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Ets1

Official Full Name
v-ets erythroblastosis virus E26 oncogene homolog 1 (avian)
Background
The proto-oncogene ETS1 (E-twenty-six-specific sequence) is the founding member of a family of transcrIPPtion factors that share a highly conserved DNA-binding domain, called the ETS domain, which recognizes a nucleotide motif with a GGAA/T core sequence.
Synonyms
ETS1; v-ets erythroblastosis virus E26 oncogene homolog 1 (avian); EWSR2, v ets avian erythroblastosis virus E26 oncogene homolog 1; protein C-ets-1; Avian erythroblastosis virus E26 (v ets) oncogene homolog 1; ets protein; ETS 1; FLJ10768; p54; v-ets avian erythroblastosis virus E2 oncogene homolog 1; Avian erythroblastosis virus E26 (v-ets) oncogene homolog-1; ETS-1; EWSR2; FLJ10768, ETS-1; v-ets erythroblastosis virus E26 oncogene; TNIP1; ETS-1A; ETS-1B; c-ets-1; c-ets-1 oncogene; p54 transcription factor; TNFAIP3 interacting protein 1; transforming protein p54/c-ets-1; transforming protein p68/c-ets-1; virion-; v-ets avian erythroblastosis virus E26 oncogene homolog 1; cb516; ets1a; id:ibd1116; zgc:110573; v-ets erythroblastosis virus E26 oncogene-like 1a; v-ets erythroblastosis virus E26 oncogene homolog 1; v-ets erythroblastosis virus E2; c-ets1

ETS1 (v-ets erythroblastosis virus E26 oncogene homolog 1 (avian)) is the most representative member of the ETS family and belongs to the first subfamily of the ETS family. The human ETS1 gene is located on chromosome 11q23.3 and encodes a protein with a relative molecular weight of 54 kD. As a transcription factor, ETS1 contains multiple functional regions, in which the transcriptional activation region (C region) is located at the center of the molecule, and the ETS region (region E) that binds to the target gene is located at the carboxyl terminus. Two regions of inhibition (D and F) are located on both sides of the ETS region, and the inhibitory region negatively regulates the binding of transcription factors to DNA. The activation mechanism of ETS1 may be mainly amplification, chromosomal translocation, and rearrangement. Studies have shown that activated ETS1 plays a major role in tumor cell proliferation, differentiation, apoptosis, tumor angiogenesis, and tumor invasion.

Regulation of ETS1

ETS1 has many physiological functions and is widely involved in the regulation of cell growth and apoptosis. Many growth factors, growth factor receptors, and integrins regulate cell growth and proliferation by the ETS1 gene. On the one hand, the ETS1 gene directly controls receptors such as granulocyte-macrophage colony stimulating factor receptors (GM-CSFR), granulocyte colony-stimulating factor receptors (G-CSFR), Toll-like receptors (Toll-like R), interleukin-2 (IL-2), and macrophage colony-stimulating factor receptors (M-CSFR), etc. to achieve its regulation of cell growth and apoptosis. On the other hand, the ETS1 gene can be regulated by other growth factors and their receptors, such as lipopolysaccharide (LPS), which stimulates ETS1 binding to TNFα promoter to exert the regulation of cell growth and apoptosis.

Nie et al. have shown that ETS1 is required for both cardiac heart palsy (NC) and cardiac mesoderm, which is essential for normal heart development. In addition, strict control of B cell differentiation into plasma cells (PC) is essential for proper immune response and prevention of autoimmunity. The role of the ETS1 transcription factor in B cells is to prevent PC differentiation.

ETS1 and Cancer

ETS1 is important in a variety of biological processes such as development, differentiation, proliferation, apoptosis, migration, and tissue remodeling. It acts as an oncogene that controls the invasive and angiogenic behavior of malignant cells in a variety of human cancers. In particular, ETS1 disorders have been reported in diffuse large B-cell lymphoma, Burkitt's lymphoma, and Hodgkin's lymphoma.

Dittmer believes that ETS1 has a selective effect in cancer and endothelial cells, as shown in Figure 1. (A) The potential role of ETS1 in EMT. EMT induction of TGFβ or HGF also results in increased expression of ETS1. ETS1 cooperates with Twist to induce the expression of ZEB1, which in turn reduces the expression of miR200 by ZEB1- and ETS1. This produced a ZEB1 / ETS1 amplification loop that promotes EMT. (B) The potential role of ETS1 in drug resistance. Once the ETS1 expression is up-regulated in cancer cells, ETS1 is able to increase the expression of various proteins involved in drug resistance, including MDR1 (multidrug resistance gene 1), CRYAB (αB-crystallin), chemokine receptor CXCR4Or glutathione upregulates the genes xCT and Gpx-1 (glutathione peroxidase 1). These proteins help to desensitize cells by lowering the level of cellular ROS (reactive oxygen species) or by blocking apoptosis through a caspase 3-dependent mechanism by pumping the drug out of the cell. (C) The potential role of ETS1 in neovascularization. ETS1 expression in endothelial cells can be induced by a number of factors, such as VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor) and the like.

ETS1 Figure 1. Selected effects of ETS1 in cancer (A and B) and endothelial cells (C). (Dittmer, et al. 2015)

Studies have shown that the expression of ETS1 is closely related to the occurrence, invasion, and metastasis of digestive tract tumors. Its role as a transcription factor in tumor metastasis and angiogenesis is mainly achieved by transcriptional activation of certain enzymes that degrade extracellular matrix (ECM). These enzymes include matrix metalloproteinases (MMPs), serine proteases and the like. The study used the Ultravision polymer system to test 117 colon adenomas and 149 colon adenocarcinoma tissues. The positive rate of ETS1 in adenomas was 22. 4%, and in adenocarcinomas it was 56.3%. The results of this study demonstrate the relevance of ETS1 to the development and progression of colon cancer from different perspectives. The expression of the ETS1 protein was determined by immunohistochemical staining of 54 gastric cancer tissues, 41 lymph node metastases and 32 control groups by gastric cancer tissue microarray. The results showed that the positive rates of ETS1 gene expression in gastric cancer tissues, paracancerous tissues, and control groups were 71.4%, 29.6%, and 18.8%, respectively. The difference between the three groups was statistically significant (P<0.01).

ETS1-Mediated Cell Signal Transduction

ETS1 has a conserved DNA binding domain at the C-terminus and a pointed domain at the N-terminus and contains a MAPK phosphorylation site that is closer to the pointed domain. Phosphorylation of these sites enhances their transcriptional function. This function is achieved by combining the Ras effect components (RREs) and serum response elements (SREs) on the early response gene promoter. In addition, ETS1 plays an important role in the TGF-β signal transduction pathway by acting on transforming growth factor-β (TGF-β) receptors. The JAK/STAT signaling pathway also regulates the function of ETS1. The RAS/ERK pathway is usually activated in cancer and promotes tumorigenesis by altering transcriptional programs. Plotnik et al. showed that ETS1 is required for RAS/ERK pathway activation and that ETS1 has a dual role in mediating epithelial-specific RAS/ERK transcriptional function.

References:

  1. Dittmer, J. (2015). The role of the transcription factor ets1 in carcinoma. Seminars in Cancer Biology, 35, 20-38.
  2. Nie, S., & Bronner, M. E. (2015). Dual developmental role of transcriptional regulator ets1 in xenopus cardiac neural crest vs. heart mesoderm. Cardiovascular Research, 106(1), 67.
  3. Mayeux, J., Skaug, B., Luo, W., Russell, L. M., John, S., & Saelee, P., et al. (2015). Genetic interaction between lyn, ets1, and btk in the control of antibody levels. Journal of Immunology, 195(5), 1955-1963.
  4. Testoni M, Chung EY, Priebe V, (2015) Bertoni F. The transcription factor ETS1 in lymphomas: friend or foe?. Leuk Lymphoma, 56(7): 1975-80.
  5. Plotnik, J. P., Budka, J. A., Ferris, M. W., & Hollenhorst, P. C. (2014). Ets1 is a genome-wide effector of ras/erk signaling in epithelial cells. Nucleic Acids Research, 42(19), 11928.

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