Alternative titles; symbols
HGNC Approved Gene Symbol: ATF2
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:175,072,259-175,168,203 (from NCBI)
The cAMP response element (CRE) is an octanucleotide motif (TGACGTCA) that mediates diverse transcriptionally regulatory effects. It was first identified as an inducible enhancer of genes that can be transcribed in response to increased cAMP levels. Some growth control genes such as FOS (164810) have CRE in their transcriptional regulatory region and their expression is induced by increase in the intracellular cAMP levels. By cDNA cloning, multiple CRE-binding proteins have been identified. CREB1, originally called simply CREB (123810), was isolated by Gonzalez et al. (1989); a gene called CREB2, or CREBP1, but officially designated ATF2 (activating transcription factor-2) was cloned by Maekawa et al. (1989). All of the CRE-binding proteins have the leucine zipper structure linked to a cluster of basic amino acids in their DNA-binding domain. The regulatory element TGACGTCA is found upstream of a number of viral and cellular genes. This element has been demonstrated to mediate cyclic AMP induction of cellular genes and activation of viral genes. The CREB, or ATF, proteins bind to this motif and mediate activation by cAMP and the adenovirus E1A protein.
The transcription factor ATF2 is a DNA-binding protein that binds to cAMP response elements (CREs), forms a homodimer or heterodimer with c-Jun (165160), and stimulates CRE-dependent transcription. Kawasaki et al. (2000) reported that ATF2 is a histone acetyltransferase (HAT) that specifically acetylates histones H2B and H4 in vitro. Motif A, which is located in the HAT domain, is responsible for the stimulation of CRE-dependent transcription. Moreover, in response to ultraviolet irradiation, phosphorylation of ATF2 is accompanied by enhanced HAT activity of ATF2 and CRE-dependent transcription. These results indicated that phosphorylation of ATF2 controls its intrinsic HAT activity and its action on CRE-dependent transcription. Kawasaki et al. (2000) concluded that ATF2 may represent a new class of sequence-specific factors that are able to activate transcription by direct effects on chromatin components.
Bailey et al. (2002) isolated 2 ATF2 proteins of 60 and 28 kD, which represent full-length ATF2 and a novel small isoform of ATF2 that they termed ATF2-small (ATF2-sm). ATF2-sm has no intrinsic HAT activity, but has potent transactivation properties in common with full-length ATF2. These proteins appear to be spatially expressed within the myometrium of the upper and lower uterine regions. The authors concluded that identification and functional characterization of these basic region/leucine zipper proteins in the myometrium may provide further insight into the molecular mechanisms regulating uterine activity during fetal maturation and parturition.
Bhoumik et al. (2005) found that ATM (607585) phosphorylated ATF2 on ser490 and ser498 following ionizing radiation in several human cell lines. The dose- and time-dependent phosphorylation of ATF2 by ATM resulted in colocalization of ATF2 with gamma-H2AX (601772) and with components of the MRE11 (600814)-RAD50 (604040)-NBS1 (602667) (MRN) complex at radiation-induced DNA repair foci. Inhibition of ATF2 expression by RNA interference decreased recruitment of MRE11 to repair foci, abrogated S-phase checkpoint, reduced activation of ATM, CHK1 (603078), and CHK2 (604373), and impaired radioresistance. Phosphorylation of ATF2 on thr69 and thr71 by JNK (see 601158)/p38 (MAPK14; 600289) is a prerequisite for its transcriptional activity, but inhibition of JNK/p38 or point mutation of thr69 and thr71 did not alter recruitment of ATF2 to DNA repair foci and S-phase checkpoint. The DNA-binding domain of mouse Atf2 was dispensable for localization of Atf2 at repair foci following irradiation of mouse embryonic fibroblasts. Bhoumik et al. (2005) concluded that ATF2 specifically recruits MRE11 and NBS1 to DNA repair foci and that the role of ATF2 in DNA damage repair is uncoupled from its transcriptional activity.
Using luciferase analysis, Kimura (2008) found that IRF2BP1 (615331) repressed ATF2-mediated transcriptional activation in the absence of JDP2 (608657), which also represses ATF2 and interacts with IRF2BP1. Coexpression analysis showed that the repressive effects of IRF2BP1 and JDP2 on ATF-dependent activation were additive. Protein pull-down assays showed that IRF2BP1 interacted with ATF2 directly.
Seong et al. (2011) found that Atf2 was involved in heterochromatin formation in flies and that stress-induced activation of Atf2 disrupted heterochromatin. Heat stress-induced heterochromatin disruption was inherited in a nonmendelian fashion by subsequent generations.
By study of human-mouse somatic cell hybrids and by fluorescence in situ hybridization, Ozawa et al. (1991) mapped the ATF4 gene to chromosome 2q32, a site very close to that of the CREB1 gene. Diep et al. (1991) also showed that the ATF4 gene is on chromosome 2 by Southern blot analysis of genomic DNA from a panel of mouse-human somatic cell hybrids. By in situ hybridization they further regionalized the gene to chromosome 2q24.1-q32. Although the genes for CREB1 and ATF4 map to a similar region on 2q, they have only limited DNA sequence homology; whether they are part of a gene cluster is unclear.
The ATF2 gene had been referred to in the literature as CREB2. The CREB2 designation had also been used for the ATF4 gene (604064).
Since knockout of the Atf2 gene in mice leads to early postnatal lethality, Bhoumik et al. (2008) selectively deleted Atf2 in keratinocytes to study its role in skin. When subjected to a 2-stage skin carcinogenesis protocol, Atf2 mutant mice showed significant increases in both the incidence and prevalence of papillomas compared with wildtype mice. Keratinocytes of Atf2 mutant mice exhibited greater anchorage-independent growth compared with wildtype keratinocytes. Papillomas of Atf2 mutant mice exhibited reduced expression of presenilin-1 (PSEN1; 104311) and Notch1 (190198) and enhanced expression of beta-catenin (CTNNB1; 116806) and cyclin D1 (CCND1; 168461). Tissue microarray analysis showed reduced nuclear ATF2 and increased beta-catenin expression in samples of human squamous and basal cell carcinomas compared with normal human skin. Bhoumik et al. (2008) concluded that ATF2 suppresses tumor formation in skin.
Chen et al. (2008) described a disorder of standard poodle puppies termed 'neonatal encephalopathy with seizures' (NEWS). Affected puppies are small and weak at birth and either die within the first week of life or develop ataxia and severe generalized seizures, leading to death by age 7 weeks. A large pedigree of 78 poodles including 20 affected puppies was examined; inheritance was consistent with autosomal recessive. Cerebella from affected puppies were reduced in size and often contained dysplastic foci of clusters of intermixed granule and Purkinje neurons. Genomewide mapping identified a candidate locus including the canine ortholog of the ATF2 gene. Sequence analysis identified a homozygous 152T-G transversion in exon 3 of the Atf2 gene, resulting in a met51-to-arg (M51R) substitution that segregated with the disorder in all affected puppies. The M51R substitution occurs adjacent to the alpha-helix that forms the backbone of the zinc finger in the transactivation domain of ATF2, and was predicted to disrupt MAPK docking sites.
Bailey, J., Phillips, R. J., Pollard, A. J., Gilmore, K., Robson, S. C., Europe-Finner, G. N. 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. Endocr. Metab. 87: 1717-1728, 2002. [PubMed: 11932306] [Full Text: https://doi.org/10.1210/jcem.87.4.8360]
Bhoumik, A., Fichtman, B., DeRossi, C., Breitwieser, W., Kluger, H. M., Davis, S., Subtil, A., Meltzer, P., Krajewski, S., Jones, N., Ronai, Z. Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proc. Nat. Acad. Sci. 105: 1674-1679, 2008. [PubMed: 18227516] [Full Text: https://doi.org/10.1073/pnas.0706057105]
Bhoumik, A., Takahashi, S., Breitweiser, W., Shiloh, Y., Jones, N., Ronai, Z. ATM-dependent phosphorylation of ATF2 is required for the DNA damage response. Molec. Cell 18: 577-587, 2005. [PubMed: 15916964] [Full Text: https://doi.org/10.1016/j.molcel.2005.04.015]
Chen, X., Johnson, G. S., Schnabel, R. D., Taylor, J. F., Johnson, G. C., Parker, H. G., Patterson, E. E., Katz, M. L., Awano, T., Khan, S., O'Brien, D. P. A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. Neurogenetics 9: 41-49, 2008. [PubMed: 18074159] [Full Text: https://doi.org/10.1007/s10048-007-0112-2]
Diep, A., Li, C., Klisak, I., Mohandas, T., Sparkes, R. S., Gaynor, R., Lusis, A. J. Assignment of the gene for cyclic AMP-response element binding protein 2 (CREB2) to human chromosome 2q24.1-q32. Genomics 11: 1161-1163, 1991. [PubMed: 1838349] [Full Text: https://doi.org/10.1016/0888-7543(91)90047-i]
Gonzalez, G. A., Yamamoto, K. K., Fischer, W. H., Karr, D., Menzel, R., Biggs, W., III, Vale, W. W., Montminy, M. R. A cluster of phosphorylation sites on the cyclic-AMP regulated nuclear factor CREB predicted by its sequence. Nature 337: 749-752, 1989. [PubMed: 2521922] [Full Text: https://doi.org/10.1038/337749a0]
Kawasaki, H., Schiltz, L., Chiu, R., Itakura, K., Taira, K., Nakatani, Y., Yokoyama, K. K. ATF-2 has intrinsic histone acetyltransferase activity which is modulated by phosphorylation. Nature 405: 195-200, 2000. [PubMed: 10821277] [Full Text: https://doi.org/10.1038/35012097]
Kimura, M. IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2-dependent transcription. FEBS Lett. 582: 2833-2837, 2008. [PubMed: 18671972] [Full Text: https://doi.org/10.1016/j.febslet.2008.07.033]
Maekawa, T., Sakura, H., Kanei-Ishii, C., Sudo, T., Yoshimura, T., Fujisawa, J., Yoshida, M., Ishii, S. Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO J. 8: 2023-2028, 1989. [PubMed: 2529117] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb03610.x]
Ozawa, K., Sudo, T., Soeda, E.-I., Yoshida, M. C., Ishii, S. Assignment of the human CREB2 (CRE-BP1) gene to 2q32. Genomics 10: 1103-1104, 1991. [PubMed: 1833307] [Full Text: https://doi.org/10.1016/0888-7543(91)90210-6]
Seong, K.-H., Li, D., Shimizu, H., Nakamura, R., Ishii, S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell 145: 1049-1061, 2011. [PubMed: 21703449] [Full Text: https://doi.org/10.1016/j.cell.2011.05.029]