Control of the cell cycle and mitosis by phosphorylated activating transcription factor 2 and its homologue 7
Chia-Chen Ku1-3, Hitomi Hasegawa5,+, Chang-Shen Lin1-4, Ming-Ho Tsai1-3, Kenly Wuputra1-3, Richard Eckner6, Naoto Yamaguchi5,*, and Kazunari K. Yokoyama1-3,*
1Center for Stem Cell
Research, 2Center for Environmental Medicine, 3Graduate
Institute of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical
University, Kaohsiung, Taiwan. 4Department of Biological Sciences,
transcription factors (ATFs) comprise a family of sequence-specific DNA-binding
proteins that possess a basic region/leucine zipper (bZIP) and they play
multiple roles in the mammalian cells. Despite their diverse physiological
roles, they all share the ability to respond to environmental stresses and
maintain cellular homeostasis. ATF2 and ATF7 are structurally very similar,
especially in terms of their bZIP DNA-binding and dimerization domains, where
they share >90% identity. In response to stress
stimuli, ATFs activate a variety of targets, including cell cycle, DNA damage,
antiproliferation, and apoptosis regulators, although most of these targets
have been studied only G1/S phase events. Recent research
demonstrates that the cycling-dependent kinase 1 specifically phosphorylates
ATF2 and ATF
ATF2 | ATF7 | DNA damage | G2/M progression | phosphorylation | oncogenesis transcription
The activation transcription factor (ATF)/cAMP-response element- binding (CREB) family comprises 16 cellular stress-responsive transcription factors, which are divided into six subgroups, according to their sequence similarity (Figure 1) [1-4]. A common feature shared by all of these proteins is the basic zipper (bZIP) element, which allows them to dimerize and bind to specific DNA sequences [5-10]. The bZIP element comprises a leucine zipper subdomain and a basic region subdomain, which are connected by a short fork . The bZIP transcription factors such as the ATF/cAMP-responsive-element (CRE) family and AP-1 (activation protein 1) family proteins homodimerize, but they can also selectively heterodimerize with each other, e.g., c-Fos, Fra2, and c-Jun [12, 13]. However, they share little similarity apart from the bZIP domain, and their binding sequences, such as binding to the ATF/CRE consensus 5ˊ-TGACGTC/AC/A-3ˊ [12, 14] or the AP-1 consensus 5ˊ-TGACTCA-3ˊ. Among the bZIP transcription factors, particularly the ATF/CREB and AP-1 families, ATF2, ATF7 and CREB5 comprise a similar subfamily based on their sequence conservation [5, 8, 12, 15, 16]. The transcriptional activation and DNA-binding domains of ATF2 and ATF7 are highly conserved and their specificity is governed mainly by posttranslational modifications and interactions with specific cofactors [17-20].
The ATF2 gene is located on chromosome 2q32 and it is encoded by a 505-amino-acid protein, which is expressed ubiquitously, with more abundant expression in the brain [21, 22]. ATF2 exhibits diverse, tissue-dependent functions [23, 24]. For example, ATF2 has been implicated in malignant and non-malignant skin tumor development [25, 26]. ATF2 also elicits a suppressor functions in mammary tumors . In addition, ATF2 has transcription-independent functions in the DNA damage response, chromatin remodeling, and mitochondrial membrane organization.
ATF7 gene is located on chromosome 12q13 and it encodes a 483-amino-acid
protein, which is also expressed ubiquitously. Depending on the cellular
context, the composition of the dimeric complex determines the regulation of
growth, survival, and apoptosis. ATF7 is known to share similarity with
TATA-binding protein associated proteins (TAFs) such as TAF 4 . ATF7 is also critical for neuron networks and social stress-related
responses . These multiple functions of ATF2 and ATF
This short review summarizes our current understanding of the phosphorylation status of ATF2 and ATF7 during the cell cycle and the possible functions of phosphorylated ATF2 and ATF7.
Figure 1. Schematic representation of members of the ATF/CREB transcription factor family. ATF/CREB protein members can be categorized into six subgroups according to their sequence similarity. The red boxes indicate the bZIP domain. (GenBank Accession numbers: AAC60616, Q02930, AAC02258, P18848, AAD51372, and AAB49921). The figure is modified as reported previously (Ref. 24, Figure 2).
Complex isoforms of ATF2 and ATF7
ATF2 has several splice variants, including mouse orthologues (CRE-BP1, CRE-BP2, and CRE-BP-3) and one human isoform (ATFs-sm). The structures of CRE-BP1 and CRE-BP3 are nearly identical, except that eight hydrophobic amino acids in CRE-BP3 replace the first 15 amino acids in CRE-BP1 . By contrast, CRE-BP2 has a 98-amino-acid N-terminal internal deletion. The splice variants of these three murine isoforms occur predominantly in the N- and extreme C-termini, whereas the bZIP domain is conserved, thereby suggesting that the transcription factor function of these variants is conserved, although their regulation might differ due to the loss of various regulatory elements in the N-termini [21, 29]. In agreement with this hypothesis, CRE-BP3 and CRE-BP1 exhibit only weak or no transcriptional activity in murine T cells, respectively, whereas CRE-BP2 exhibits strong transcriptional activity. The human ATF2 splice isoform ATF2-sm lacks the entire bZIP domain and it only retains the first and the last two exons of the full-length ATF2. However, despite the absence of the bZIP domain, ATF2-sm still exhibits its transcriptional activity . ATF2-sm is specifically expressed in endometrial tissue and its protein levels fluctuate dynamically throughout pregnancy . This distinct expression pattern suggests that ATF2 splice variants might elicit tissue- and temporal-specific functions, which may be distinct from those regulated by the full-length ATF2 .
In the case of ATF7, three major different transcripts are encoded in humans. i.e., ATF7-1, ATF7-2, and ATF7-4, whereas only one, ATF7-2, is encoded in the mouse [32, 33]. The ATF7-4 protein contains the common ATF7 N-terminal moiety (88 residues), which encompasses the transcriptional activation domain , but it lacks the entire C-terminal bZIP domain (residues 89–494), and the DNA binding/nuclear localization signal, and a dimerization domain. The ATF7-4 isoform is potentially encoded in many mammalian genomes, but not in the mouse and rat, and it is localized mainly in the cytoplasm . The human ATF2 and human ATF7 genes generate 13 and six transcripts variants, respectively, including noncoding RNA. In order to prepare specific ATF2 and ATF7 short hairpin (sh) knockdown constructs, the care should be taken when selecting the corresponding sequences, as they might present splice variants or noncoding transcripts.
Specificity of antibodies against ATF2 and ATF7
Hasegawa et al. (2014) reported a problem with reagents such as antibodies against ATF2 and ATF7 . Surprisingly, most of the widely used ATF2 antibodies such as N-96 (sc-63233; Santa Cruz Biotechnology Inc.) and phopsho-ATF2 (pT71) (#922; Cell Signaling Technology) can cross-react with ATF7. Thus, most previous studies that used these antibodies also analyzed the ATF7 protein. It is possible to differentiate ATF2 and ATF7 proteins using antibodies from Sigma-Aldrich Co. ATF2 [ss-16] is specific for ATF2 (#A4086; Sigma-Aldrich) and anti-ATF7 antibodies (#SAB250013 and #HPA003384; Sigma-Aldrich) are specific for ATF7. Thus, we consider that the critical observation might lead to re-investigation of previously obtained results.
Role of ATF
of tumor samples in breast cancer and melanoma suggest that ATF2 may possess
tumor suppressive and promoting functions, respectively [27, 36]. Furthermore, the enhanced presence of
activated (Thr71 phosphorylated) ATF2 has been reported in common types of skin
carcinoma, e.g., squamous cell carcinoma, Bowen’s disease, and basal cell
carcinoma, thereby suggesting the involvement of ATF
Loss of function of ATF2 and ATF
et al. (1996) reported that the first Atf2 mouse knockout led to
decreased postnatal viability and reduced growth in animals, as well as defects
in endochondral ossification and in the central nervous system . However, this knockout was subsequently shown
to be hypomorphic because it retained some of the ATF2 activity due to alternative splicing in the targeted allele . Another knockout of ATF2 (Atf20/0) was generated by the deletion of the DNA-binding
domain, which produced, at least transcrip- tionally, a functional null mutation.
All of the Atf20/0
mutant mice died shortly after birth because of severe respiratory distress . Furthermore, Maekawa et al. demonstrated that a knock-in mutant mouse line where the Thr69
and Thr71 (Thr51 and Thr
Figure 2. Phosphorylation of ATF2 protein and ATF7 protein. Schematic representation of various kinases that can phosphorylate ATF2 protein. The model designated as (Cell cycle) was modified (33). Most of the phosphorylation sites are shown during the G1/S phase. Hasegawa et al. (35) reported the cdk1–cycling B complex was phosphorylated in the G2/M phase.
Posttranslational regulation of ATF2 and ATF7
ATF-2 is phosphorylated by many upstream kinases
including stress-activating kinase or protein kinase C (PKC) in the G1/S phase
(Figure 2). JNK,
p38, and Erk, which are activated by stress stimuli, phosphorylate ATF2 at
Thr-69 and Thr-71 (Thr-69/Thr-71) and
lead to its transcriptional activation [47-52]. Moreover, the
phosphorylation of ATF2 at Ser-121 by several PKC isoforms (including α, βI,
βII, and γ) plays a role in the c-Jun-mediated activation of transcription in response
to 12-O-tetradecanoylphorbol-13-acetate . It is known that ATF7
is phosphorylated by p38 at Thr-51 and Thr-53, which correspond to Thr-69 and
Recently, Hasegawa et al. (2014) identified a new kinase
that phosphorylates ATF2 and ATF
ATF-2 is also acetylated on Lys-357 and Lys-374 by p300 or CREB-binding protein (CBP, also known as CREBBP), which contributes to its transcriptional activity . The binding of ATF2 suppresses the acetyltransferase activity of the transcriptional coactivator p300/CBP. The cross-regulation between the acetylation and phosphorylation of ATF2 has yet to be elucidated in the context of its transcriptional activities.
The stability of ATF2 protein is regulated by ubiquitylation and SUMOylation. However, the exact model has not been elucidated in detail. N-terminal phosphorylation and heterodimerization of ATF2 reduce its transcriptional activity by promoting ubiquitylation-dependent degradation . The binding of JNK to ATF2 serves to limit the availability of ATF2 by promoting its degradation, but the E3 ubiquitin ligases involved in the ubiquitylation and degradation of ATF2 have not been identified. The SUMO-conjugating enzyme Ubc9 has been shown to interact with ATF2 and to affect its stability , although ATF2 SUMOylation has not been demonstrated formally.
Interplay between mitochondria and nuclear ATF2
Although the phosphorylation of ATF2 by PKCε is a key determinant of its subcellular localization and function, the precise mechanism underlying its nuclear export and localization to the mitochondria has yet to be determined. PKCε functions as an addicting signal to maintain the nuclear localization of ATF2, which prevents its pro-apoptotic function in the mitochondria. Thus, provides that the activity of PKCε activity is sustained, ATF2 will exhibit oncogenic functions within the nucleus. This interplay might be a critical regulatory effect of ATF2/ATF7 transcription factors.
ATF7 phosphorylation is
al. (2014) showed that the mitotic phosphorylation of ATF7 is involved in
of the kinase activity of Cdk1 induces Aurora A inactivation, although Cdk1
does not directly phosphorylate Aurora A . Activated
Aurora B phosphorylates histone H3 at Ser-10 [68-71]. However,
after Cdk1 is activated, the mitotic phosphorylation of ATF7 precedes the
phosphorylation of histone H3 at Ser-10, which suggests that ATF7 is located
upstream of the
3. Possible roles of ATF2 and ATF7 phosphorylation in G2/M
progression. During the late stages of the G2 and M phases, Thr-51/Thr
Potential functions of ATF2/ATF7 function in
It is well
known that the correct assembly and timely disassembly of the mitotic spindle
is crucial for the propagation of the genome during cell division . The main aim of
mitosis is ensuring that the replicated sister chromatids are segregated with
the highest possible accuracy among the daughter cells. In principal, this is a
mechanical problem related to the generation of a force that segregates the two
sister chromatids of each chromosome and moves them to opposite ends of the
cell division plane. The mitotic spindle provides a platform that facilitates
the accurate alignment of the condensed chromosomes and it comprises a
molecular machine that segregates the sister chromatids . It is essential that
the segregation process is only initiated when each chromosome is aligned in
the center of the spindle and bi-oriented, so the sister chromatids in each
network are subjected to various checkpoints to ensure the accuracy of this
timing . The
proteasome is also known to function at the onset of mitosis [78, 79]. Thus, Hesegawa et al.
(2014) examined the role of ATF
Future studies will reveal the roles of this novel mechanism of ATF2/ATF7 during mitosis progression in cell growth control, transformation, and cancer development.
ATF2 and ATF7 are known to be important as transcription
factors, DNA-damage response proteins and during G2/M progression, but they
also implicated in the regulation of cellular growth and cell division control.
ATF2 and ATF7 have functions in checkpoint control during the intra-S phase and
probably in mitosis, as well as in transcriptional regulation via distinct
upstream regulatory kinases. It is still necessary to clarify whether different
pools of ATF2 and ATF7 are utilized for each of these functions, and whether
their roles in the DNA repair axis affects the transcriptional activities of
ATF2 and ATF7. Novel functions of ATF2 and ATF7 during G2/M progression might
We thank Drs.
O Lee, K Kato, K Nagata, S Lin, YC, G Gachelin and M. Horikoshi for their
advice and discussions. This study was supported by grants from the
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Conflict of interest: No conflicts declared.
*Corresponding Authors: Naoto Yamaguchi (email@example.com), and Kazunari K. yokoyama (firstname.lastname@example.org).
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