# ATF2

## Overview
ATF2, or activating transcription factor 2, is a gene that encodes a protein belonging to the leucine zipper family of DNA-binding proteins. The ATF2 protein functions as a transcription factor, playing a pivotal role in regulating gene expression in response to various physiological and stress signals. It is characterized by its ability to form heterodimers with other proteins, such as c-Jun, to bind specific DNA response elements and initiate transcriptional programs. The protein's activity is modulated by post-translational modifications, particularly phosphorylation by kinases like JNK/SAPK, which are activated under stress conditions. ATF2 is involved in diverse cellular processes, including stress response, immune response, and cellular growth, and has significant implications in various diseases, including cancer and metabolic disorders (Lau2012ATF2; Livingstone1995ATF2; Watson2017ATF2).

## Structure
The ATF2 protein is a member of the leucine zipper family of DNA-binding proteins, characterized by its basic region for DNA binding and a leucine zipper for dimerization (Panne2004Crystal). The primary structure of ATF2 includes an N-terminal transactivation domain and a C-terminal DNA-binding domain. The transactivation domain is composed of two subdomains: the N-subdomain, which has a zinc finger-like motif, and the C-subdomain, which is flexible and disordered (Nagadoi1999Solution).

The secondary structure of the N-subdomain features an antiparallel beta-sheet and an alpha-helix, stabilized by a zinc atom coordinated by cysteine and histidine residues (Nagadoi1999Solution). The C-subdomain contains threonine residues that are phosphorylated by stress-activated protein kinases, enhancing ATF2's transactivating capacity (Nagadoi1999Solution).

In terms of quaternary structure, ATF2 typically forms a heterodimer with proteins like c-Jun, binding to DNA in a sequence-specific manner (Panne2004Crystal). The ATF2/c-Jun heterodimer binds to DNA with the basic-region helices lying in the major groove, contributing to the regulation of gene expression (Panne2004Crystal). The protein's activity is regulated by post-translational modifications such as phosphorylation (Nagadoi1999Solution).

## Function
ATF2 (activating transcription factor 2) is a transcription factor that plays a crucial role in regulating gene expression in response to various physiological and stress signals in healthy human cells. It is part of the ATF/CREB family and functions primarily through heterodimerization with other proteins, such as CREB and Jun, to bind specific DNA response elements and initiate distinct transcriptional programs (Lau2012ATF2; Livingstone1995ATF2). ATF2 is involved in the transcriptional regulation of genes associated with stress responses, immune responses, and cellular growth (Lau2012ATF2).

ATF2's activity is regulated by phosphorylation, particularly by the JNK/SAPK family of kinases, which are activated by stress conditions. This phosphorylation is essential for ATF2's activation potential and its response to stimuli such as UV irradiation and serum (Livingstone1995ATF2; Watson2017ATF2). In the context of DNA damage, ATF2 is phosphorylated by ATM, which is necessary for the intra-S-phase checkpoint response to halt DNA replication following damage (Bhoumik2008ATF2:).

ATF2 also interacts with coactivators like p300/CBP, which can enhance its transcriptional activity by disrupting its autoinhibition (Lau2012ATF2). These interactions highlight ATF2's role in maintaining cellular homeostasis and responding to environmental stimuli in healthy human cells.

## Clinical Significance
ATF2 plays a significant role in various diseases due to its involvement in gene regulation and cellular processes. In cancer, ATF2 is implicated in tumorigenesis and progression. In melanoma, high nuclear ATF2 expression is associated with poor prognosis and metastatic disease, as it negatively regulates MITF, a key factor in melanocyte transformation (Shah2010A). In breast cancer, ATF2 contributes to endocrine therapy resistance, particularly in tamoxifen-resistant cells, by altering signaling pathways and gene expression, suggesting that targeting ATF2 could overcome this resistance (Giannoudis2020Activating).

In colorectal cancer, reduced ATF2 levels promote tumor invasion and migration through the upregulation of TROP2, a cancer driver associated with aggressive tumors and poor survival outcomes (Huebner2022ATF2). ATF2 also has roles in non-cancerous conditions. In type II diabetes mellitus, ATF2, along with the intronic microRNA hsa-miR-933, regulates genes involved in glucose homeostasis and insulin signaling, contributing to hyperglycemia and insulin resistance (Islam2020Aberration). In neurodegenerative diseases, ATF2 is involved in neuronal protection and regeneration, with its dysregulation linked to conditions like Huntington's and Parkinson's diseases (Islam2020Aberration).

## Interactions
ATF2 interacts with various proteins and is involved in forming multiprotein complexes. It can form homodimers or heterodimers with other bZIP proteins, notably with c-Jun, which enhances its transcriptional activity (Ouwens2002Growth). ATF2 is phosphorylated by JNK and p38 MAPK, which are crucial for its activation and function in response to stress signals (van1995ATF2; Gupta1995Transcription). The retinoblastoma protein (Rb) enhances the association between ATF2 and JNK/p38, leading to increased phosphorylation of ATF2, indicating a synergistic effect in modulating ATF2 activity (Li2001Retinoblastoma).

ATF2 also interacts with the coactivator ASC-2, which enforces its interaction with C/EBPα, crucial for granulocytic differentiation (Hong2004Activation). This interaction is enhanced by retinoic acid, which induces phosphorylation of ATF2, facilitating its role in differentiation (Hong2004Activation). Additionally, ATF2 interacts with viral proteins such as adenovirus E1A and cellular proteins like the tumor suppressor Rb, which modulate its transcriptional activity (Livingstone1995ATF2; Gupta1995Transcription). These interactions highlight ATF2's role in various cellular processes, including stress response and differentiation.


## References


[1. (Panne2004Crystal) Daniel Panne, Tom Maniatis, and Stephen C Harrison. Crystal structure of atf-2/c-jun and irf-3 bound to the interferon-β enhancer. The EMBO Journal, 23(22):4384–4393, October 2004. URL: http://dx.doi.org/10.1038/sj.emboj.7600453, doi:10.1038/sj.emboj.7600453. This article has 144 citations.](https://doi.org/10.1038/sj.emboj.7600453)

[2. (Ouwens2002Growth) D.M. Ouwens. Growth factors can activate atf2 via a two-step mechanism: phosphorylation of thr71 through the ras-mek-erk pathway and of thr69 through ralgds-src-p38. The EMBO Journal, 21(14):3782–3793, July 2002. URL: http://dx.doi.org/10.1093/emboj/cdf361, doi:10.1093/emboj/cdf361. This article has 183 citations.](https://doi.org/10.1093/emboj/cdf361)

[3. (Shah2010A) Meera Shah, Anindita Bhoumik, Vikas Goel, Antimone Dewing, Wolfgang Breitwieser, Harriet Kluger, Stan Krajewski, Maryla Krajewska, Jason DeHart, Eric Lau, David M. Kallenberg, Hyeongnam Jeong, Alexey Eroshkin, Dorothy C. Bennett, Lynda Chin, Marcus Bosenberg, Nic Jones, and Ze’ev A. Ronai. A role for atf2 in regulating mitf and melanoma development. PLoS Genetics, 6(12):e1001258, December 2010. URL: http://dx.doi.org/10.1371/journal.pgen.1001258, doi:10.1371/journal.pgen.1001258. This article has 57 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1371/journal.pgen.1001258)

[4. (Islam2020Aberration) Abul Bashar Mir Md. Khademul Islam, Eusra Mohammad, and Md. Abdullah-Al-Kamran Khan. Aberration of the modulatory functions of intronic microrna hsa-mir-933 on its host gene atf2 results in type ii diabetes mellitus and neurodegenerative disease development. Human Genomics, September 2020. URL: http://dx.doi.org/10.1186/s40246-020-00285-1, doi:10.1186/s40246-020-00285-1. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s40246-020-00285-1)

[5. (Hong2004Activation) SunHwa Hong, Hyun Mi Choi, Min Jung Park, Young Hee Kim, Yoon Ha Choi, Hyung Hoi Kim, Young Hyun Choi, and JaeHun Cheong. Activation and interaction of atf2 with the coactivator asc-2 are responsive for granulocytic differentiation by retinoic acid. Journal of Biological Chemistry, 279(17):16996–17003, April 2004. URL: http://dx.doi.org/10.1074/JBC.M311752200, doi:10.1074/jbc.m311752200. This article has 20 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/JBC.M311752200)

[6. (Li2001Retinoblastoma) Huo Li and Wesley D. Wicks. Retinoblastoma protein interacts with atf2 and jnk/p38 in stimulating the transforming growth factor-β2 promoter. Archives of Biochemistry and Biophysics, 394(1):1–12, October 2001. URL: http://dx.doi.org/10.1006/abbi.2001.2518, doi:10.1006/abbi.2001.2518. This article has 11 citations and is from a peer-reviewed journal.](https://doi.org/10.1006/abbi.2001.2518)

[7. (Livingstone1995ATF2) C. Livingstone, G. Patel, and N. Jones. Atf-2 contains a phosphorylation-dependent transcriptional activation domain. The EMBO Journal, 14(8):1785–1797, April 1995. URL: http://dx.doi.org/10.1002/j.1460-2075.1995.tb07167.x, doi:10.1002/j.1460-2075.1995.tb07167.x. This article has 406 citations.](https://doi.org/10.1002/j.1460-2075.1995.tb07167.x)

[8. (van1995ATF2) H. van Dam, D. Wilhelm, I. Herr, A. Steffen, P. Herrlich, and P. Angel. Atf-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. The EMBO Journal, 14(8):1798–1811, April 1995. URL: http://dx.doi.org/10.1002/j.1460-2075.1995.tb07168.x, doi:10.1002/j.1460-2075.1995.tb07168.x. This article has 468 citations.](https://doi.org/10.1002/j.1460-2075.1995.tb07168.x)

[9. (Watson2017ATF2) Gregory Watson, Ze’ev A. Ronai, and Eric Lau. Atf2, a paradigm of the multifaceted regulation of transcription factors in biology and disease. Pharmacological Research, 119:347–357, May 2017. URL: http://dx.doi.org/10.1016/j.phrs.2017.02.004, doi:10.1016/j.phrs.2017.02.004. This article has 105 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.phrs.2017.02.004)

[10. (Huebner2022ATF2) Kerstin Huebner, Katharina Erlenbach-Wuensch, Jan Prochazka, Ilir Sheraj, Chuanpit Hampel, Blanka Mrazkova, Tereza Michalcikova, Jolana Tureckova, Veronika Iatsiuk, Anne Weissmann, Fulvia Ferrazzi, Philipp Kunze, Enise Nalli, Elisabeth Sammer, Annemarie Gehring, Marie M. Cheema, Markus Eckstein, Eva-Maria Paap, Agnes Soederberg, Corinna Fischer, Sushmita Paul, Vijayalakshmi Mahadevan, Benardina Ndreshkjana, Melanie A. Meier, Susanne Muehlich, Carol I. Geppert, Susanne Merkel, Robert Grutzmann, Adriana Roehe, Sreeparna Banerjee, Arndt Hartmann, Radislav Sedlacek, and Regine Schneider-Stock. Atf2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver trop2. Cellular and Molecular Life Sciences, July 2022. URL: http://dx.doi.org/10.1007/s00018-022-04445-5, doi:10.1007/s00018-022-04445-5. This article has 15 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-022-04445-5)

[11. (Gupta1995Transcription) Shashi Gupta, Debra Campbell, Benoit Dérijard, and Roger J. Davis. Transcription factor atf2 regulation by the jnk signal transduction pathway. Science, 267(5196):389–393, January 1995. URL: http://dx.doi.org/10.1126/science.7824938, doi:10.1126/science.7824938. This article has 1162 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.7824938)

[12. (Nagadoi1999Solution) Aritaka Nagadoi, Ken-ichi Nakazawa, Hiroko Uda, Koichi Okuno, Toshio Maekawa, Shunsuke Ishii, and Yoshifumi Nishimura. Solution structure of the transactivation domain of atf-2 comprising a zinc finger-like subdomain and a flexiblesubdomain. Journal of Molecular Biology, 287(3):593–607, April 1999. URL: http://dx.doi.org/10.1006/jmbi.1999.2620, doi:10.1006/jmbi.1999.2620. This article has 46 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1006/jmbi.1999.2620)

[13. (Lau2012ATF2) Eric Lau and Ze’ev A. Ronai. Atf2 – at the crossroad of nuclear and cytosolic functions. Journal of Cell Science, January 2012. URL: http://dx.doi.org/10.1242/jcs.095000, doi:10.1242/jcs.095000. This article has 66 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.095000)

[14. (Giannoudis2020Activating) Athina Giannoudis, Mohammed Imad Malki, Bharath Rudraraju, Hisham Mohhamed, Suraj Menon, Triantafillos Liloglou, Simak Ali, Jason S. Carroll, and Carlo Palmieri. Activating transcription factor-2 (atf2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer. Breast Cancer Research, November 2020. URL: http://dx.doi.org/10.1186/s13058-020-01359-7, doi:10.1186/s13058-020-01359-7. This article has 13 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/s13058-020-01359-7)

[15. (Bhoumik2008ATF2:) Anindita Bhoumik and Ze’ev Ronai. Atf2: a transcription factor that elicits oncogenic or tumor suppressor activities. Cell Cycle, 7(15):2341–2345, August 2008. URL: http://dx.doi.org/10.4161/cc.6388, doi:10.4161/cc.6388. This article has 81 citations and is from a peer-reviewed journal.](https://doi.org/10.4161/cc.6388)