, and Egr1 which might recruit ATF3 to promoters indirectly.
Increasing number of genes have been shown to be regulated by ATF3 (currently about 40 target genes are known). ATF3 plays an important role in repressing IL-6, IL-12, and other cytokine genes downstream of Toll-like receptor 4 (TLR4) thereby providing a negative feedback to contain excessive inflammatory responses. A splice variant of ATF3 (dZip2) forms complex with p65 subunit of NF-kB and inhibits recruitment of CBP, thus repressing inhibitors of apoptosis (IAPs) genes. ATF3 can also interfere with Nrf2-mediated gene activation by causing dissociation of CBP from Nrf2. Thus, it is likely that ATF3 is a regulator of stress response.
ATF3 is one of immediate early response genes and plays role in determining cell fate. However, its biological function of ATF3 in vivo remains largely elusive since targeted disruption of the ATF3 gene causes no obvious phenotype. Studies mostly carried out in vitro using established cancer cell lines show that ATF3 has dual functions in promoting either cell death or cell survival under different conditions. On one hand, the ATF3 gene is overexpressed in a large fraction of cancers including solid tumors in the breast, lungs, prostate, colon or Hodgkin Reed-Sternberg cells, suggesting that ATF3 may promote proliferation and/or survival of cancer cells. On the other, expression of ATF3 has been shown to cause cell death of various cancer cell lines in response to DNA damage, UV, or various anti-cancer drugs.
ATF3 is also proposed to be a causative gene in hypospadia.
Homology ATF3 share a highly homologous leucine zipper domain with other CREB/ATF family members. ATF3 has been found widely in vertebrates and there is also a paralogue of ATF3 called JDP2 which differ from ATF3 in the C-terminal region. Higher vertebrates have both ATF3 and JDP2 homologues, whereas Ciona intestinalis has only one copy of either ATF3 or JDP2 (it is not clear which). Drosophila melanogaster A3-3 share 55% identity with aa 81-149 of human ATF3 and is thought to be a fly homologue of ATF3/JDP2.

Mutations

Germinal Unknown.
Somatic Unknown.

Implicated in

Note
  
Entity Solid tumors and Hodgkin's disease
Note ATF3 is overexpressed in many cancer cells.
Disease ATF3 is overexpressed in a large fraction of various cancers including solid tumors in the breast, lungs, pancreas, and colon ATF3 is hyperactivated in most cells in Hodgkin's disease.
Overexpression of ATF3 in cancer cells have been proposed to promote proliferation and inhibit cell death.
Prognosis Over-expression of ATF3 in cancer cells correlates with higher incidence of metastasis and poor prognosis in human prostate cancer, breast cancer or murine melanoma.
Cytogenetics Unknown.
Hybrid/Mutated Gene Unknown.
Abnormal Protein Unknown.
Oncogenesis ATF3 is a major mediator of activated ras and express of ATF3 alone can cause mitogen-induce MAP kinase activation. ATF3 is overexpressed in a large fraction of cancer cells including various solid tumors and Hodgkin cells.
  
  
Entity Insulin resistance
Note Obese conditions activate the ATF3 gene in adipocytes thereby causing repression of GLUT4 gene and inhibition of gluconeogenetic pathway in liver cells.
Disease Obesity.
Prognosis Unknown.
Cytogenetics Unknown.
Hybrid/Mutated Gene Unknown.
Abnormal Protein Unknown.
  
  
Entity Congenital anomaly
Note ATF3 is up-regulated in the penile skin tissues of boys with hypospadias, suggesting a role for this transcription factor in the development of this abnormality. Because the etiology of hypospadias may include exposure to estrogenic compounds, the responsiveness of ATF3 to estrogen might be involved.
Disease Hypospadias.
Prognosis Unknown.
Cytogenetics Unknown.
Abnormal Protein Unknown.
  

Bibliography

The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer.
Bandyopadhyay S, Wang Y, Zhan R, Pai SK, Watabe M, Iiizumi M, Furuta E, Mohinta S, Liu W, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Commes T, Piquemal D, Hai T, Watabe K.
Cancer Res. 2006 Dec 15;66(24):11983-90.
PMID 17178897
 
Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias.
Beleza-Meireles A, Tohonen V, Soderhall C, Schwentner C, Radmayr C, Kockum I, Nordenskjold A.
Eur J Endocrinol. 2008 May;158(5):729-39.
PMID 18426833
 
ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms.
Chen BP, Liang G, Whelan J, Hai T.
J Biol Chem. 1994 Jun 3;269(22):15819-26.
PMID 7515060
 
Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4.
Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Roach JC, Kennedy K, Hai T, Bolouri H, Aderem A.
Nature. 2006 May 11;441(7090):173-8.
PMID 16688168
 
ATF3 and stress responses.
Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U.
Gene Expr. 1999;7(4-6):321-35.
PMID 10440233
 
An alternatively spliced isoform of transcriptional repressor ATF3 and its induction by stress stimuli.
Hashimoto Y, Zhang C, Kawauchi J, Imoto I, Adachi MT, Inazawa J, Amagasa T, Hai T, Kitajima S.
Nucleic Acids Res. 2002 Jun 1;30(11):2398-406.
PMID 12034827
 
Classical Hodgkin lymphoma is characterized by high constitutive expression of activating transcription factor 3 (ATF3), which promotes viability of Hodgkin/Reed-Sternberg cells.
Janz M, Hummel M, Truss M, Wollert-Wulf B, Mathas S, Johrens K, Hagemeier C, Bommert K, Stein H, Dorken B, Bargou RC.
Blood. 2006 Mar 15;107(6):2536-9. Epub 2005 Nov 1.
PMID 16263788
 
The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic beta-cell apoptosis.
Li D, Yin X, Zmuda EJ, Wolford CC, Dong X, White MF, Hai T.
Diabetes. 2008 Mar;57(3):635-44. Epub 2007 Dec 5.
PMID 18057093
 
ATF3 gene. Genomic organization, promoter, and regulation.
Liang G, Wolfgang CD, Chen BP, Chen TH, Hai T.
J Biol Chem. 1996 Jan 19;271(3):1695-701.
PMID 8576171
 
Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.
Miyazaki K, Inoue S, Yamada K, Watanabe M, Liu Q, Watanabe T, Adachi MT, Tanaka Y, Kitajima S.
Nucleic Acids Res. 2009 Apr;37(5):1438-51. Epub 2009 Jan 9.
PMID 19136462
 
Role of activating transcription factor 3 on TAp73 stability and apoptosis in paclitaxel-treated cervical cancer cells.
Oh YK, Lee HJ, Jeong MH, Rhee M, Mo JW, Song EH, Lim JY, Choi KH, Jo I, Park SI, Gao B, Kwon Y, Kim WH.
Mol Cancer Res. 2008 Jul;6(7):1232-49.
PMID 18644986
 
Adipocyte CREB promotes insulin resistance in obesity.
Qi L, Saberi M, Zmuda E, Wang Y, Altarejos J, Zhang X, Dentin R, Hedrick S, Bandyopadhyay G, Hai T, Olefsky J, Montminy M.
Cell Metab. 2009 Mar;9(3):277-86.
PMID 19254572
 
Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation.
Tamura K, Hua B, Adachi S, Guney I, Kawauchi J, Morioka M, Tamamori-Adachi M, Tanaka Y, Nakabeppu Y, Sunamori M, Sedivy JM, Kitajima S.
EMBO J. 2005 Jul 20;24(14):2590-601. Epub 2005 Jun 30.
PMID 15990869
 
Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.
Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K, Yonenobu K, Ochi T, Noguchi K.
Mol Cell Neurosci. 2000 Feb;15(2):170-82.
PMID 10673325
 
The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis.
Wang A, Arantes S, Yan L, Kiguchi K, McArthur MJ, Sahin A, Thames HD, Aldaz CM, Macleod MC.
BMC Cancer. 2008 Sep 22;8:268.
PMID 18808719
 
Transcriptional autorepression of the stress-inducible gene ATF3.
Wolfgang CD, Liang G, Okamoto Y, Allen AE, Hai T.
J Biol Chem. 2000 Jun 2;275(22):16865-70.
PMID 10748147
 
ATF3 regulates the stability of p53: a link to cancer.
Yan C, Boyd DD.
Cell Cycle. 2006 May;5(9):926-9. Epub 2006 May 1.
PMID 16628010
 

Citation

This paper should be referenced as such :
Kitajima, S ; Tanaka, Y ; Kawauchi, J
ATF3 (activating transcription factor 3)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(5):437-439.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ATF3ID719ch1q32.html


External links

Nomenclature
HGNC (Hugo)ATF3   785
Cards
AtlasATF3ID719ch1q32
Entrez_Gene (NCBI)ATF3  467  activating transcription factor 3
Aliases
GeneCards (Weizmann)ATF3
Ensembl hg19 (Hinxton)ENSG00000162772 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000162772 [Gene_View]  chr1:212565334-212620777 [Contig_View]  ATF3 [Vega]
ICGC DataPortalENSG00000162772
TCGA cBioPortalATF3
AceView (NCBI)ATF3
Genatlas (Paris)ATF3
WikiGenes467
SOURCE (Princeton)ATF3
Genetics Home Reference (NIH)ATF3
Genomic and cartography
GoldenPath hg38 (UCSC)ATF3  -     chr1:212565334-212620777 +  1q32.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ATF3  -     1q32.3   [Description]    (hg19-Feb_2009)
EnsemblATF3 - 1q32.3 [CytoView hg19]  ATF3 - 1q32.3 [CytoView hg38]
Mapping of homologs : NCBIATF3 [Mapview hg19]  ATF3 [Mapview hg38]
OMIM603148   
Gene and transcription
Genbank (Entrez)###############################################################################################################################################################################################################################################################
RefSeq transcript (Entrez)NM_001030287 NM_001040619 NM_001206484 NM_001206485 NM_001206486 NM_001206488 NM_001674 NM_004024
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ATF3
Cluster EST : UnigeneHs.460 [ NCBI ]
CGAP (NCI)Hs.460
Alternative Splicing GalleryENSG00000162772
Gene ExpressionATF3 [ NCBI-GEO ]   ATF3 [ EBI - ARRAY_EXPRESS ]   ATF3 [ SEEK ]   ATF3 [ MEM ]
Gene Expression Viewer (FireBrowse)ATF3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)467
GTEX Portal (Tissue expression)ATF3
Human Protein AtlasENSG00000162772-ATF3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP18847   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP18847  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP18847
Splice isoforms : SwissVarP18847
PhosPhoSitePlusP18847
Domaine pattern : Prosite (Expaxy)BZIP (PS50217)    BZIP_BASIC (PS00036)   
Domains : Interpro (EBI)AP-1    ATF3    bZIP   
Domain families : Pfam (Sanger)bZIP_1 (PF00170)   
Domain families : Pfam (NCBI)pfam00170   
Domain families : Smart (EMBL)BRLZ (SM00338)  
Conserved Domain (NCBI)ATF3
DMDM Disease mutations467
Blocks (Seattle)ATF3
SuperfamilyP18847
Human Protein Atlas [tissue]ENSG00000162772-ATF3 [tissue]
Peptide AtlasP18847
HPRD04395
IPIIPI00002502   IPI00556074   IPI01009242   IPI00642183   IPI00413177   IPI00385188   IPI00644308   
Protein Interaction databases
DIP (DOE-UCLA)P18847
IntAct (EBI)P18847
FunCoupENSG00000162772
BioGRIDATF3
STRING (EMBL)ATF3
ZODIACATF3
Ontologies - Pathways
QuickGOP18847
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  transcription regulatory region sequence-specific DNA binding  RNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding  transcription factor activity, sequence-specific DNA binding  transcription corepressor activity  protein binding  nucleus  nucleoplasm  nucleolus  gluconeogenesis  transcription from RNA polymerase II promoter  positive regulation of cell proliferation  cellular response to amino acid starvation  skeletal muscle cell differentiation  PERK-mediated unfolded protein response  identical protein binding  protein homodimerization activity  transcription regulatory region DNA binding  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance  negative regulation of ERK1 and ERK2 cascade  positive regulation of TRAIL-activated apoptotic signaling pathway  positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress  CHOP-ATF3 complex  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  transcription regulatory region sequence-specific DNA binding  RNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding  transcription factor activity, sequence-specific DNA binding  transcription corepressor activity  protein binding  nucleus  nucleoplasm  nucleolus  gluconeogenesis  transcription from RNA polymerase II promoter  positive regulation of cell proliferation  cellular response to amino acid starvation  skeletal muscle cell differentiation  PERK-mediated unfolded protein response  identical protein binding  protein homodimerization activity  transcription regulatory region DNA binding  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance  negative regulation of ERK1 and ERK2 cascade  positive regulation of TRAIL-activated apoptotic signaling pathway  positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress  CHOP-ATF3 complex  
Pathways : KEGGHTLV-I infection   
REACTOMEP18847 [protein]
REACTOME PathwaysR-HSA-380994 [pathway]   
NDEx NetworkATF3
Atlas of Cancer Signalling NetworkATF3
Wikipedia pathwaysATF3
Orthology - Evolution
OrthoDB467
GeneTree (enSembl)ENSG00000162772
Phylogenetic Trees/Animal Genes : TreeFamATF3
HOVERGENP18847
HOGENOMP18847
Homologs : HomoloGeneATF3
Homology/Alignments : Family Browser (UCSC)ATF3
Gene fusions - Rearrangements
Fusion : MitelmanATF3/CDH20 [1q32.3/18q21.33]  
Fusion : MitelmanDAP3/ATF3 [1q22/1q32.3]  [t(1;1)(q22;q32)]  
Fusion: TCGA_MDACCATF3 1q32.3 CDH20 18q21.33 LUSC
Tumor Fusion PortalATF3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerATF3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ATF3
dbVarATF3
ClinVarATF3
1000_GenomesATF3 
Exome Variant ServerATF3
ExAC (Exome Aggregation Consortium)ENSG00000162772
GNOMAD BrowserENSG00000162772
Genetic variants : HAPMAP467
Genomic Variants (DGV)ATF3 [DGVbeta]
DECIPHERATF3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisATF3 
Mutations
ICGC Data PortalATF3 
TCGA Data PortalATF3 
Broad Tumor PortalATF3
OASIS PortalATF3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICATF3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDATF3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ATF3
DgiDB (Drug Gene Interaction Database)ATF3
DoCM (Curated mutations)ATF3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ATF3 (select a term)
intoGenATF3
NCG5 (London)ATF3
Cancer3DATF3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603148   
Orphanet
DisGeNETATF3
MedgenATF3
Genetic Testing Registry ATF3
NextProtP18847 [Medical]
TSGene467
GENETestsATF3
Target ValidationATF3
Huge Navigator ATF3 [HugePedia]
snp3D : Map Gene to Disease467
BioCentury BCIQATF3
ClinGenATF3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD467
Chemical/Pharm GKB GenePA25085
Clinical trialATF3
Miscellaneous
canSAR (ICR)ATF3 (select the gene name)
Probes
Litterature
PubMed193 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineATF3
EVEXATF3
GoPubMedATF3
iHOPATF3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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