# ATF1

## Overview
The ATF1 gene encodes the activating transcription factor 1, a member of the basic leucine zipper (bZIP) family of transcription factors. This protein is integral to the regulation of gene expression in response to various signaling pathways, including those mediated by cyclic AMP (cAMP) and calcium ions (Ca2+). ATF1 functions by forming dimers, either as homodimers or heterodimers with other bZIP family members such as CREB, to bind specific DNA sequences known as cAMP response elements (CRE) (Rehfuss1991The; Liu1993Activating). The protein's activity is modulated through phosphorylation by kinases such as protein kinase A (PKA), which is essential for its role in mediating transcriptional responses to cellular signals (Liu1993Activating). ATF1 is involved in various cellular processes, including growth, differentiation, and stress response, and has been implicated in the regulation of genes related to atheroprotection and cancer progression (Boyle2012Activating; Li2022Phosphorylated). Its interactions with coactivators and chromatin-remodeling factors further underscore its significance in transcriptional regulation and its potential as a therapeutic target in oncology (KingsleyKallesen1999Transcriptional; Takii2015ATF1).

## Structure
The ATF1 protein is a member of the bZIP (basic leucine zipper) family of transcription factors, characterized by a leucine zipper domain that facilitates dimerization and a basic region for DNA binding (Gao2008Distinct). The bZIP domain is essential for its function, enabling sequence-specific DNA-binding and protein dimerization, which are crucial for its role in stress responses and meiotic recombination (Gao2008Distinct). The protein also contains distinct regions that influence various biological processes, such as the osmotic stress activation (OSA) region and the homologous recombination activation (HRA) region (Gao2008Distinct).

ATF1 undergoes post-translational modifications, including phosphorylation, which can affect its activity and interactions. Specifically, phosphorylation by the Sty1 kinase is a key regulatory mechanism that facilitates transcription initiation by creating an interacting platform for other factors (SalatCanela2017Deciphering). The protein's structure includes an intermediate domain rich in positively charged amino acids, which may promote DNA binding and buffer negative charges from phosphorylation (SalatCanela2017Deciphering).

The ATF1 gene spans over 40 kb and consists of 7 exons, with exon 2 containing the initiation ATG codon and exons 6 and 7 encoding the basic domain and leucine zipper (Panagopoulos2002Molecular).

## Function
Activating Transcription Factor 1 (ATF1) is a transcription factor involved in regulating gene expression in response to cAMP and Ca2+ signaling pathways. It shares significant homology with CREB (cAMP response element-binding protein) and can form homodimers and heterodimers that bind to cAMP response elements (CRE) in DNA, facilitating transcriptional activation (Rehfuss1991The; Liu1993Activating). ATF1 is phosphorylated by protein kinase A (PKA) and Ca2+/calmodulin-dependent kinases, which is crucial for its function in mediating transcriptional responses (Liu1993Activating).

ATF1 plays a role in the regulation of genes involved in cellular processes such as growth, differentiation, and stress response. It is active in the nucleus and influences various physiological outcomes by integrating cAMP and Ca2+ signaling pathways (Liu1993Activating). In macrophages, ATF1 is involved in the regulation of genes related to iron handling and lipid transport, contributing to atheroprotective functions by promoting cholesterol export and reducing oxidative stress (Boyle2012Activating). ATF1's activity is modulated by its interaction with coactivators such as p300 and CREB-binding protein, which enhance its transcriptional effects (KingsleyKallesen1999Transcriptional).

## Clinical Significance
The ATF1 gene plays a significant role in various cancers due to alterations in its expression and phosphorylation. In gastric cancer, phosphorylated ATF1 at threonine 184 (p-ATF1-T184) is linked to increased metastasis and poor survival outcomes. This phosphorylation enhances ATF1's transcriptional activity, regulating the expression of Matrix Metalloproteinase 2 (MMP2), which is crucial for cancer metastasis (Li2022Phosphorylated). 

In colorectal cancer (CRC), ATF1 is identified as a key oncogene. Its expression is modulated by promoter-enhancer interactions involving transcription factors SP1 and GATA3. Specific risk alleles, such as rs61926301 and rs7959129, are associated with increased ATF1 expression, correlating with early onset of CRC. ATF1 activates genes in pathways like Wnt, TGF-beta, and MAPK, contributing to tumorigenesis (Tian2019Systematic). 

ATF1 also plays a role in nasopharyngeal carcinoma, where its overexpression and phosphorylation are associated with disease progression. The prolyl isomerase Pin1 regulates ATF1, enhancing its transcriptional activity and promoting tumorigenesis (Huang2016The). These findings underscore ATF1's clinical significance as a potential therapeutic target in cancer treatment.

## Interactions
ATF1 (activating transcription factor 1) is known to participate in various protein-protein and protein-DNA interactions that are crucial for its role in transcriptional regulation. ATF1 can form heterodimers with CREB (cAMP response element-binding protein), facilitated by their homologous basic/leucine-zipper DNA-binding domains. This interaction allows ATF1 to mediate Ca2+- and cAMP-inducible transcriptional activation, similar to CREB (Liu1993Activating).

In the context of the heat shock response, ATF1 interacts with heat shock factor 1 (HSF1) to modulate the expression of heat shock proteins. This interaction is essential for the recruitment of coactivators such as p300 and CREB-binding protein (CBP) to the HSP70 promoter during heat shock. The phosphorylation of ATF1 at specific serine residues is crucial for these interactions, affecting the recruitment of coactivators and the establishment of an active chromatin state (Takii2015ATF1).

ATF1 also interacts with the chromatin-remodeling factor BRG1, which is necessary for the activation of the HSP70 promoter. These interactions highlight ATF1's role in regulating the heat shock response and its involvement in forming transcription complexes that influence gene expression under stress conditions (Takii2015ATF1).


## References


[1. (SalatCanela2017Deciphering) Clàudia Salat-Canela, Esther Paulo, Laura Sánchez-Mir, Mercè Carmona, José Ayté, Baldo Oliva, and Elena Hidalgo. Deciphering the role of the signal- and sty1 kinase-dependent phosphorylation of the stress-responsive transcription factor atf1 on gene activation. Journal of Biological Chemistry, 292(33):13635–13644, August 2017. URL: http://dx.doi.org/10.1074/jbc.m117.794339, doi:10.1074/jbc.m117.794339. This article has 32 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m117.794339)

[2. (Gao2008Distinct) J. Gao, M. K. Davidson, and W. P. Wahls. Distinct regions of atf/creb proteins atf1 and pcr1 control recombination hotspot ade6-m26 and the osmotic stress response. Nucleic Acids Research, 36(9):2838–2851, March 2008. URL: http://dx.doi.org/10.1093/nar/gkn037, doi:10.1093/nar/gkn037. This article has 40 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkn037)

[3. (Tian2019Systematic) Jianbo Tian, Jiang Chang, Jing Gong, Jiao Lou, Mingpeng Fu, Jiaoyuan Li, Juntao Ke, Ying Zhu, Yajie Gong, Yang Yang, Danyi Zou, Xiating Peng, Nan Yang, Shufang Mei, Xiaoyang Wang, Rong Zhong, Kailin Cai, and Xiaoping Miao. Systematic functional interrogation of genes in gwas loci identified atf1 as a key driver in colorectal cancer modulated by a promoter-enhancer interaction. The American Journal of Human Genetics, 105(1):29–47, July 2019. URL: http://dx.doi.org/10.1016/j.ajhg.2019.05.004, doi:10.1016/j.ajhg.2019.05.004. This article has 42 citations.](https://doi.org/10.1016/j.ajhg.2019.05.004)

[4. (Liu1993Activating) F. Liu, M.A. Thompson, S. Wagner, M.E. Greenberg, and M.R. Green. Activating transcription factor-1 can mediate ca(2+)- and camp-inducible transcriptional activation. Journal of Biological Chemistry, 268(9):6714–6720, March 1993. URL: http://dx.doi.org/10.1016/s0021-9258(18)53308-1, doi:10.1016/s0021-9258(18)53308-1. This article has 110 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0021-9258(18)53308-1)

[5. (Takii2015ATF1) Ryosuke Takii, Mitsuaki Fujimoto, Ke Tan, Eiichi Takaki, Naoki Hayashida, Ryuichiro Nakato, Katsuhiko Shirahige, and Akira Nakai. Atf1 modulates the heat shock response by regulating the stress-inducible heat shock factor 1 transcription complex. Molecular and Cellular Biology, 35(1):11–25, January 2015. URL: http://dx.doi.org/10.1128/mcb.00754-14, doi:10.1128/mcb.00754-14. This article has 47 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.00754-14)

[6. (Li2022Phosphorylated) Tong Li, Huiyuan Cao, Sa Wu, Peimin Zhong, Jie Ding, Jing Wang, Fangfang Wang, Zhiwei He, and Guo-Liang Huang. Phosphorylated atf1 at thr184 promotes metastasis and regulates mmp2 expression in gastric cancer. Journal of Translational Medicine, April 2022. URL: http://dx.doi.org/10.1186/s12967-022-03361-3, doi:10.1186/s12967-022-03361-3. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12967-022-03361-3)

[7. (Panagopoulos2002Molecular) Ioannis Panagopoulos, Fredrik Mertens, Maria Dêbiec‐Rychter, Margareth Isaksson, Janusz Limon, Iwona Kardas, Henryk A. Domanski, Raf Sciot, Danuta Perek, Sead Crnalic, Olle Larsson, and Nils Mandahl. Molecular genetic characterization of the ews/atf1 fusion gene in clear cell sarcoma of tendons and aponeuroses. International Journal of Cancer, 99(4):560–567, April 2002. URL: http://dx.doi.org/10.1002/ijc.10404, doi:10.1002/ijc.10404. This article has 126 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/ijc.10404)

[8. (Boyle2012Activating) Joseph J. Boyle, Michael Johns, Theresa Kampfer, Aivi T. Nguyen, Laurence Game, Dominik J. Schaer, Justin C. Mason, and Dorian O. Haskard. Activating transcription factor 1 directs mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circulation Research, 110(1):20–33, January 2012. URL: http://dx.doi.org/10.1161/circresaha.111.247577, doi:10.1161/circresaha.111.247577. This article has 168 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1161/circresaha.111.247577)

[9. (KingsleyKallesen1999Transcriptional) Michelle L. Kingsley-Kallesen, David Kelly, and Angie Rizzino. Transcriptional regulation of the transforming growth factor-β2 promoter by camp-responsive element-binding protein (creb) and activating transcription factor-1 (atf-1) is modulated by protein kinases and the coactivators p300 and creb-binding protein. Journal of Biological Chemistry, 274(48):34020–34028, November 1999. URL: http://dx.doi.org/10.1074/jbc.274.48.34020, doi:10.1074/jbc.274.48.34020. This article has 51 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.274.48.34020)

[10. (Huang2016The) Guo-Liang Huang, Dan Liao, Hua Chen, Yan Lu, Liyong Chen, Huahui Li, Binbin Li, Weilong Liu, Caiguo Ye, Tong Li, Zhu Zhu, Jian Wang, Takafumi Uchida, Ying Zou, Zigang Dong, and Zhiwei He. The protein level and transcription activity of activating transcription factor 1 is regulated by prolyl isomerase pin1 in nasopharyngeal carcinoma progression. Cell Death & Disease, 7(12):e2571–e2571, December 2016. URL: http://dx.doi.org/10.1038/cddis.2016.349, doi:10.1038/cddis.2016.349. This article has 26 citations.](https://doi.org/10.1038/cddis.2016.349)

[11. (Rehfuss1991The) R.P. Rehfuss, K.M. Walton, M.M. Loriaux, and R.H. Goodman. The camp-regulated enhancer-binding protein atf-1 activates transcription in response to camp-dependent protein kinase a. Journal of Biological Chemistry, 266(28):18431–18434, October 1991. URL: http://dx.doi.org/10.1016/s0021-9258(18)55078-x, doi:10.1016/s0021-9258(18)55078-x. This article has 168 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0021-9258(18)55078-x)