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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review ATF2 (activating transcription factor 2) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: October 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/ATF2ID718ch2q31.html DOI: 10.4267/2042/48757 This article is an update of : Lazo PA, Sevilla A. ATF2 (activating transcription factor 2). Atlas Genet Cytogenet Oncol Haematol 2008;12(1):33-34. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology angiomatoid fibrous histiocytoma) harboring a t(2;22)(q33;q12) or a t(12;22)(q13;q12) respectively (review in Huret, 2010). Identity Other names: CREB1, CRE-BP1, CREB2, CREBP1, HB16, MGC111558, TREB7 HGNC (Hugo): ATF2 Location: 2q31.1 Note ATF2 (2q31.1) is sometimes confused with CREB1 (2q33.3), because an alias of ATF2 is CREB1, also because they are both CREB-related proteins, a family of transcription factors of the bZIP superfamily, whose members have the ability to heterodimerize with each other, and, finally, because CREB1, like ATF1 (but not ATF2 so far), is a fusion partner of EWSR1 in various soft tissue tumors (clear cell sarcoma of the soft tissue, DNA/RNA Description Gene size: 96 Kb. Transcription Initiation codon located in exon 3. Normal message is 1518 nucleotides. Numerous splice variants (24 according to Ensembl). A small isoform of ATF2, ATF2-small (ATF2-sm), with a calculated mass of 15 kDa, has no histone acetyltransferase (HAT) activity, but, still, has the ability to bind CRE-containing DNA. ATF2 gene structure based on data available in the Ensembl release 44. Upstream non-coding exons (green). Coding exons (pink), 3' untranslated sequence (red). The size of the exons in nucleotides is indicated below each exon. Exon number is indicated within the exon. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) 167 ATF2 (activating transcription factor 2) Huret JL ATF2-sm is only composed of the first two and last two exons of ATF2. Within the body of the uterus, ATF2 full length is expressed only in the lower segment, whereas there is a gradient of expression of the ATF2sm protein with the highest level in the upper segment. A significant number of genes are differentially regulated by the ATF2-fl and ATF2-sm transcription factors (Bailey et al., 2002; Bailey and Europe-Finner, 2005). Expression Ubiquitously expressed. High expression in brain and in regenerating liver (Takeda et al., 1991). Localisation Cytoplasmic and nuclear protein. The nuclear transport signals (NLS and NES) contribute to the shuttling of ATF2 between the cytoplasm and the nucleus. ATF2 homodimers are localized in the cytoplasm, and prevent its nuclear import. Heterodimerization with JUN prevents nuclear export of ATF2. JUN-dependent nuclear localization of ATF2 occurs upon stimulating conditions (retinoic acid-induced differentiation and UV-induced cell death) (Liu et al., 2006). Phosphorylation of ATF2 on Thr52 by PRKCE (PKCE) promotes its nuclear retention and transcriptional activity (Lau et al., 2012). Stress- or damage-induced cytosolic localization of ATF2 could be associated with cell death (Lau and Ronai, 2012). When ATF2 translocates to the cytoplasm, it localizes at the mitochondrial outer membrane (Lau et al., 2012). Protein Description ATF2 is one of 16 members of the ATF and CREB group of bZIP transcription factors, components of the activating protein 1 (AP-1). The canonical form of ATF2 is made of 505 amino acids, 54.537 kDa according to Swiss-Prot. ATF2 comprises from N-term to C-term a zinc finger (C2H2-type; DNA binding) (amino acids 25-49), a transactivation domain (aa 19106, Nagadoi et al., 1999), two proline-rich domain, (involved in protein-protein interaction) (Pro202, 207, 210, 212, 214, 216, 222, 228, 231 and 243, 247, 251, 256, 259, 261, 263, 267, 269), two glutamine-rich domains (involved in transcriptional trans-activation) (Gln268, 271, 284, 285 and 306, 313, 316, 317), a basic motif (amino acids 351-374), and a leucine zipper domain (amino acids 380-408, and a nuclear export signal), making a basic leucine zipper required for dimerization, and involved in CRE-binding (Kara et al., 1990 and Swiss-Prot.). ATF2 contains two canonical nuclear localization signals (NLS) in its basic motif, and two nuclear export signal (NES) in its leucine zipper, one of which in N-term: (1)MKFKLHV(7) (Liu et al., 2006; Hsu and Hu, 2012). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) Function - ATF2 is a transcription factor. ATF2 forms a homodimer or a heterodimer with JUN (Hai and Curran, 1991), or other proteins (see below). - Typically, it binds to the cAMP-responsive element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many cellular promoters (Hai et al.,1989). However, depending on the heterodimeric partner, ATF2 binds to different response elements on target genes. ATF2/JUN and ATF2/CREB1 bind the above noted concensus sequence. ATF2 is mainly a transcription activator, but it also may be a transcription repressor (reviews in Bhoumik and Ronai, 168 ATF2 (activating transcription factor 2) Huret JL "b-ZIP") of ATF2 enables homo- or heterodimerization. The main dimerization partners of ATF2 are the following: ATF2, BRCA1, CREB1, JDP2, JUN, JUNB, JUND, MAFA, NF1, NFYA, PDX1, POU2F1, TCF3 (Lau and Ronai, 2012). ATF2 homodimers have a low transcriptional activity. MAPKAP1 (SIN1) binds to the b-ZIP region of ATF2, and also binds MAPK14, and is required for MAPK14induced phosphorylation of ATF2 in response to osmotic stress, and activates the transcription of apoptosis-related genes (Makino et al., 2006). In response to stress, ATF2 binds to POU2F1 (OCT1), NFI, and BRCA1 to activate transcription of GADD45. The b-Zip region of ATF2 is critical for binding to BRCA1. ATF2 also binds and activates SERPINB5 (Maspin) (Maekawa et al., 2008). ATF2 also forms a heterodimer with JDP2, a repressor of AP-1. JDP2 inhibits the transactivation of JUN by ATF2 (Jin et al., 2002). ATF2 target genes Under genotoxic stress, a study showed that 269 genes were found to be bound by ATF2/JUN dimers. Immediate-early genes were a notable subset and included EGR family members, FOS family members, and JUN family members, but the largest group of genes belonged to the DNA repair machinery (Hayakawa et al., 2004, see below). Among the ATF2 target genes are : - Transcription factors, such as JUN, ATF3, DDIT3 (CHOP), FOS, JUNB, - DNA damage proteins (see below), - Cell cycle regulators (CCNA2, CCND1), see below, - Regulators of apoptosis (see below and Hayakawa et al., 2004), - Growth factor receptors and cytokines such as PDGFRA (Maekawa et al., 1999), IL8 (Agelopoulos and Thanos, 2006), FASLG (Fas ligand), TNF (TNFalpha), TNFSF10 family (Herr et al., 2000; Faris et al., 1998), - Proteins related with invasion such as MMP2 (Hamsa and Kuttan, 2012) and PLAU (UPA): ATF2/JUN heterodimer binds to and activates PLAU (De Cesare et al., 1995), - Cell adhesion molecules, such as SELE, SELP, and VCAM1 (Reimold et al., 2001), - Proteins engaged in the response to endoplasmic reticulum (ER) stress. ATF2/CREB dimers bind the CRE-like element TGACGTGA of HSPA5 (Grp78) and activates it (Chen et al., 1997), - Genes encoding extracellular matrix components seem to constitute an important subset of ATF2/JUNtarget genes (van Dam and Castellazzi, 2001). - PTEN, a negative regulator of the PI3K/AKT signaling pathway, is positively regulated by ATF2 (Qian et al., 2012). - ATF1 and ATF2 regulate TCRA and TCRB gene transcription. 2008; Lopez-Bergami et al., 2010; Lau and Ronai, 2012). Activation of ATF2 ATF2 is activated by stress kinases, including JNK (MAPK8, MAPK9, MAPK10) and p38 (MAPK1, MAPK11, MAPK12, MAPK13, MAPK14) and is implicated in transcriptional regulation of immediate early genes regulating stress and DNA damage responses (Gupta et al., 1995; van Dam et al., 1995) and cell cycle control under normal growth conditions.(up-regulation of the CCNA2 (cyclin A) promoter at the G1/S boundary) (Nakamura et al., 1995). In response to stimuli, ATF2 is phosphorylated on threonine 69 and/or 71 by JNK or by p38. Phosphorylation on Thr69 and Thr71 of ATF2 and its dimerization are required to activate ATF2 transcription factor activity. Phosphorylation on Thr69 occurs through the RALGDS-SRC-P38 pathway, and phosphorylation on Thr71 occurs through the RASMEK-ERK pathway (MAPK1, MAPK3 (ERK1), MAPK11, MAPK12 and MAPK14) (Gupta et al., 1995; Ouwens et al., 2002). The intrinsic histone acetylase activity of ATF2 promotes its DNA binding ability (Abdel-Hafiz et al., 1992; Kawasaki et al., 2000). Interaction of ATF2 with CREBBP (CREB-binding protein, also called p300/CBP) is dependent upon phosphorylation at Ser121 induced by PRKCA. ATF2 and CREBBP cooperate in the activation of transcription (Kawasaki et al., 1998; Yamasaki et al., 2009). VRK1 activates and stabilizes ATF2 through direct phosphorylation of Ser62 and Thr73 (Sevilla et al., 2004). Down regulation of ATF2 Among other down regulation mechanisms, ATF2 is down regulated, by MIR26B in response to ionizing radiation (Arora et al., 2011). Transcriptionally active dimers of ATF2 protein are regulated by ubiquitylation and proteosomal degradation (Fuchs et al., 1999); phosphorylation of ATF2 on Thr69 and Thr71 promotes its ubiquitylation and degradation (Firestein and Feuerstein, 1998). A cytoplasmic alternatively spliced isoform of ATF7, ATF7-4, is a cytoplasmic negative regulator of both ATF2 and ATF7. It impairs ATF2 and ATF7 phosphorylation (ATF7-4 indeed sequesters the Thr53phosphorylating kinase in the cytoplasm, preventing Thr53 phosphorylation of ATF7) and transcriptional activity (Diring et al., 2011). The activity of ATF2 is repressed by an intramolecular interaction between the N-terminal domain and the bZIP domain (Li and Green, 1996). The N-terminal nuclear export signal (NES) of ATF2 negatively regulates ATF2 transcriptional activity (Hsu and Hu, 2012). Dimerization of ATF2 The basic leucine zipper (basic motif + leucine zipper, Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) 169 ATF2 (activating transcription factor 2) Huret JL Under non-stressed conditions, ATF2 in cooperation with the ubiquitin ligase CUL3 promotes the degradation of KAT5 (Bhoumik et al., 2008a). Following genotoxic stress, 269 genes were found to be bound by ATF2/JUN dimers (see above), of which were 23 DNA repair or repair-associated genes (ERCC1, ERCC3, XPA, MSH2, MSH6, RAD50, RAD23B, MLH1, HIST1H2AC, PMS2, FOXN3 (CHES1), LIG1, ERCC8 (CKN1), UNG, XRCC6 (G22P1), TREX1, PNP, GTF2H1, ATM, FOXD1, DDX3X, DMC1, and the DNA repair-associated GADD45G), derived from several recognized DNA repair mechanisms (Hayakawa et al., 2004). Cell Cycle RB1 constrains cellular proliferation by activating the expression of the inhibitory growth factor TGFB2 (TGF-beta 2) through ATF2 (Kim et al., 1992). CREB1 dimerizes with ATF2 to bind to the CCND1 (cyclin D1) promoter, to increase CCD1 expression (Beier et al., 1999). JUND dimerizes with ATF2 to repress CDK4 transcription, a protein necessary for the G1-to-S phase transition during the cell cycle, by binding to the proximal region of the CDK4-promoter, contributing to the inhibition of cell growth. The physical interactions of ATF2 with JUND implicates the b-ZIP domain of ATF2 (Xiao et al., 2010). Heterodimerization of JUND with ATF2 activates CCNA2 (cyclin A) promoter. CCNA2 is essential for the control at the G1/S and the G2/M transitions of the cell cycle. In contrast, ATF4 expression suppresses the promoter activation mediated by ATF2 (Shimizu et al., 1998). Apoptosis ATF2/CREB1 heterodimer binds to the CRE element of the BCL2 promoter (Ma et al., 2007). ATF2 induces BAK upregulation (Chen et al., 2010). MAP3K5 (ASK1) activates ATF2 and FADD-CASP8BID signalling, resulting in the translocation of BAX and BAK, and subsequently mitochondrial dysregulation (Hassan et al., 2009). ATF2/JUN heterodimers bind and activate CASP3, a key executor of neuronal apoptosis (Song et al., 2011). Following death receptor stimulation, there is phosphorylation and binding of ATF2/JUN to deathinducing ligands promoters (FASLG, TNF, TNFSF10), which allows the spread of death signals (Herr et al., 2000). Neuronal apoptosis requires the concomitant activation of ATF2/JUN and downregulation of FOS (Yuan et al., 2009). Many drugs are currently being tested for their ability to inhibit cell proliferation and induce apoptosis through various pathways, including ATF2 pathway. In the cytoplasm, ATF2 abrogates formation of complexes containing HK1 and VDAC1, deregulating mitochondrial outer-membrane permeability and initiating apoptosis. This function is negatively regulated phosphorylation of ATF2 by PRKCE, which dictates its nuclear localization (Lau et al., 2012). Histones, Chromatin UV treatment or ATF2 phosphorylation increases its histone acetyltransferase (HAT) activity as well as its transcriptional activities. Lys296, Gly297 and Gly299, are essential both for histone acetyltransferase activity and for transactivation (Kawasaki et al., 2000). Binding of ATF2 to the histone acetyltransferase RUVBL2 (TIP49b) suppresses ATF2 transcriptional activity. RUVBL2's association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2 (Cho et al., 2001). ATF2 interacts with the acetyltransferase domains of CREBBP. ATF2 b-ZIP could serve as an acetyltransferase substrate for the acetyltransferase domains of CREBBP. ATF2 is acetylated on Lys357 and Lys374 by CREBBP, which contributes to its transcriptional activity (Karanam et al., 2007). ATF2 and ATF4 are essential for the transcriptional activation of DDIT3 (CHOP) upon amino acid starvation. ATF2 is essential in the acetylation of histone H4 and H2B, and thereby may be involved in the modification of the chromatin structure. An ATF2-independent HAT activity is involved in the amino acid regulation of ASNS transcription (Bruhat et al., 2007). The histone variant macroH2A recruitement into nucleosomes could confer an epigenetic mark for gene repression. The constitutive DNA binding of the ATF2/JUND heterodimer to the IL-8 enhancer recruits macroH2A-containing nucleosomes in B cells, thus inhibiting transcriptional activation (Agelopoulos and Thanos, 2006). Heat shock or osmotic stress induces phosphorylation of dATF2 (ATF2 in Drosophila), results in its release from heterochromatin, and heterochromatic disruption. dATF2 regulates heterochromatin formation. ATF2 may be involved in the epigenetic silencing of target genes in euchromatin. The stress-induced ATF2dependent epigenetic change was maintained over generations, suggesting a mechanism by which the effects of stress can be inherited (Seong et al., 2011). DNA damage response Phosphorylation on Ser490 and Ser498 by ATM is required for the activation of ATF2 in DNA damage response. Phosphorylation of ATF2 results in the localisation of ATF2 in ionizing radiation induced foci (in cells exposed to ionizing radiation (IR), several proteins phosphorylated by ATM translocate and colocalize to common intranuclear sites. The resulting IR-induced nuclear foci (IRIF) accumulate at the sites of DNA damage). ATF2 expression contributes to the selective recruitment of MRE11A, RAD50, and NBN (NBS1) into IRIF. ATF2 is required for the IR-induced S phase checkpoint, and this function is independant of its transcriptional activity (Bhoumik et al., 2005). KAT5 (TIP60) is a histone acetyltransferase and chromatin-modifying protein involved in double strand breaks (DSB) repair, interacting with and acetylating ATM. ATF2 associates with KAT5 and RUVBL2. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) 170 ATF2 (activating transcription factor 2) Huret JL JUNB dimerizes with either ATF2 or FOS to increased CBFB promoter activity, and further expression of MMP13, which suggests important role in neovascularization (Licht et al., 2006). Metabolic control and Insulin signalling ATF2 has been implicated in the regulation of proteins involved in metabolic control, including the control of the expression of UCP1, a protein involved in thermogenic response in brown adipose tissue (Cao et al., 2004) and phosphoenolpyruvate carboxykinase (PEPCK), a protein regulating gluconeogenesis (Cheong et al., 1998). Insulin activates ATF2 by phosphorylation of Thr69 and Thr71 (Baan et al., 2006). Co-expression of ATF2, MAFA, PDX1, and TCF3 results in a synergistic activation of the insulin promoter in endocrine cells of pancreatic islets. ATF2, MAFA, PDX1, and TCF3 form a multi-protein complex to facilitate insulin gene transcription (Han et al., 2011). ATF2 target genes in insulin signalling are ATF3, JUN, EGR1, DUSP1 (MKP1), and SREBF1. Deregulation of these genes is linked to the pathogenesis of insulin resistance, beta-cell dysfunction and vascular complications found in type 2 diabetes. Therefore, aberrant ATF2 activation under conditions of insulin resistance may contribute to the development of type 2 diabetes (Baan et al., manuscript in preparation). Iron depletion Iron depletion induced by chelators increases the phosphorylation of JNK and MAPK14, as well as the phosphorylation of their downstream targets p53 and ATF2 (Yu and Richardson, 2011). Epithelial mesenchymal transition Note Epithelial mesenchymal transition (EMT) is characterized by the loss of the epithelial cell properties and the development of mesenchymal properties of cells, with altered cytoskeletal organization and enhanced migratory and invasive potentials. EMT is seen in embryonic development, organogenesis, wound healing, and oncogenesis. TGFbeta induces EMT, and is up-regulated by ATF2 (Bakin et al., 2002; Venkov et al., 2011; Xu et al., 2012). Allergic asthma Note In a mouse model of allergic asthma, Aspergillus fumigatus provokes the secretion TNF (TNFalpha) by A. fumigatus-activated macrophages. In response to TNF, ATF2/JUN, RELA/RELA (p65/p65) and USF1/USF2 complexes are recruited to the PLA2G4C enhancer in lung epithelial cells (Bickford et al., 2012). Autoimmune diseases Note SMAD3 and ATF2 are activated during Theiler's virus (TMEV) infection (which may provoke an autoimmune demyelinating disease). SMAD3 and ATF2 activate IL-23 p19 promoter (AlSalleeh and Petro, 2008). IL-23 consists of a p40 subunit IL12B coupled to the p19 subunit IL23A, and has an essential role in the development of T cell-mediated autoimmune diseases (Inoue, 2010). Mutations Note v-Rel-mediated transformation suggests opposing roles for ATF2 in oncogenesis. The increase in ATF2 expression observed in v-Rel-transformed cells promotes oncogenesis. On the other hand, enhanced expression of ATF2 inhibits transformation by v-Rel. ATF2 can regulate signaling pathways in a cell typespecific and/or context-dependent manner. Differences were found in the stage at which ATF2 regulated the RAS/RAF/MAPK signaling pathway in fibroblast (where it blocked the activation of RAF, MAP2K1/MAP2K2, MAPK1/MAPK3) and in the lymphoid DT40 B-cell line (where overexpression of ATF2 increased HRAS activity and phosphorylated RAF. ATF2 exhibits both oncogenic and tumor suppressor properties (Liss et al., 2010). Vascular homeostasis Note CD39 is a transmembrane protein expressed on the surface of vascular and immune cells. CD39 inhibits platelet activation, maintains vascular fluidity, and provides protection from both cardiac and cerebral ischemia and reperfusion injuries. cAMP regulates CD39 expression through ATF2, which binds a CRElike regulatory element lying 210 bp upstream of the CD39 transcriptional start point (Liao et al., 2010). Somatic Bone development V258I in lung cancer cell lines (Woo et al., 2002). K105T in pancreatic cancer cell lines (Jones et al., 2008). Note ATF2 promotes chondrocyte proliferation and cartilage development through CCND1 upregulation in chondrocytes (Beier et al., 1999); mice carrying a germline mutation in ATF2 have a defect in endochondral ossification (Reimold et al., 1996). ATF2 regulates the expression of RB1, which regulates the G1- to S-phase transition by sequestering the E2F family members, necessary for cell cycle progression. When E2Fs are released, the cell is committed to Implicated in Angiogenesis Note The basic leucine zipper (basic motif + leucine zipper, Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) 171 ATF2 (activating transcription factor 2) Huret JL Table 1. Induction of activating transcription factors in the nucleus accumbens and their regulation of emotional behavior. (from Green et al., 2008). ATF2/JUN heterodimers bind and activate CASP3, a key executor of neuronal apoptosis, in cerebellar granule neurons (Song et al., 2011). ATF2/JUN heterodimers bind and activate HRK (DP5, death protein 5/harakiri), a proapoptotic gene, promoting the death of sympathetic neurons (Ma et al., 2007; Towers et al., 2009), but also ATF2/JUN binds to two conserved CRE sites in the DUSP1 (MKP1) promoter; overexpression of DUSP1 inhibits JNKmediated phosphorylation of JUN and protect sympathetic neurons from apoptosis (Kristiansen et al., 2010). ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressantlike responses (Green et al., 2008), see Table 1. progress through the cell cycle, which is essential in regulating cell proliferation vs differentiation.of chondrocytes and endochondral bone growth (ValeCruz et al., 2008). ATF2/CREB1 binds to CRE domain of TNFSF11 (RANKL) promoter and TNFSF11 expression stimulates osteoclastogenesis in mouse stromal/osteoblast cells (Bai et al., 2005). Binding of JUN CREB1, ATF1, and ATF2 complexes are required for COL24A1 transcription, a marker of late osteoblast differentiation (Matsuo et al., 2006). Luteolin, a flavonoid, inhibits TNFSF11-induced osteoclastogenesis through the inhibition of ATF2 phosphorylation (Lee et al., 2009). Brain Skin and skin cancers Note ATF2 is expressed with large variations in intensity (and often highly expressed), according to the brain region examined. Altogether, ATF2 seems to play a fundamental role in neuronal viability and in neurological functions in the normal brain and is down-regulated in the hippocampus and the caudate nucleus in Alzheimer, Parkinson and Huntington diseases (Pearson et al., 2005). Mice carrying a germline mutation in ATF2 had a reduced number of cerebellar Purkinje cells, atrophic vestibular sense organs, an ataxic gait, hyperactivity,and decreased hearing (Reimold et al., 1996). A missense mutation in ATF2 in dogs has shown to provoke an autosomal recessive disease with short stature and weakness at birth, ataxia and generalized seizures, dysplastic foci consisting of clusters of intermixed granule and Purkinje cells, and death before 7 weeks of age (Chen et al., 2008d). ATF2 plays critical roles for the expression of the TH gene (tyrosine hydroxylase) and for neurite extension of catecholaminergic neurons (Kojima et al., 2008). Neuronal-specific ATF2 expression is required for embryonic survival, ATF2 has a strong pro-survival role in somatic motoneurons of the brainstem, and loss of functional ATF2 leads to hyperphosphorylated JNK and p38, and results in somatic and visceral motoneuron degeneration (Ackermann et al., 2011). On the other hand, activated ATF2 promotes apoptosis of various brain cells, of which are cerebellar granule neurons (Ramiro-Cortés et al., 2011; Song et al., 2011). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) Note Inhibition of ATF2 with increased JNK/JUN and JUND induces apoptosis of melanoma cells (Bhoumik et al., 2004). MITF downregulation is mediated by ATF2/JUNB-dependent suppression of SOX10 transcription (Shah et al., 2010); MITF is a transcription factor for tyrosinase (TYR) and plays a role in melanocyte development. ATF2 attenuates melanoma susceptibility to apoptosis. ATF2 control of melanoma development is mediated through its negative regulation of SOX10 and consequently of MITF transcription. The ratio of nuclear ATF2 to MITF expression is associated with poor prognosis (Shah et al., 2010). Assignment to the low-risk group in stage II melanoma requires elevated levels of overall CTNNB1 (beta-catenin) and nuclear CDKN1A (p21WAF1), decreased levels of fibronectin, and distributions that favor nuclear concentration for CDKN2A (p16INK4A) but cytoplasmic concentration for ATF2 (Gould Rothberg et al., 2009). Phosphorylated ATF2 (p-ATF2) is significantly overexpressed in cutaneous angiosarcoma (malignant tumor) and pyogenic granuloma (benign tumor) than in normal dermal vessels (Chen et al., 2008a); p-ATF2 is also overexpressed in cutaneous squamous cell carcinoma, Bowen's disease, and basal cell carcinomas, as compared to its expression in normal skin (Chen et al., 2008b). p-ATF2 is also overexpressed in eccrine porocarcinoma and eccrine poroma (Chen et al., 2008c). 172 ATF2 (activating transcription factor 2) Huret JL ATF2 mutant mice in which the ATM phosphoacceptor sites (S472/S480) were mutated (ATF2KI mice) are more sensitive to ionizing radiation IR, exhibit increased intestinal cell apoptosis, develop a higher number of low-grade skin tumors (papillomas, squamous cell carcinomas, spindle cell carcinomas) (Li et al., 2010). A decrease of nuclear ATF2 and high CTNNB1 (beta-catenin) expression is seen in squamous cell carcinoma and basal cell carcinoma, compared to normal skin, while the cytoplasmic ATF2 expression was not significantly different in cancer and normal skin (Bhoumik et al., 2008b). A nuclear localization of ATF2 would be associated with its oncogenic properties, and a cytosolic localization with its tumor suppressor properties (Lau and Ronai, 2012). High levels of ATF2/JUN dimers induce autocrine growth and primary tumor formation of fibrosarcomas in the chicken (van Dam and Castellazzi, 2001). gland development, a function that may be crucial to its ability to suppress breast cancer. (Wen et al., 2011). ATF2/JUN binds to a potential CRE element of FOXP3, and induces its expression. FOXP3 acts as a transcriptional repressor of oncogenes such as ERBB2 and SKP2, and is able to cause apoptosis of breast cancer cells. The use of this ATF2-FOXP3 pathway may be of potential interest in future therapeutic approach of breast cancer. (Liu et al., 2009). Aggressive basal-like breast cancer cells exhibit high expression of FOSL1 (FRA1)/JUN dimers rather than ATF2/JUN dimers (Baan et al., 2010). Uterus cancer Note In PTEN-deficient endometrial cancers (which represent 1/3 to 3/4 of endometrial cancers), ATF2 is activated, while ATF2 shows a reduced expression in PTEN-positive endometrial cancers (Xiao et al., 2010). Soft tissue sarcomas Note In human and murine synovial sarcoma cells with t(X;18)(p11.2;q11.2) and a hybrid SS18-SSX, BCL2 expression is increased, but other anti-apoptotic genes, including MCL1 and BCL2A1 are repressed via binding of ATF2 to the cAMP-responsive element (CRE) in the promoters of these genes (Jones et al., 2012). Prostate cancer Leukemias Lung cancer Note ATF2 was found to upregulate Fas/FasL in a human chronic myeloid leukemia cell line (Chen et al., 2009). NFE2L2 (NRF2) is a transcription activator of the bZIP family which binds to antioxidant response elements (ARE) in the promoter regions of target genes in response to oxidative stress. NFE2L2 positively regulates the expression the AP-1 family proteins ATF2, JUN and FOS. NFE2L2/ARE pathway plays an important role in the induction of differentiation of myeloid leukemia cells by 1alpha,25dihydroxyvitamin D3 (1,25D), a strong differentiation agent (Bobilev et al., 2011). A crosstalk between NFE2L2 and ATF2 has also been noted in prostate cancer cells (Nair et al., 2010). Note Patients with lung cancer showing high ANGPTL2 expression in cancer cells had a poor prognosis. ANGPTL2 increases tumor angiogenesis, enhances tumor cell motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. NFATc (NFATC1 to NFATC4 and NFAT5) function in tumor cell development and metastasis. It has been found that NFATc form a complex with ATF2/JUN heterodimers that bind to the CRE site of ANGPTL2 and enhances ANGPTL2 expression (Endo et al., 2012). Note Heparan-sulfate proteoglycans are required for maximal growth factor signaling in prostate cancer progression. HS2ST1 (heparan sulfate 2-Osulfotransferase, 2OST) is essential for maximal proliferation and invasion. HS2ST1 is upregulated by ATF2 (Ferguson and Datta, 2011). Other cancers Note Increased expression of ATF2 and ATF1 in nasopharyngeal carcinoma cells was associated with clinical stages (Su et al., 2011). Breast cancer Note The loss of one copy of p53 in ATF2+/- mice led to mammary tumor development, which supports the notion that ATF2 and p53 independently activate SERPINB5 and GADD45 expression (Maekawa et al., 2008). ATF2/JUN mediate increased BIM expression in response to MAPK14 (p38alpha) signaling in cells detached from the extracellular matrix, indicating a contributing role for ATF2 in regulating acinar lumen formation, crucial for the development of mammary Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) References Hai TW, Liu F, Coukos WJ, Green MR. Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 1989 Dec;3(12B):2083-90 Kara CJ, Liou HC, Ivashkiv LB, Glimcher LH. A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain. Mol Cell Biol. 1990 Apr;10(4):1347-57 173 ATF2 (activating transcription factor 2) Huret JL Hai T, Curran T. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3720-4 suppression by ATF4. Exp Cell Res. 1998 Feb 25;239(1):93103 Beier F, Lee RJ, Taylor AC, Pestell RG, LuValle P. Identification of the cyclin D1 gene as a target of activating transcription factor 2 in chondrocytes. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1433-8 Takeda J, Maekawa T, Sudo T, Seino Y, Imura H, Saito N, Tanaka C, Ishii S. Expression of the CRE-BP1 transcriptional regulator binding to the cyclic AMP response element in central nervous system, regenerating liver, and human tumors. Oncogene. 1991 Jun;6(6):1009-14 Fuchs SY, Ronai Z. Ubiquitination and degradation of ATF2 are dimerization dependent. Mol Cell Biol. 1999 May;19(5):3289-98 Kim SJ, Wagner S, Liu F, O'Reilly MA, Robbins PD, Green MR. Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2. Nature. 1992 Jul 23;358(6384):331-4 Maekawa T, Bernier F, Sato M, Nomura S, Singh M, Inoue Y, Tokunaga T, Imai H, Yokoyama M, Reimold A, Glimcher LH, Ishii S. Mouse ATF-2 null mutants display features of a severe type of meconium aspiration syndrome. J Biol Chem. 1999 Jun 18;274(25):17813-9 De Cesare D, Vallone D, Caracciolo A, Sassone-Corsi P, Nerlov C, Verde P. Heterodimerization of c-Jun with ATF-2 and c-Fos is required for positive and negative regulation of the human urokinase enhancer. Oncogene. 1995 Jul 20;11(2):36576 Nagadoi A, Nakazawa K, Uda H, Okuno K, Maekawa T, Ishii S, Nishimura Y. Solution structure of the transactivation domain of ATF-2 comprising a zinc finger-like subdomain and a flexible subdomain. J Mol Biol. 1999 Apr 2;287(3):593-607 Gupta S, Campbell D, Dérijard B, Davis RJ. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389-93 Fuchs SY, Tappin I, Ronai Z. Stability of the ATF2 transcription factor is regulated by phosphorylation and dephosphorylation. J Biol Chem. 2000 Apr 28;275(17):12560-4 Livingstone C, Patel G, Jones N. ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 1995 Apr 18;14(8):1785-97 Herr I, Posovszky C, Di Marzio LD, Cifone MG, Boehler T, Debatin KM. Autoamplification of apoptosis following ligation of CD95-L, TRAIL and TNF-alpha. Oncogene. 2000 Aug 31;19(37):4255-62 Nakamura T, Okuyama S, Okamoto S, Nakajima T, Sekiya S, Oda K. Down-regulation of the cyclin A promoter in differentiating human embryonal carcinoma cells is mediated by depletion of ATF-1 and ATF-2 in the complex at the ATF/CRE site. Exp Cell Res. 1995 Feb;216(2):422-30 Bhoumik A, Ivanov V, Ronai Z. Activating transcription factor 2derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment. Clin Cancer Res. 2001 Feb;7(2):331-42 Li XY, Green MR. Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain. Genes Dev. 1996 Mar 1;10(5):517-27 Cho SG, Bhoumik A, Broday L, Ivanov V, Rosenstein B, Ronai Z. TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage. Mol Cell Biol. 2001 Dec;21(24):8398-413 Reimold AM, Grusby MJ, Kosaras B, Fries JW, Mori R, Maniwa S, Clauss IM, Collins T, Sidman RL, Glimcher MJ, Glimcher LH. Chondrodysplasia and neurological abnormalities in ATF-2-deficient mice. Nature. 1996 Jan 18;379(6562):262-5 Mayr BM, Canettieri G, Montminy MR. Distinct effects of cAMP and mitogenic signals on CREB-binding protein recruitment impart specificity to target gene activation via CREB. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10936-41 Chen KD, Hung JJ, Huang HL, Chang MD, Lai YK. Rapid induction of the Grp78 gene by cooperative actions of okadaic acid and heat-shock in 9L rat brain tumor cells--involvement of a cAMP responsive element-like promoter sequence and a protein kinase A signaling pathway. Eur J Biochem. 1997 Aug 15;248(1):120-9 Reimold AM, Kim J, Finberg R, Glimcher LH. Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice. Int Immunol. 2001 Feb;13(2):241-8 Cheong J, Coligan JE, Shuman JD. Activating transcription factor-2 regulates phosphoenolpyruvate carboxykinase transcription through a stress-inducible mitogen-activated protein kinase pathway. J Biol Chem. 1998 Aug 28;273(35):22714-8 van Dam H, Castellazzi M. Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis. Oncogene. 2001 Apr 30;20(19):2453-64 Bailey J, Phillips RJ, Pollard AJ, Gilmore K, Robson SC, Europe-Finner GN. Characterization and functional analysis of cAMP response element modulator protein and activating transcription factor 2 (ATF2) isoforms in the human myometrium during pregnancy and labor: identification of a novel ATF2 species with potent transactivation properties. J Clin Endocrinol Metab. 2002 Apr;87(4):1717-28 Faris M, Latinis KM, Kempiak SJ, Koretzky GA, Nel A. Stressinduced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter. Mol Cell Biol. 1998 Sep;18(9):5414-24 Firestein R, Feuerstein N. Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells. J Biol Chem. 1998 Mar 6;273(10):5892-902 Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFbetamediated fibroblastic transdifferentiation and cell migration. J Cell Sci. 2002 Aug 1;115(Pt 15):3193-206 Kawasaki H, Song J, Eckner R, Ugai H, Chiu R, Taira K, Shi Y, Jones N, Yokoyama KK. p300 and ATF-2 are components of the DRF complex, which regulates retinoic acid- and E1Amediated transcription of the c-jun gene in F9 cells. Genes Dev. 1998 Jan 15;12(2):233-45 Jin C, Li H, Murata T, Sun K, Horikoshi M, Chiu R, Yokoyama KK. JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells. Mol Cell Biol. 2002 Jul;22(13):4815-26 Shimizu M, Nomura Y, Suzuki H, Ichikawa E, Takeuchi A, Suzuki M, Nakamura T, Nakajima T, Oda K. Activation of the rat cyclin A promoter by ATF2 and Jun family members and its Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der Burgt C, Kooistra K, Bos JL, Maassen JA, van Dam H. Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK- Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) 174 ATF2 (activating transcription factor 2) Huret JL ERK pathway and of Thr69 through RalGDS-Src-p38. EMBO J. 2002 Jul 15;21(14):3782-93 Matsuo N, Tanaka S, Gordon MK, Koch M, Yoshioka H, Ramirez F. CREB-AP1 protein complexes regulate transcription of the collagen XXIV gene (Col24a1) in osteoblasts. J Biol Chem. 2006 Mar 3;281(9):5445-52 Woo IS, Kohno T, Inoue K, Ishii S, Yokota J. Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer. Int J Oncol. 2002 Mar;20(3):527-31 Bhoumik A, Lopez-Bergami P, Ronai Z. ATF2 on the double activating transcription factor and DNA damage response protein. Pigment Cell Res. 2007 Dec;20(6):498-506 Ivanov VN, Bhoumik A, Ronai Z. Death receptors and melanoma resistance to apoptosis. Oncogene. 2003 May 19;22(20):3152-61 Bruhat A, Chérasse Y, Maurin AC, Breitwieser W, Parry L, Deval C, Jones N, Jousse C, Fafournoux P. ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation. Nucleic Acids Res. 2007;35(4):1312-21 Bhoumik A, Jones N, Ronai Z. Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity. Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4222-7 Karanam B, Wang L, Wang D, Liu X, Marmorstein R, Cotter R, Cole PA. Multiple roles for acetylation in the interaction of p300 HAT with ATF-2. Biochemistry. 2007 Jul 17;46(28):8207-16 Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S. p38 mitogenactivated protein kinase is the central regulator of cyclic AMPdependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol. 2004 Apr;24(7):3057-67 Ma Q, Li X, Vale-Cruz D, Brown ML, Beier F, LuValle P. Activating transcription factor 2 controls Bcl-2 promoter activity in growth plate chondrocytes. J Cell Biochem. 2007 May 15;101(2):477-87 Hayakawa J, Mittal S, Wang Y, Korkmaz KS, Adamson E, English C, Ohmichi M, McClelland M, Mercola D. Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress. Mol Cell. 2004 Nov 19;16(4):521-35 Ma C, Ying C, Yuan Z, Song B, Li D, Liu Y, Lai B, Li W, Chen R, Ching YP, Li M. dp5/HRK is a c-Jun target gene and required for apoptosis induced by potassium deprivation in cerebellar granule neurons. J Biol Chem. 2007 Oct 19;282(42):30901-9 Sevilla A, Santos CR, Vega FM, Lazo PA. Human vacciniarelated kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK. J Biol Chem. 2004 Jun 25;279(26):27458-65 Al-Salleeh F, Petro TM. Promoter analysis reveals critical roles for SMAD-3 and ATF-2 in expression of IL-23 p19 in macrophages. J Immunol. 2008 Oct 1;181(7):4523-33 Bhoumik A, Ronai Z. ATF2: a transcription factor that elicits oncogenic or tumor suppressor activities. Cell Cycle. 2008 Aug;7(15):2341-5 Bai XC, Lu D, Liu AL, Zhang ZM, Li XM, Zou ZP, Zeng WS, Cheng BL, Luo SQ. Reactive oxygen species stimulates receptor activator of NF-kappaB ligand expression in osteoblast. J Biol Chem. 2005 Apr 29;280(17):17497-506 Bhoumik A, Singha N, O'Connell MJ, Ronai ZA. Regulation of TIP60 by ATF2 modulates ATM activation. J Biol Chem. 2008a Jun 20;283(25):17605-14 Bailey J, Europe-Finner GN. Identification of human myometrial target genes of the c-Jun NH2-terminal kinase (JNK) pathway: the role of activating transcription factor 2 (ATF2) and a novel spliced isoform ATF2-small. J Mol Endocrinol. 2005 Feb;34(1):19-35 Bhoumik A, Fichtman B, Derossi C, Breitwieser W, Kluger HM, Davis S, Subtil A, Meltzer P, Krajewski S, Jones N, Ronai Z. Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proc Natl Acad Sci U S A. 2008b Feb 5;105(5):1674-9 Bhoumik A, Takahashi S, Breitweiser W, Shiloh Y, Jones N, Ronai Z. ATM-dependent phosphorylation of ATF2 is required for the DNA damage response. Mol Cell. 2005 May 27;18(5):577-87 Chen SY, Takeuchi S, Urabe K, Hayashida S, Kido M, Tomoeda H, Uchi H, Dainichi T, Takahara M, Shibata S, Tu YT, Furue M, Moroi Y. Overexpression of phosphorylatedATF2 and STAT3 in cutaneous angiosarcoma and pyogenic granuloma. J Cutan Pathol. 2008a Aug;35(8):722-30 Pearson AG, Curtis MA, Waldvogel HJ, Faull RL, Dragunow M. Activating transcription factor 2 expression in the adult human brain: association with both neurodegeneration and neurogenesis. Neuroscience. 2005;133(2):437-51 Chen SY, Takeuchi S, Moroi Y, Hayashida S, Kido M, Chen SJ, Tomoeda H, Uenotsuchi T, Tu YT, Furue M, Urabe K. Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous squamous cell carcinoma, Bowen's disease and basal cell carcinoma. J Dermatol Sci. 2008b Sep;51(3):210-5 Agelopoulos M, Thanos D. Epigenetic determination of a cellspecific gene expression program by ATF-2 and the histone variant macroH2A. EMBO J. 2006 Oct 18;25(20):4843-53 Chen SY, Takeuchi S, Urabe K, Kido M, Hayashida S, Tomoeda H, Uchi H, Dainichi T, Takahara M, Shibata S, Furue M, Moroi Y, Tu YT. Overexpression of phosphorylated ATF2 and STAT3 in eccrine porocarcinoma and eccrine poroma. J Dermatol Sci. 2008c Feb;49(2):170-3 Baan B, van Dam H, van der Zon GC, Maassen JA, Ouwens DM. The role of c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase in insulin-induced Thr69 and Thr71 phosphorylation of activating transcription factor 2. Mol Endocrinol. 2006 Aug;20(8):1786-95 Chen X, Johnson GS, Schnabel RD, Taylor JF, Johnson GC, Parker HG, Patterson EE, Katz ML, Awano T, Khan S, O'Brien DP. A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. Neurogenetics. 2008d Feb;9(1):41-9 Licht AH, Pein OT, Florin L, Hartenstein B, Reuter H, Arnold B, Lichter P, Angel P, Schorpp-Kistner M. JunB is required for endothelial cell morphogenesis by regulating core-binding factor beta. J Cell Biol. 2006 Dec 18;175(6):981-91 Liu H, Deng X, Shyu YJ, Li JJ, Taparowsky EJ, Hu CD. Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. EMBO J. 2006 Mar 8;25(5):1058-69 Green TA, Alibhai IN, Unterberg S, Neve RL, Ghose S, Tamminga CA, Nestler EJ. Induction of activating transcription factors (ATFs) ATF2, ATF3, and ATF4 in the nucleus accumbens and their regulation of emotional behavior. J Neurosci. 2008 Feb 27;28(9):2025-32 Makino C, Sano Y, Shinagawa T, Millar JB, Ishii S. Sin1 binds to both ATF-2 and p38 and enhances ATF-2-dependent transcription in an SAPK signaling pathway. Genes Cells. 2006 Nov;11(11):1239-51 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu 175 ATF2 (activating transcription factor 2) Huret JL B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008 Sep 26;321(5897):1801-6 Inoue N.. IL23A (interleukin 23, alpha subunit p19). Atlas Genet Cytogenet Oncol Haematol. May 2010. URL : http://AtlasGeneticsOncology.org/Genes/IL23AID44517ch12q1 3.html Kristiansen M, Hughes R, Patel P, Jacques TS, Clark AR, Ham J.. Mkp1 is a c-Jun target gene that antagonizes JNKdependent apoptosis in sympathetic neurons. Neurosci. 2010 Aug 11;30(32):10820-32. doi: 10.1523/JNEUROSCI.282410.2010. Kojima M, Suzuki T, Maekawa T, Ishii S, Sumi-Ichinose C, Nomura T, Ichinose H. Increased expression of tyrosine hydroxylase and anomalous neurites in catecholaminergic neurons of ATF-2 null mice. J Neurosci Res. 2008 Feb 15;86(3):544-52 Li S, Ezhevsky S, Dewing A, Cato MH, Scortegagna M, Bhoumik A, Breitwieser W, Braddock D, Eroshkin A, Qi J, Chen M, Kim JY, Jones S, Jones N, Rickert R, Ronai ZA.. Radiation Sensitivity and Tumor Susceptibility in ATM Phospho-Mutant ATF2 Mice. Genes Cancer. 2010 Apr 1;1(4):316-330. Maekawa T, Sano Y, Shinagawa T, Rahman Z, Sakuma T, Nomura S, Licht JD, Ishii S. ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors. Oncogene. 2008 Feb 14;27(8):1045-54 Liao H, Hyman MC, Baek AE, Fukase K, Pinsky DJ.. cAMP/CREB-mediated transcriptional regulation of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) expression. J Biol Chem. 2010 May 7;285(19):14791-805. doi: 10.1074/jbc.M110.116905. Epub 2010 Feb 23. Vale-Cruz DS, Ma Q, Syme J, LuValle PA. Activating transcription factor-2 affects skeletal growth by modulating pRb gene expression. Mech Dev. 2008 Sep-Oct;125(9-10):843-56 Liss AS, Tiwari R, Kralova J, Bose HR Jr.. Cell transformation by v-Rel reveals distinct roles of AP-1 family members in Rel/NF-kappaB oncogenesis. Oncogene. 2010 Sep 2;29(35):4925-37. doi: 10.1038/onc.2010.239. Epub 2010 Jun 21. Chen KC, Chiou YL, Chang LS. JNK1/c-Jun and p38 alpha MAPK/ATF-2 pathways are responsible for upregulation of Fas/FasL in human chronic myeloid leukemia K562 cells upon exposure to Taiwan cobra phospholipase A2. J Cell Biochem. 2009 Oct 15;108(3):612-20 Lopez-Bergami P, Lau E, Ronai Z.. Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer. 2010 Jan;10(1):65-76. doi: 10.1038/nrc2681. Gould Rothberg BE, Berger AJ, Molinaro AM, Subtil A, Krauthammer MO, Camp RL, Bradley WR, Ariyan S, Kluger HM, Rimm DL. Melanoma prognostic model using tissue microarrays and genetic algorithms. J Clin Oncol. 2009 Dec 1;27(34):5772-80 Nair S, Barve A, Khor TO, Shen GX, Lin W, Chan JY, Cai L, Kong AN.. Regulation of Nrf2- and AP-1-mediated gene expression by epigallocatechin-3-gallate and sulforaphane in prostate of Nrf2-knockout or C57BL/6J mice and PC-3 AP-1 human prostate cancer cells. Acta Pharmacol Sin. 2010 Sep;31(9):1223-40. doi: 10.1038/aps.2010.147. Epub 2010 Aug 23. Hassan M, Feyen O, Grinstein E. Fas-induced apoptosis of renal cell carcinoma is mediated by apoptosis signal-regulating kinase 1 via mitochondrial damage-dependent caspase-8 activation. Cell Oncol. 2009;31(6):437-56 Lee JW, Ahn JY, Hasegawa S, Cha BY, Yonezawa T, Nagai K, Seo HJ, Jeon WB, Woo JT. Inhibitory effect of luteolin on osteoclast differentiation and function. Cytotechnology. 2009 Dec;61(3):125-34 Shah M, Bhoumik A, Goel V, Dewing A, Breitwieser W, Kluger H, Krajewski S, Krajewska M, Dehart J, Lau E, Kallenberg DM, Jeong H, Eroshkin A, Bennett DC, Chin L, Bosenberg M, Jones N, Ronai ZA.. A role for ATF2 in regulating MITF and melanoma development. PLoS Genet. 2010 Dec 23;6(12):e1001258. doi: 10.1371/journal.pgen.1001258. Liu Y, Wang Y, Li W, Zheng P, Liu Y. Activating transcription factor 2 and c-Jun-mediated induction of FoxP3 for experimental therapy of mammary tumor in the mouse. Cancer Res. 2009 Jul 15;69(14):5954-60 Xiao L, Rao JN, Zou T, Liu L, Yu TX, Zhu XY, Donahue JM, Wang JY.. Induced ATF-2 represses CDK4 transcription through dimerization with JunD inhibiting intestinal epithelial cell growth after polyamine depletion. Am J Physiol Cell Physiol. 2010 May;298(5):C1226-34. doi: 10.1152/ajpcell.00021.2010. Epub 2010 Feb 24. Towers E, Gilley J, Randall R, Hughes R, Kristiansen M, Ham J. The proapoptotic dp5 gene is a direct target of the MLKJNK-c-Jun pathway in sympathetic neurons. Nucleic Acids Res. 2009 May;37(9):3044-60 Xiao L, Yang YB, Li XM, Xu CF, Li T, Wang XY.. Differential sensitivity of human endometrial carcinoma cells with different PTEN expression to mitogen-activated protein kinase signaling inhibits and implications for therapy. J Cancer Res Clin Oncol. 2010 Jul;136(7):1089-99. doi: 10.1007/s00432-009-0756-4. Epub 2010 Jan 20. Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK. Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription. J Biol Chem. 2009 Mar 27;284(13):8567-81 Yuan Z, Gong S, Luo J, Zheng Z, Song B, Ma S, Guo J, Hu C, Thiel G, Vinson C, Hu CD, Wang Y, Li M. Opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis. Mol Cell Biol. 2009 May;29(9):2431-42 Ackermann J, Ashton G, Lyons S, James D, Hornung JP, Jones N, Breitwieser W.. Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development. PLoS One. 2011 Apr 21;6(4):e19090. doi: 10.1371/journal.pone.0019090. Chen KC, Liu WH, Kao PH, Chang LS. Calcium-stimulated mitogen-activated protein kinase activation elicits Bcl-xL downregulation and Bak upregulation in notexin-treated human neuroblastoma SK-N-SH cells. J Cell Physiol. 2010 Jan;222(1):177-86 Arora H, Qureshi R, Park AK, Park WY.. Coordinated regulation of ATF2 by miR-26b in γ-irradiated lung cancer cells. PLoS One. 2011;6(8):e23802. doi: 10.1371/journal.pone.0023802. Epub 2011 Aug 25. Huret JL.. EWSR1 (Ewing sarcoma breakpoint region 1). Atlas Genet Cytogenet Oncol Haematol. August 2010. URL : http://AtlasGeneticsOncology.org/Genes/EWSR1ID85.html. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) Bobilev I, Novik V, Levi I, Shpilberg O, Levy J, Sharoni Y, Studzinski GP, Danilenko M.. The Nrf2 transcription factor is a positive regulator of myeloid differentiation of acute myeloid 176 ATF2 (activating transcription factor 2) Huret JL leukemia cells. Cancer Biol Ther. 2011 Feb 1;11(3):317-29. Epub 2011 Feb 1. of group IVC phospholipase A2 in allergic asthma: transcriptional regulation by TNFα in bronchoepithelial cells. Biochem J. 2012 Feb 15;442(1):127-37. doi: 10.1042/BJ20111269. Diring J, Camuzeaux B, Donzeau M, Vigneron M, RosaCalatrava M, Kedinger C, Chatton B.. A cytoplasmic negative regulator isoform of ATF7 impairs ATF7 and ATF2 phosphorylation and transcriptional activity. PLoS One. 2011;6(8):e23351. doi: 10.1371/journal.pone.0023351. Epub 2011 Aug 16. Endo M, Nakano M, Kadomatsu T, Fukuhara S, Kuroda H, Mikami S, Hato T, Aoi J, Horiguchi H, Miyata K, Odagiri H, Masuda T, Harada M, Horio H, Hishima T, Nomori H, Ito T, Yamamoto Y, Minami T, Okada S, Takahashi T, Mochizuki N, Iwase H, Oike Y.. Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis. Cancer Res. 2012 Apr 1;72(7):1784-94. doi: 10.1158/0008-5472.CAN-11-3878. Epub 2012 Feb 16. Ferguson BW, Datta S.. Role of heparan sulfate 2-osulfotransferase in prostate cancer cell proliferation, invasion, and growth factor signaling. Prostate Cancer. 2011;2011:893208. doi: 10.1155/2011/893208. Epub 2011 Oct 23. Hamsa TP, Kuttan G.. Berberine inhibits pulmonary metastasis through down-regulation of MMP in metastatic B16F-10 melanoma cells. Phytother Res. 2012 Apr;26(4):568-78. doi: 10.1002/ptr.3586. Epub 2011 Sep 26. Han SI, Yasuda K, Kataoka K.. ATF2 interacts with beta-cellenriched transcription factors, MafA, Pdx1, and beta2, and activates insulin gene transcription. J Biol Chem. 2011 Mar 25;286(12):10449-56. doi: 10.1074/jbc.M110.209510. Epub 2011 Jan 28. Hsu CC, Hu CD.. Critical role of N-terminal end-localized nuclear export signal in regulation of activating transcription factor 2 (ATF2) subcellular localization and transcriptional activity. J Biol Chem. 2012 Mar 9;287(11):8621-32. doi: 10.1074/jbc.M111.294272. Epub 2012 Jan 24. Ramiro-Cortes Y, Guemez-Gamboa A, Moran J.. Reactive oxygen species participate in the p38-mediated apoptosis induced by potassium deprivation and staurosporine in cerebellar granule neurons. Int J Biochem Cell Biol. 2011 Sep;43(9):1373-82. doi: 10.1016/j.biocel.2011.06.001. Epub 2011 Jun 12. Jones KB, Su L, Jin H, Lenz C, Randall RL, Underhill TM, Nielsen TO, Sharma S, Capecchi MR.. SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene. 2012 Jul 16. doi: 10.1038/onc.2012.247. [Epub ahead of print] Seong KH, Li D, Shimizu H, Nakamura R, Ishii S.. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell. 2011 Jun 24;145(7):1049-61. doi: 10.1016/j.cell.2011.05.029. Lau E, Kluger H, Varsano T, Lee K, Scheffler I, Rimm DL, Ideker T, Ronai ZA.. PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell. 2012 Feb 3;148(3):543-55. doi: 10.1016/j.cell.2012.01.016. Song B, Xie B, Wang C, Li M.. Caspase-3 is a target gene of cJun:ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons. Neurosci Lett. 2011 Nov 14;505(2):76-81. doi: 10.1016/j.neulet.2011.09.060. Epub 2011 Oct 1. Lau E, Ronai ZA.. ATF2 - at the crossroad of nuclear and cytosolic functions. J Cell Sci. 2012 Jun 15;125(Pt 12):281524. doi: 10.1242/jcs.095000. Epub 2012 Jun 8. Venkov C, Plieth D, Ni T, Karmaker A, Bian A, George AL Jr, Neilson EG.. Transcriptional networks in epithelialmesenchymal transition. PLoS One. 2011;6(9):e25354. doi: 10.1371/journal.pone.0025354. Epub 2011 Sep 30. Qian J, Ling S, Castillo AC, Long B, Birnbaum Y, Ye Y.. Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia. Am J Physiol Heart Circ Physiol. 2012 May 1;302(9):H1806-17. doi: 10.1152/ajpheart.00929.2011. Epub 2012 Feb 24. Yu Y, Richardson DR.. Cellular iron depletion stimulates the JNK and p38 MAPK signaling transduction pathways, dissociation of ASK1-thioredoxin, and activation of ASK1. J Biol Chem. 2011 Apr 29;286(17):15413-27. doi: 10.1074/jbc.M111.225946. Epub 2011 Mar 5. Xu Y, Liu Z, Guo K.. The effect of JDP2 and ATF2 on the epithelial-mesenchymal transition of human pancreatic cancer cell lines. Pathol Oncol Res. 2012 Jul;18(3):571-7. doi: 10.1007/s12253-011-9476-6. Epub 2011 Nov 23. Baan B, Wanga TAT, van der Zon GCM, Maassen JA , Ouwens DM.. Identification of insulin-regulated ATF2-target genes in 3T3L1 adipocytes and A14 fibroblasts. https://openaccess.leidenuniv.nl/bitstream/handle/1887/13861/ 05.pdf?sequence=8 This article should be referenced as such: Huret JL. ATF2 (activating transcription factor 2). Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3):167-177. Bickford JS, Newsom KJ, Herlihy JD, Mueller C, Keeler B, Qiu X, Walters JN, Su N, Wallet SM, Flotte TR, Nick HS.. Induction Atlas Genet Cytogenet Oncol Haematol. 2013; 17(3) 177