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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.
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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,
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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.
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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,
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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).
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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)
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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
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