HGNC Approved Gene Symbol: ATF3
Cytogenetic location: 1q32.3 Genomic coordinates (GRCh38): 1:212,565,407-212,620,777 (from NCBI)
ATF3 belongs to the ATF/CREB family of transcription factors, which regulate gene expression by binding via their basic region-leucine zipper (bZIP) domain to consensus ATF/CREB elements in DNA. ATF3 can also interact with proteins via its bZIP domain and regulate cellular functions independently of its transcriptional activity (Wang et al., 2012).
An activating transcription factor (ATF)-binding site is a promoter element present in a wide variety of viral and cellular genes, including E1A-inducible adenoviral genes and cAMP-inducible cellular genes. By screening expression cDNA libraries with a DNA probe containing 3 tandem ATF-binding sites, Hai et al. (1989) isolated human cDNAs derived from 8 separate genes encoding ATF consensus-binding proteins, including ATF3. Members of this family share significant sequence similarity within a leucine zipper DNA-binding motif and an adjacent basic region; the proteins show little similarity outside of these regions.
By screening a HeLa cell cDNA library with a partial ATF3 cDNA (Hai et al., 1989), Chen et al. (1994) isolated a full-length ATF3 cDNA. The deduced protein has 181 amino acids and a calculated molecular mass of 22 kD. Chen et al. (1994) also isolated an alternatively spliced form of ATF3 cDNA that encodes a truncated 118-residue ATF3 protein, called ATF3-delta-zip, that lacks the leucine zipper dimerization domain.
Hashimoto et al. (2002) cloned 2 splice variants of ATF3, ATF3-delta-zip2a and AFT3-delta-zip2b, that both encode a truncated, 135-amino acid protein lacking the C-terminal leucine zipper domain. The N-terminal 115 residues of ATF3-delta-zip2 are identical to those of full-length ATF3 and AFT3-delta-zip. When expressed in COS-7 cells, all fluorescence-tagged ATF3 isoforms were expressed in nuclei.
Hashimoto et al. (2002) found that the ATF3 gene has at least 5 exons.
Hartz (2018) mapped the ATF3 gene to chromosome 1q32.3 based on an alignment of the ATF3 sequence (GenBank L19871) with the genomic sequence (GRCh38).
Using cotransfection studies, Chen et al. (1994) demonstrated that ATF3, which is a member of the mammalian activation transcription factor/cAMP responsive element-binding (CREB) protein family of transcription factors, actually represses transcription from promoters with ATF sites. The truncated ATF3 variant, which does not bind DNA, stimulates transcription and antagonizes the action of ATF3. Chen et al. (1994) presented evidence for a 'cofactor model' of ATF3 repression in which ATF3 stabilizes the binding of inhibitory cofactors at the promoter.
Hashimoto et al. (2002) found that ATF3-delta-zip2 and full-length ATF3 were induced by stress stimuli that perturbed calcium homeostasis, inhibited N-glycosylation, or induced proinflammatory cytokines. In human umbilical vein endothelial cells (HUVECs), stress-induced ATF3-delta-zip2 countered transcriptional repression by full-length ATF3.
Using cluster analysis of transcriptome data derived from Tlr4 (603030)-activated mouse macrophages, Gilchrist et al. (2006) identified a group of genes regulated by Atf3. Network analysis predicted that Atf3 belongs to a transcriptional complex that includes members of the Nfkb (see 164011) transcription factor family. Promoter analysis, followed by chromatin immunoprecipitation (ChIP) and microarray analyses, indicated an overrepresentation of closely apposed Atf3- and Nfkb-binding sites within the putative Atf3-regulated genes, which included Il6 (147620) and Il12b (161561). After activation of mouse macrophages, Atf3 and the Nfkb component Rel (164910) bound to the regulatory regions of Il6 and Il12b, with Rel functioning as a transcriptional activator and Atf3 functioning as a negative regulator. Injection of Atf3 -/- mice with lipopolysaccharide (LPS) increased circulating levels of Il6, Il12b, and Tnf (191160) more than 10-fold compared with wildtype mice. ChIP analysis of LPS-treated wildtype mouse macrophages showed that decreased histone acetylation coincided with decreased binding of Rel and increased binding of Atf3 to the Il6 promoter. Histone deacetylation did not occur in Atf3-deficient mouse macrophages, suggesting that ATF3 inhibits IL6 and IL12B transcription by altering chromatin structure and restricting access to transcription factors. Gilchrist et al. (2006) concluded that ATF3 regulates TLR-stimulated inflammatory responses as part of a negative feedback loop.
Wu et al. (2010) reported that the genetic and pharmacologic suppression of calcineurin (601302)/nuclear factor of activated T cells (NFAT; see 600489) function promotes tumor formation in mouse skin and in xenografts, in immune-compromised mice, of H-ras(V12) (190020.0001)-expressing primary human keratinocytes, or keratinocyte-derived squamous cell carcinoma cells. Calcineurin/NFAT inhibition counteracts p53 (191170)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumors, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, Wu et al. (2010) concluded that intact calcineurin/NFAT signaling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.
By analysis of whole blood and peripheral blood mononuclear cells, Hoetzenecker et al. (2012) found that individuals with sepsis had declining levels of the reactive oxygen species (ROS) scavenger, glutathione (see 601002), that correlated with increased ATF3 levels and decreased IL6 levels during sepsis-associated immunosuppression (SAIS). Stimulation of monocytes with endotoxin superinduced NRF2 (NFE2L2; 600492)-dependent ATF3.
Using protein pull-down and coimmunoprecipitation analyses, Wang et al. (2012) found that ATF3 interacted with androgen receptor (AR; 313700). Mutation analysis revealed that the bZIP domain of ATF3 interacted with the DNA-binding and ligand-binding domains of AR. Binding of ATF3 inhibited interaction of AR with androgen-responsive elements (AREs) in DNA and inhibited intramolecular interactions between the N- and C-terminal regions of AR. ATF3 did not interfere with binding between AR and androgen ligand, nor did it inhibit ligand-dependent nuclear translocation of AR. Expression of ATF3 repressed AR-mediated transactivation of an ARE reporter in a dose-dependent manner. Repression was independent of ATF3 transcriptional activity, but it required binding of ATF3 to AR, which blocked binding of AR to target promoters/enhancers. Knockdown of ATF3 via short hairpin RNA in human prostate cancer cell lines increased expression of AR-dependent genes, and knockout of Atf3 in mice promoted proliferation of prostate epithelial cells.
Using mouse models and the rat INS-1 pancreatic beta cell line, Kim et al. (2014) found that chronic ethanol consumption induced Atf3, which then inhibited glucokinase (GCK; 138079) transcriptional activity. Atf3 directly bound to a putative ATF/CREB site in the Gck promoter. Atf3 also counteracted the positive effect of Pdx1 (600733) on Gck transcriptional activity.
Bambouskova et al. (2018) showed that itaconate and dimethylitaconate induce electrophilic stress, react with glutathione and subsequently induce both NRF2-dependent and -independent responses. Bambouskova et al. (2018) found that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to Toll-like receptor stimulation via inhibition of I-kappa-B-zeta (608004) protein induction. The regulation of I-kappa-B-zeta is independent of NRF2, and the authors identified ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of dimethylitaconate could ameliorate IL17 (603149)-I-kappa-B-zeta-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway.
Rosenberger et al. (2008) found that Atf3-deficient mice had enhanced protection against murine cytomegalovirus (MCMV) infection, with reduced liver viral load and hepatic histopathology, compared with wildtype mice. ChIP analysis showed that Atf3 interacted with a cis regulatory element of the Ifng gene (147570). Atf3-deficient natural killer (NK) cells had increased transcription and secretion of Ifng, a factor involved in protection against MCMV. Reconstitution of NK-deficient mice with Atf3-deficient NK cells was more effective against MCMV than replacement with wildtype NK cells. Rosenberger et al. (2008) concluded that ATF3 acts within NK cells to regulate antiviral responses.
Hoetzenecker et al. (2012) found that mice lacking Atf3 were susceptible to endotoxic shock, even under conditions of ROS stress. However, superinduction of Atf3 caused high susceptibility to bacterial and fungal infections, whereas Atf3 -/- mice were resistant to these infections. Mice lacking both Atf3 and Il6 were highly susceptible to bacterial and fungal infections. In a model of SAIS, secondary infections caused less mortality in Atf3 -/- mice than in wildtype mice. Hoetzenecker et al. (2012) concluded that ROS-induced ATF3 is crucial in determining susceptibility to secondary infections during SAIS.
Bambouskova, M., Gorvel, L., Lampropoulou, V., Sergushichev, A., Loginicheva, E., Johnson, K., Korenfeld, D., Mathyer, M. E., Kim, H., Huang, L.-H., Duncan, D., Bregman, H., and 19 others. Electrophilic properties of itaconate and derivatives regulate the I-kappa-B-zeta-ATF3 inflammatory axis. Nature 556: 501-504, 2018. [PubMed: 29670287] [Full Text: https://doi.org/10.1038/s41586-018-0052-z]
Chen, B. P. C., Liang, G., Whelan, J., Hai, T. ATF3 and ATF3-delta-Zip: transcriptional repression versus activation by alternatively spliced isoforms. J. Biol. Chem. 269: 15819-15826, 1994. [PubMed: 7515060]
Gilchrist, M., Thorsson, V., Li, B., Rust, A. G., Korb, M., Roach, J. C., Kennedy, K., Hai, T., Bolouri, H., Aderem, A. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441: 173-178, 2006. Note: Erratum: Nature 451: 1022 only, 2008. [PubMed: 16688168] [Full Text: https://doi.org/10.1038/nature04768]
Hai, T., Liu, F., Coukos, W. J., Green, M. R. Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. Genes Dev. 3: 2083-2090, 1989. Note: Erratum: Genes Dev. 4: 682 only, 1990. [PubMed: 2516827] [Full Text: https://doi.org/10.1101/gad.3.12b.2083]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/14/2018.
Hashimoto, Y., Zhang, C., Kawauchi, J., Imoto, I., Adachi, M. T., Inazawa, J., Amagasa, T., Hai, T., Kitajima, S. An alternatively spliced isoform of transcriptional repressor ATF3 and its induction by stress stimuli. Nucleic Acids Res. 30: 2398-2406, 2002. [PubMed: 12034827] [Full Text: https://doi.org/10.1093/nar/30.11.2398]
Hoetzenecker, W., Echtenacher, B., Guenova, E., Hoetzenecker, K., Woelbing, F., Bruck, J., Teske, A., Valtcheva, N., Fuchs, K., Kneilling, M., Park, J.-H., Kim, K.-H., Kim, K.-W., Hoffmann, P., Krenn, C., Hai, T., Ghoreschi, K., Biedermann, T., Rocken, M. ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Nature Med. 18: 128-134, 2012. [PubMed: 22179317] [Full Text: https://doi.org/10.1038/nm.2557]
Kim, J. Y., Hwang, J.-Y., Lee, D. Y., Song, E. H., Park, K. J., Kim, G. H., Jeong, E. A., Lee, Y. J., Go, M. J., Kim, D. J., Lee, S. S., Kim, B.-J., Song, J., Roh, G. S., Gao, B., Kim, W.-H. Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo. J. Biol. Chem. 289: 27065-27079, 2014. [PubMed: 25074928] [Full Text: https://doi.org/10.1074/jbc.M114.585653]
Rosenberger, C. M., Clark, A. E., Treuting, P. M., Johnson, C. D., Aderem, A. ATF3 regulates MCMV infection in mice by modulating IFN-gamma expression in natural killer cells. Proc. Nat. Acad. Sci. 105: 2544-2549, 2008. [PubMed: 18268321] [Full Text: https://doi.org/10.1073/pnas.0712182105]
Wang, H., Jiang, M., Cui, H., Chen, M., Buttyan, R., Hayward, S. W., Hai, T., Wang, Z., Yan, C. The stress response mediator ATF3 represses androgen signaling by binding the androgen receptor. Molec. Cell. Biol. 32: 3190-3202, 2012. [PubMed: 22665497] [Full Text: https://doi.org/10.1128/MCB.00159-12]
Wu, X., Nguyen, B.-C., Dziunycz, P., Chang, S., Brooks, Y., Lefort, K., Hofbauer, G. F. L., Dotto, G. P. Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature 465: 368-372, 2010. [PubMed: 20485437] [Full Text: https://doi.org/10.1038/nature08996]