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ATF2 (activating transcription factor 2)

Written2012-10Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
This article is an update of :
2007-07Pedro A Lazo, Ana Sevilla
Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain

(Note : for Links provided by Atlas : click)


HGNC (Hugo) ATF2
HGNC Alias symbTREB7
HGNC Previous nameCREB2
HGNC Previous namecAMP responsive element binding protein 2
LocusID (NCBI) 1386
Atlas_Id 718
Location 2q31.1  [Link to chromosome band 2q31]
Location_base_pair Starts at 175072259 and ends at 175168203 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ATF2.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)
DDIT3 (12q13.3)::ATF2 (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, angiomatoid fibrous histiocytoma) harboring a or a respectively (review in Huret, 2010).


  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.
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-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 ATF2-sm 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).


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 19-106, 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).
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).
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, 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 RAS-MEK-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 Thr53-phosphorylating 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 b-ZIP 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, "b-ZIP") of ATF2 enables homo- or hetero-dimerization.
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 MAPK14-induced 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/JUN-target 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.

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 ATF2-dependent 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. 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).

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-CASP8-BID 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 death-inducing 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).

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).


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 type-specific 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).
Somatic V258I in lung cancer cell lines (Woo et al., 2002). K105T in pancreatic cancer cell lines (Jones et al., 2008).

Implicated in

Entity Angiogenesis
Note 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).
Entity 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. TGF-beta induces EMT, and is up-regulated by ATF2 (Bakin et al., 2002; Venkov et al., 2011; Xu et al., 2012).
Entity 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).
Entity 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 (Al-Salleeh 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).
Entity 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 CRE-like regulatory element lying 210 bp upstream of the CD39 transcriptional start point (Liao et al., 2010).
Entity Bone development
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 progress through the cell cycle, which is essential in regulating cell proliferation vs differentiation.of chondrocytes and endochondral bone growth (Vale-Cruz 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).
Entity Brain
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). 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 JNK-mediated phosphorylation of JUN and protect sympathetic neurons from apoptosis (Kristiansen et al., 2010).
ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses (Green et al., 2008), see Table 1.
Table 1. Induction of activating transcription factors in the nucleus accumbens and their regulation of emotional behavior. (from Green et al., 2008).
Entity Skin and skin cancers
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).
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).
Entity 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).
Entity Leukemias
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,25-dihydroxyvitamin 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).
Entity 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 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).
Entity 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).
Entity Prostate cancer
Note Heparan-sulfate proteoglycans are required for maximal growth factor signaling in prostate cancer progression. HS2ST1 (heparan sulfate 2-O-sulfotransferase, 2OST) is essential for maximal proliferation and invasion. HS2ST1 is upregulated by ATF2 (Ferguson and Datta, 2011).
Entity Lung cancer
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).
Entity Other cancers
Note Increased expression of ATF2 and ATF1 in nasopharyngeal carcinoma cells was associated with clinical stages (Su et al., 2011).


Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development.
Ackermann J, Ashton G, Lyons S, James D, Hornung JP, Jones N, Breitwieser W.
PLoS One. 2011 Apr 21;6(4):e19090. doi: 10.1371/journal.pone.0019090.
PMID 21533046
Epigenetic determination of a cell-specific gene expression program by ATF-2 and the histone variant macroH2A.
Agelopoulos M, Thanos D.
EMBO J. 2006 Oct 18;25(20):4843-53. Epub 2006 Oct 12.
PMID 17036053
Promoter analysis reveals critical roles for SMAD-3 and ATF-2 in expression of IL-23 p19 in macrophages.
Al-Salleeh F, Petro TM.
J Immunol. 2008 Oct 1;181(7):4523-33.
PMID 18802055
Coordinated regulation of ATF2 by miR-26b in γ-irradiated lung cancer cells.
Arora H, Qureshi R, Park AK, Park WY.
PLoS One. 2011;6(8):e23802. doi: 10.1371/journal.pone.0023802. Epub 2011 Aug 25.
PMID 21901137
Identification of insulin-regulated ATF2-target genes in 3T3L1 adipocytes and A14 fibroblasts.
Baan B, Wanga TAT, van der Zon GCM, 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.
Baan B, van Dam H, van der Zon GC, Maassen JA, Ouwens DM.
Mol Endocrinol. 2006 Aug;20(8):1786-95. Epub 2006 Apr 6.
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Xiao L, Yang YB, Li XM, Xu CF, Li T, Wang XY.
J Cancer Res Clin Oncol. 2010 Jul;136(7):1089-99. doi: 10.1007/s00432-009-0756-4. Epub 2010 Jan 20.
PMID 20087603
The effect of JDP2 and ATF2 on the epithelial-mesenchymal transition of human pancreatic cancer cell lines.
Xu Y, Liu Z, Guo K.
Pathol Oncol Res. 2012 Jul;18(3):571-7. doi: 10.1007/s12253-011-9476-6. Epub 2011 Nov 23.
PMID 22109562
Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription.
Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK.
J Biol Chem. 2009 Mar 27;284(13):8567-81. Epub 2009 Jan 28.
PMID 19176525
Cellular iron depletion stimulates the JNK and p38 MAPK signaling transduction pathways, dissociation of ASK1-thioredoxin, and activation of ASK1.
Yu Y, Richardson DR.
J Biol Chem. 2011 Apr 29;286(17):15413-27. doi: 10.1074/jbc.M111.225946. Epub 2011 Mar 5.
PMID 21378396
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Mol Cell Biol. 2009 May;29(9):2431-42. Epub 2009 Mar 2.
PMID 19255142
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This paper should be referenced as such :
Huret, JL
ATF2 (activating transcription factor 2)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(3):167-177.
Free journal version : [ pdf ]   [ DOI ]
History of this paper:
Lazo, PA ; Sevilla, A. ATF2 (activating transcription factor 2). Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):33-34.

External links

HGNC (Hugo)ATF2   784
Atlas Explorer : (Salamanque)ATF2
Entrez_Gene (NCBI)ATF2    activating transcription factor 2
AliasesCRE-BP1; CREB-2; CREB2; HB16; 
GeneCards (Weizmann)ATF2
Ensembl hg19 (Hinxton)ENSG00000115966 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000115966 [Gene_View]  ENSG00000115966 [Sequence]  chr2:175072259-175168203 [Contig_View]  ATF2 [Vega]
ICGC DataPortalENSG00000115966
TCGA cBioPortalATF2
AceView (NCBI)ATF2
Genatlas (Paris)ATF2
SOURCE (Princeton)ATF2
Genetics Home Reference (NIH)ATF2
Genomic and cartography
GoldenPath hg38 (UCSC)ATF2  -     chr2:175072259-175168203 -  2q31.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ATF2  -     2q31.1   [Description]    (hg19-Feb_2009)
GoldenPathATF2 - 2q31.1 [CytoView hg19]  ATF2 - 2q31.1 [CytoView hg38]
Genome Data Viewer NCBIATF2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF283776 AI200584 AK128731 AL050192 AY029364
RefSeq transcript (Entrez)NM_001256090 NM_001256091 NM_001256092 NM_001256093 NM_001256094 NM_001880
Consensus coding sequences : CCDS (NCBI)ATF2
Gene ExpressionATF2 [ NCBI-GEO ]   ATF2 [ EBI - ARRAY_EXPRESS ]   ATF2 [ SEEK ]   ATF2 [ MEM ]
Gene Expression Viewer (FireBrowse)ATF2 [ Firebrowse - Broad ]
GenevisibleExpression of ATF2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1386
GTEX Portal (Tissue expression)ATF2
Human Protein AtlasENSG00000115966-ATF2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)ATF2
Human Protein Atlas [tissue]ENSG00000115966-ATF2 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed279 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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