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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review 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