Download Gene Section ATF3 (activating transcription factor 3) Atlas of Genetics and Cytogenetics

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ATF3 (activating transcription factor 3)
Shigetaka Kitajima, Yujiro Tanaka, Junya Kawauchi
Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima,
Bunkyoku, Tokyo 113-8510, Japan (SK, YT, JK)
Published in Atlas Database: June 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/ATF3ID719ch1q32.html
DOI: 10.4267/2042/44748
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: ATF3deltaZip2;
ATF3deltaZip3
HGNC (Hugo): ATF3
Location: 1q32.3
Protein
ATF3deltaZip2c;
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.
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.
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.
Transcription
Transcribed from centromere to telomere orientation.
The P1 and P2 promoters are differentially activated by
growth and stress stimuli.
Expression
Pseudogene
ATF3 is expressed ubiquitously but its level is
maintained low in the absence of cellular stresses.
Unknown.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
437
ATF3 (activating transcription factor 3)
Kitajima S, et al.
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.
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.
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 IL6, IL-12, and other cytokine genes downstream of Tolllike 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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
Mutations
Germinal
Unknown.
Somatic
Unknown.
Implicated in
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.
438
ATF3 (activating transcription factor 3)
Kitajima S, et al.
Wolfgang CD, Liang G, Okamoto Y, Allen AE, Hai T.
Transcriptional autorepression of the stress-inducible gene
ATF3. J Biol Chem. 2000 Jun 2;275(22):16865-70
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.
Hashimoto Y, Zhang C, Kawauchi J, Imoto I, Adachi MT,
Inazawa J, Amagasa T, Hai T, Kitajima S. An alternatively
spliced isoform of transcriptional repressor ATF3 and its
induction by stress stimuli. Nucleic Acids Res. 2002 Jun
1;30(11):2398-406
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. Stress response gene ATF3 is a target
of c-myc in serum-induced cell proliferation. EMBO J. 2005 Jul
20;24(14):2590-601
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.
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. The tumor metastasis suppressor gene
Drg-1 down-regulates the expression of activating transcription
factor 3 in prostate cancer. Cancer Res. 2006 Dec
15;66(24):11983-90
Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Roach JC,
Kennedy K, Hai T, Bolouri H, Aderem A. Systems biology
approaches identify ATF3 as a negative regulator of Toll-like
receptor 4. Nature. 2006 May 11;441(7090):173-8
Janz M, Hummel M, Truss M, Wollert-Wulf B, Mathas S,
Jöhrens K, Hagemeier C, Bommert K, Stein H, Dörken B,
Bargou RC. Classical Hodgkin lymphoma is characterized by
high constitutive expression of activating transcription factor 3
(ATF3), which promotes viability of Hodgkin/Reed-Sternberg
cells. Blood. 2006 Mar 15;107(6):2536-9
Congenital anomaly
Yan C, Boyd DD. ATF3 regulates the stability of p53: a link to
cancer. Cell Cycle. 2006 May;5(9):926-9
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.
Beleza-Meireles A, Töhönen V, Söderhäll C, Schwentner C,
Radmayr C, Kockum I, Nordenskjöld A. Activating transcription
factor 3: a hormone responsive gene in the etiology of
hypospadias. Eur J Endocrinol. 2008 May;158(5):729-39
Li D, Yin X, Zmuda EJ, Wolford CC, Dong X, White MF, Hai T.
The repression of IRS2 gene by ATF3, a stress-inducible gene,
contributes to pancreatic beta-cell apoptosis. Diabetes. 2008
Mar;57(3):635-44
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. Role of
activating transcription factor 3 on TAp73 stability and
apoptosis in paclitaxel-treated cervical cancer cells. Mol
Cancer Res. 2008 Jul;6(7):1232-49
Wang A, Arantes S, Yan L, Kiguchi K, McArthur MJ, Sahin A,
Thames HD, Aldaz CM, Macleod MC. The transcription factor
ATF3 acts as an oncogene in mouse mammary tumorigenesis.
BMC Cancer. 2008 Sep 22;8:268
References
Miyazaki K, Inoue S, Yamada K, Watanabe M, Liu Q,
Watanabe T, Adachi MT, Tanaka Y, Kitajima S. Differential
usage of alternate promoters of the human stress response
gene ATF3 in stress response and cancer cells. Nucleic Acids
Res. 2009 Apr;37(5):1438-51
Chen BP, Liang G, Whelan J, Hai T. ATF3 and ATF3 delta Zip.
Transcriptional repression versus activation by alternatively
spliced isoforms. J Biol Chem. 1994 Jun 3;269(22):15819-26
Qi L, Saberi M, Zmuda E, Wang Y, Altarejos J, Zhang X,
Dentin R, Hedrick S, Bandyopadhyay G, Hai T, Olefsky J,
Montminy M. Adipocyte CREB promotes insulin resistance in
obesity. Cell Metab. 2009 Mar;9(3):277-86
Liang G, Wolfgang CD, Chen BP, Chen TH, Hai T. ATF3 gene.
Genomic organization, promoter, and regulation. J Biol Chem.
1996 Jan 19;271(3):1695-701
Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U.
ATF3 and stress responses. Gene Expr. 1999;7(4-6):321-35
This article should be referenced as such:
Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K,
Yonenobu K, Ochi T, Noguchi K. Activating transcription factor
3 (ATF3) induction by axotomy in sensory and motoneurons: A
novel neuronal marker of nerve injury. Mol Cell Neurosci. 2000
Feb;15(2):170-82
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
Kitajima S, Tanaka Y, Kawauchi J. ATF3 (activating
transcription factor 3). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(5):437-439.
439