ATF3 (activating transcription factor 3)

2009-06-01   Shigetaka Kitajima , Yujiro Tanaka , Junya Kawauchi 

Biochemical Genetics, Medical Research Institute, Tokyo Medical, Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8510, Japan

Identity

HGNC
LOCATION
1q32.3
LOCUSID
ALIAS
-
FUSION GENES

DNA/RNA

Atlas Image

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.

Proteins

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.
Atlas Image

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

Entity name
Solid tumors and Hodgkins 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 Hodgkins 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 gene
Unknown.
Fusion 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 name
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 gene
Unknown.
Fusion protein
Unknown.
Entity name
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.
Fusion protein
Unknown.

Bibliography

Pubmed IDLast YearTitleAuthors
171788972006The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer.Bandyopadhyay S et al
184268332008Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias.Beleza-Meireles A et al
75150601994ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms.Chen BP et al
166881682006Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4.Gilchrist M et al
104402331999ATF3 and stress responses.Hai T et al
120348272002An alternatively spliced isoform of transcriptional repressor ATF3 and its induction by stress stimuli.Hashimoto Y et al
162637882006Classical Hodgkin lymphoma is characterized by high constitutive expression of activating transcription factor 3 (ATF3), which promotes viability of Hodgkin/Reed-Sternberg cells.Janz M et al
180570932008The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic beta-cell apoptosis.Li D et al
85761711996ATF3 gene. Genomic organization, promoter, and regulation.Liang G et al
191364622009Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells.Miyazaki K et al
186449862008Role of activating transcription factor 3 on TAp73 stability and apoptosis in paclitaxel-treated cervical cancer cells.Oh YK et al
192545722009Adipocyte CREB promotes insulin resistance in obesity.Qi L et al
159908692005Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation.Tamura K et al
106733252000Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.Tsujino H et al
188087192008The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis.Wang A et al
107481472000Transcriptional autorepression of the stress-inducible gene ATF3.Wolfgang CD et al
166280102006ATF3 regulates the stability of p53: a link to cancer.Yan C et al

Other Information

Locus ID:

NCBI: 467
MIM: 603148
HGNC: 785
Ensembl: ENSG00000162772

Variants:

dbSNP: 467
ClinVar: 467
TCGA: ENSG00000162772
COSMIC: ATF3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000162772ENST00000336937P18847
ENSG00000162772ENST00000341491P18847
ENSG00000162772ENST00000366981Q5VTZ4
ENSG00000162772ENST00000366983P18847
ENSG00000162772ENST00000366985A0A0A0MRJ2
ENSG00000162772ENST00000366987P18847
ENSG00000162772ENST00000464547P18847
ENSG00000162772ENST00000613104P18847
ENSG00000162772ENST00000613954P18847

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Metabolism of proteinsREACTOMER-HSA-392499
Unfolded Protein Response (UPR)REACTOMER-HSA-381119
PERK regulates gene expressionREACTOMER-HSA-381042
ATF4 activates genesREACTOMER-HSA-380994

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA283MAPK8GenePathwayassociated23922006
PA30621MAPK14GenePathwayassociated23922006

References

Pubmed IDYearTitleCitations
153855332004Amino acid deprivation induces the transcription rate of the human asparagine synthetase gene through a timed program of expression and promoter binding of nutrient-responsive basic region/leucine zipper transcription factors as well as localized histone acetylation.87
179521192008A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development.86
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
204854372010Opposing roles for calcineurin and ATF3 in squamous skin cancer.84
210619132010ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: is modulation of inflammation a unifying component?80
123868112002ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth.66
296702872018Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.64
170144222007The regulation of ATF3 gene expression by mitogen-activated protein kinases.57
214510462011Diffuse traumatic axonal injury in the mouse induces atrophy, c-Jun activation, and axonal outgrowth in the axotomized neuronal population.56
221793172011ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.56

Citation

Shigetaka Kitajima ; Yujiro Tanaka ; Junya Kawauchi

ATF3 (activating transcription factor 3)

Atlas Genet Cytogenet Oncol Haematol. 2009-06-01

Online version: http://atlasgeneticsoncology.org/gene/719/atf3