# ETS1

## Overview
ETS1 is a gene that encodes the ETS proto-oncogene 1, a transcription factor that belongs to the ETS family of proteins. This transcription factor is characterized by its ability to bind specific DNA sequences, thereby regulating the expression of genes involved in various cellular processes, including immune response, cell proliferation, and differentiation. The ETS1 protein is particularly significant in the immune system, where it influences the development and function of lymphocytes such as B cells, T cells, and natural killer cells (Garrett-Sinha2013Review). Structurally, ETS1 contains a distinctive ETS DNA-binding domain and a Pointed (PNT) domain, which facilitate its interactions with DNA and other proteins (Xu2018Structural; Slupsky1998Structure). The activity of ETS1 is modulated by post-translational modifications, including phosphorylation and sumoylation, which affect its transcriptional regulatory functions (Garrett-Sinha2013Review). Aberrations in ETS1 expression or function are implicated in various pathological conditions, notably autoimmune diseases and cancers, where it can act as an oncogene (A2018Aberrant; Wang2005Ets1).

## Structure
The ETS1 protein is a transcription factor characterized by a complex structure that includes several key domains. The primary structure of ETS1 consists of 441 amino acids in humans, with alternative splicing leading to different isoforms such as p42 and p27, which have distinct functional properties (Garrett-Sinha2013Review). The secondary structure features include the ETS DNA-binding domain, which is composed of five α helices and four-stranded antiparallel β sheets. The H3 helix of the ETS domain specifically inserts into the major groove of DNA, interacting with the GGAA core sequence (Xu2018Structural).

The tertiary structure of ETS1 involves the folding of these domains, with the autoinhibitory module playing a crucial role in regulating DNA binding. This module includes inhibitory helices that pack against the ETS domain, reducing its DNA-binding affinity (Xu2018Structural). The Pointed (PNT) domain, another significant structural feature, is involved in protein-protein interactions and is characterized by a five-helix bundle (Slupsky1998Structure).

Post-translational modifications such as phosphorylation and sumoylation regulate ETS1's activity. Phosphorylation at specific serine and threonine residues can enhance transcriptional activation, while sumoylation generally inhibits its activity (Garrett-Sinha2013Review). These structural and regulatory features are essential for ETS1's role in transcriptional regulation.

## Function
The ETS1 gene encodes a transcription factor that plays a significant role in regulating gene expression in various cellular processes, particularly within the immune system. In healthy human cells, ETS1 is highly expressed in immune tissues such as the thymus, spleen, and lymph nodes, and is involved in the development and functional differentiation of lymphocytes, including B cells, T cells, and natural killer (NK) cells (Garrett-Sinha2013Review). 

ETS1 is crucial for the regulation of cytokine and chemokine gene expression. It acts as a repressor of the cytokine IL-2 by binding to its promoter, displacing positive-acting transcription factors, and is essential for maximal IL-2 production in T cells (Russell2010Transcription). ETS1 also regulates the expression of the inositol 1,4,5-triphosphate receptor type 3 (Itpr3) gene, which is important for T-cell receptor-induced calcium flux and cytokine secretion (Russell2010Transcription).

In B cells, ETS1 is highly expressed in naïve and memory B cells but is downregulated upon activation, which is necessary for their differentiation into plasma cells (Garrett-Sinha2013Review). ETS1 also influences the expression of several cytokines, including IL-2, IFN-γ, IL-4, IL-5, and IL-13, while inhibiting IL-17A production (Russell2010Transcription).

## Clinical Significance
Mutations and alterations in the expression of the ETS1 gene are associated with various diseases, particularly autoimmune disorders and cancers. In autoimmune diseases, ETS1 deficiency in mice leads to altered B cell differentiation and hyperresponsiveness to TLR9, resulting in systemic autoimmune disease characterized by polyclonal B cell activation and production of autoreactive antibodies (Wang2005Ets1). Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) in the ETS1 locus linked to systemic lupus erythematosus (SLE), rheumatoid arthritis, and psoriasis, suggesting a role in these conditions (Garrett-Sinha2013Review).

In cancer, ETS1 is frequently upregulated and can act as an oncogene, promoting invasiveness and poor prognosis in breast cancer and contributing to the pathogenesis of acute monocytic leukemia through translocations (A2018Aberrant). It is also implicated in various hematological malignancies, such as diffuse large B-cell lymphoma and Burkitt lymphoma, where its deregulation contributes to malignant transformation (Testoni2015The). ETS1's role in promoting epithelial-mesenchymal transition and drug resistance further underscores its significance in cancer progression (Dittmer2015The). These findings highlight the clinical importance of ETS1 in both autoimmune and oncogenic processes.

## Interactions
The ETS1 protein, a member of the Ets family of transcription factors, engages in various interactions with both proteins and nucleic acids. ETS1 is known for its ability to form homodimers through the swapping of HI1 helices, which allows it to bind cooperatively to two antiparallel pieces of DNA. This dimerization enhances DNA-binding affinity and may play a regulatory role at high local concentrations (Babayeva2012Structural). ETS1 can also bind to widely separated DNA sites, potentially through DNA looping or on nucleosome core particles, which enhances its competitive ability against other Ets family members (Babayeva2012Structural).

Phosphorylation of ETS1 affects its DNA binding affinity, primarily by influencing the on-rate of binding. This modification can lead to the formation of salt bridges that inhibit DNA binding by masking positive charges (Kasahara2018Phosphorylation). ETS1 also interacts with other transcription factors, such as Runx1, where the C-terminal region of the Runt domain enhances cooperativity with ETS1 on the TCRα enhancer (Shiina2015A). These interactions are crucial for the allosteric regulation of transcription factor-DNA complexes, influencing gene expression in a cell-specific manner (Shiina2015A).


## References


[1. (Garrett-Sinha2013Review) Lee Ann Garrett-Sinha. Review of ets1 structure, function, and roles in immunity. Cellular and Molecular Life Sciences, 70(18):3375–3390, January 2013. URL: http://dx.doi.org/10.1007/s00018-012-1243-7, doi:10.1007/s00018-012-1243-7. This article has 147 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-012-1243-7)

[2. (Babayeva2012Structural) Nigar D. Babayeva, Oxana I. Baranovskaya, and Tahir H. Tahirov. Structural basis of ets1 cooperative binding to widely separated sites on promoter dna. PLoS ONE, 7(3):e33698, March 2012. URL: http://dx.doi.org/10.1371/journal.pone.0033698, doi:10.1371/journal.pone.0033698. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0033698)

[3. (Wang2005Ets1) Duncheng Wang, Shinu A. John, James L. Clements, Dean H. Percy, Kevin P. Barton, and Lee Ann Garrett-Sinha. Ets-1 deficiency leads to altered b cell differentiation, hyperresponsiveness to tlr9 and autoimmune disease. International Immunology, 17(9):1179–1191, July 2005. URL: http://dx.doi.org/10.1093/intimm/dxh295, doi:10.1093/intimm/dxh295. This article has 101 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/intimm/dxh295)

[4. (Testoni2015The) Monica Testoni, Elaine Yee Lin Chung, Valdemar Priebe, and Francesco Bertoni. The transcription factor ets1 in lymphomas: friend or foe? Leukemia & Lymphoma, 56(7):1975–1980, January 2015. URL: http://dx.doi.org/10.3109/10428194.2014.981670, doi:10.3109/10428194.2014.981670. This article has 19 citations.](https://doi.org/10.3109/10428194.2014.981670)

[5. (Kasahara2018Phosphorylation) Kota Kasahara, Masaaki Shiina, Junichi Higo, Kazuhiro Ogata, and Haruki Nakamura. Phosphorylation of an intrinsically disordered region of ets1 shifts a multi-modal interaction ensemble to an auto-inhibitory state. Nucleic Acids Research, 46(5):2243–2251, January 2018. URL: http://dx.doi.org/10.1093/nar/gkx1297, doi:10.1093/nar/gkx1297. This article has 34 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/gkx1297)

[6. (Russell2010Transcription) Lisa Russell and Lee Ann Garrett-Sinha. Transcription factor ets-1 in cytokine and chemokine gene regulation. Cytokine, 51(3):217–226, September 2010. URL: http://dx.doi.org/10.1016/j.cyto.2010.03.006, doi:10.1016/j.cyto.2010.03.006. This article has 81 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.cyto.2010.03.006)

[7. (A2018Aberrant) Elizabeth A Fry and Kazushi Inoue. Aberrant expression of ets1 and ets2 proteins in cancer. Cancer Reports and Reviews, 2018. URL: http://dx.doi.org/10.15761/crr.1000151, doi:10.15761/crr.1000151. This article has 45 citations.](https://doi.org/10.15761/crr.1000151)

[8. (Slupsky1998Structure) Carolyn M. Slupsky, Lisa N. Gentile, Logan W. Donaldson, Cameron D. Mackereth, Jeffrey J. Seidel, Barbara J. Graves, and Lawrence P. McIntosh. Structure of the ets-1 pointed domain and mitogen-activated protein kinase phosphorylation site. Proceedings of the National Academy of Sciences, 95(21):12129–12134, October 1998. URL: http://dx.doi.org/10.1073/pnas.95.21.12129, doi:10.1073/pnas.95.21.12129. This article has 184 citations.](https://doi.org/10.1073/pnas.95.21.12129)

[9. (Dittmer2015The) Jürgen Dittmer. The role of the transcription factor ets1 in carcinoma. Seminars in Cancer Biology, 35:20–38, December 2015. URL: http://dx.doi.org/10.1016/j.semcancer.2015.09.010, doi:10.1016/j.semcancer.2015.09.010. This article has 145 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.semcancer.2015.09.010)

[10. (Xu2018Structural) Xueyong Xu, Yinghui Li, Sakshibeedu R. Bharath, Mert Burak Ozturk, Matthew W. Bowler, Bryan Zong Lin Loo, Vinay Tergaonkar, and Haiwei Song. Structural basis for reactivating the mutant tert promoter by cooperative binding of p52 and ets1. Nature Communications, August 2018. URL: http://dx.doi.org/10.1038/s41467-018-05644-0, doi:10.1038/s41467-018-05644-0. This article has 53 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-018-05644-0)

[11. (Shiina2015A) Masaaki Shiina, Keisuke Hamada, Taiko Inoue-Bungo, Mariko Shimamura, Akiko Uchiyama, Shiho Baba, Ko Sato, Masaki Yamamoto, and Kazuhiro Ogata. A novel allosteric mechanism on protein–dna interactions underlying the phosphorylation-dependent regulation of ets1 target gene expressions. Journal of Molecular Biology, 427(8):1655–1669, April 2015. URL: http://dx.doi.org/10.1016/j.jmb.2014.07.020, doi:10.1016/j.jmb.2014.07.020. This article has 22 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2014.07.020)