* 164720

ETS PROTOONCOGENE 1, TRANSCRIPTION FACTOR; ETS1


Alternative titles; symbols

V-ETS AVIAN ERYTHROBLASTOSIS VIRUS E26 ONCOGENE HOMOLOG 1
ONCOGENE ETS1
ETS1 ONCOGENE


HGNC Approved Gene Symbol: ETS1

Cytogenetic location: 11q24.3     Genomic coordinates (GRCh38): 11:128,458,765-128,587,558 (from NCBI)


TEXT

Description

ETS transcription factors, such as ETS1, regulate numerous genes and are involved in stem cell development, cell senescence and death, and tumorigenesis. The conserved ETS domain within these proteins is a winged helix-turn-helix DNA-binding domain that recognizes the core consensus DNA sequence GGAA/T of target genes (summary by Dwyer et al., 2007).


Cloning and Expression

Watson et al. (1988) sequenced human ETS1 cDNA and ETS2 (164740) cDNA clones obtained from human and mouse. The human ETS1 gene encodes a deduced 441-amino acid protein that is more than 95% identical to the chicken Ets1 gene product. Human and mouse ETS2 cDNA clones are closely related and encode proteins of 469 and 468 residues, respectively. The equivalent of the ETS1 and ETS2 genes are contiguous, i.e., located on the same chromosome, and are coordinately transcribed in birds (Watson et al., 1985). Whereas the chicken ETS protein, which contains both the ETS1 and ETS2 domains, distributes equally between the cytoplasm and nucleus, in the human and other mammals, the ETS1 protein is cytoplasmic and the ETS2 protein is nuclear. This, together with their noncoordinate expression, suggests that ETS1 and ETS2 have different biologic functions (Fujiwara et al., 1988).

Fisher et al. (1992) isolated the ETS1 protooncogene protein by immunoaffinity chromatography and obtained 4 isoforms ranging in size from 39 to 52 kD.

Dwyer et al. (2007) stated that ETS1 is a 441-amino acid protein that contains an N-terminal pointed domain and a C-terminal ETS DNA-binding domain. It also has a MAPK (see MAPK1; 176948) phosphorylation site at thr38 that likely mediates transcriptional regulation.

Laitem et al. (2009) noted that 2 ETS1 transcripts had been characterized: full-length ETS1, which encodes a 51-kD protein (ETS1-p51), and ETS1-delta(VII), which lacks exon 7 and encodes ETS1-p42. ETS-p42 lacks the N-terminal inhibitory domain found in ETS1-p51, and it has unique DNA-binding and transcriptional properties and regulates different target genes. By RT-PCR of rabbit synovial fibroblasts and human osteosarcoma and mammary adenocarcinoma cell lines, Laitem et al. (2009) cloned an ETS1 splice variant that lacks exons 3 through 6, which they called ETS1-delta(III-VI). ETS1-delta(III-VI) encodes a deduced 225-amino acid protein, ETS1-p27, that contains only the N-terminal sequence and C-terminal DNA-binding domain flanked by inhibitory domains of full-length ETS1-p51. It lacks thr38, the pointed domain, and the transactivation domain, all of which are required for transactivation of ETS1 target genes. RT-PCR analysis detected variable expression of full-length ETS1 and ETS1-delta(III-VI) in all fetal tissues examined and in adult spleen, thymus, placenta, and ovary, but not in adult brain or kidney. Both transcripts were expressed in tumor mammary tissues, but not in normal breast tissue. Western blot analysis detected endogenous ETS1-p27 at an apparent molecular mass of 27 kD in rabbit and human cell lines. Fluorescence-tagged ETS1-p27 localized to both the nucleus and cytoplasm of transfected HEK293 cells.


Mapping

By in situ hybridization, de Taisne et al. (1984) assigned human oncogene ETS to chromosome 11q23-q24. Watson et al. (1985) identified 2 distinct DNA segments homologous to the ETS region of the transforming gene of avian erythroblastosis virus, E26. ETS1, located on chromosome 11, encodes a single mRNA of 6.8 kb; ETS2, on chromosome 21, encodes 3 mRNAs of 4.7, 3.2, and 2.7 kb. Mapping was done by somatic cell hybridization.

By in situ hybridization in cells from a person with an 11q23.3-qter deletion, Griffin et al. (1986) refined the assignment of ETS1 to 11q23.3-q24.

By in situ hybridization to pachytene bivalents, Bello et al. (1989) provided sublocalization to 11q23.3.

Simmers and Sutherland (1988) refined the assignment of the ETS1 gene to demonstrate that it is separate from fragile site FRA11B (600651) which is just distal to the midpoint of band 11q23.3. They specifically assigned ETS1 to 11q24.

On the basis of multipoint linkage analysis of CEPH families, Concannon et al. (1990) concluded that ETS1 is located approximately 19.2 cM telomeric to THY1.


Gene Family

The ETS family of transcription factors was originally defined on the basis of the conserved primary sequence of their DNA-binding domains. ETS domain proteins function as either transcriptional activators or repressors and their activities are often regulated by signal transduction pathways, including MAP kinase pathways (Sharrocks et al., 1997).


Evolution

The oncogene v-ets was originally discovered as a component of a chimeric genome, along with a truncated v-myb (189990) gene, present in the genome of E26, an avian leukosis virus. Members of the ETS gene family have been cloned and sequenced from a variety of species ranging from human to Drosophila; their encoded products are highly conserved, more so than other known nuclear protooncogene products. The several classes of ETS family members could be due to an ancestral gene duplication, followed by genetic recombination(s) or divergence; however, since all of the classes are present in both invertebrates and vertebrates, such an ancestral duplication must predate the emergence of chordates more than 500 million years ago (review by Seth et al., 1992).


Gene Function

Bhat et al. (1990) found that, on T-cell activation, ETS2 mRNA and proteins are induced, whereas ETS1 gene expression decreases to very low levels.

Suzuki et al. (1995) found that when ETS1 was ectopically expressed in 2 highly tumorigenic human colon cancer cell lines devoid of endogenous ETS1 protein, the ETS1 transcription factor reversed the transformed phenotype and tumorigenicity of the cells in a dose-dependent manner. In contrast, expression in 1 cell line of a variant form of ETS1 lacking its native transcriptional activity did not alter the tumorigenic properties of the cells, suggesting that the reduction in tumorigenicity was specific for the wildtype ETS1 gene product. Since these colon cancer cells have multiple genetic alterations, Suzuki et al. (1995) suggested that the system could be a good model for studying suppression of tumorigenicity at a transcriptional level, leading to the design and development of novel drugs for cancer treatment.

The p16(INK4A) cyclin-dependent kinase inhibitor (CDKN2A; 600160) is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signaling in somatic cells. Ohtani et al. (2001) demonstrated a role for the ETS1 and ETS2 transcription factors in regulating the expression of p16(INK4A) in these different contexts based on their ability to activate the p16(INK4A) promoter through an ETS binding site and their patterns of expression during the life span of human diploid fibroblasts. The induction of p16(INK4A) by ETS2, which is abundant in young human diploid fibroblasts, is potentiated by signaling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein ID1 (600349). In senescent cells, where the ETS2 levels and MEK signaling decline, the marked increase in p16(INK4A) expression is consistent with the reciprocal reduction of ID1 and accumulation of ETS1.

Hashiya et al. (2004) transfected human ETS1 into rat hindlimb and found that it stimulated angiogenesis, as measured by increased capillary density and blood flow. Overexpression of ETS1 upregulated the concentrations of Hgf (142409) and Vegf (192240) in rat hindlimb, and administration of neutralizing antibodies against Hgf and Vegf attenuated the increases in blood flow and endothelial cells induced by ETS1. Hashiya et al. (2004) found a similar upregulation of HGF and VEGF following overexpression of ETS1 in human vascular smooth muscle cells.

Drane et al. (2004) found that ETS1 was phosphorylated by the multisubunit transcription/repair factor TFIIH, of which ERCC2 (126340) is a subunit. Phosphorylation of ETS1 enhanced vitamin D receptor (VDR; 601769)-mediated transactivation.

Using chromatin immunoprecipitation coupled with genomewide promoter microarrays to query endogenous promoter occupancy by 3 ETS proteins, ETS1, ELF1 (189973), and GABPA (600609), in the Jurkat human T-cell line, Hollenhorst et al. (2007) found frequent redundant promoter occupancy and less frequent specific promoter occupancy. Redundant binding correlated with housekeeping classes of genes, whereas specific binding examples represented more specialized genes. Redundant binding correlated with consensus ETS-binding sequences near transcription start sites, whereas specific binding sites diverged dramatically from the consensus and were further from transcription start sites. A subset of ETS1-binding events correlated with an ETS-RUNX composite site that differed dramatically from ETS1 or RUNX1 consensus sites.

Dwyer et al. (2007) reviewed the roles of ETS proteins in regulating telomerase (see TERT; 187270) activity and telomere length.

Using electrophoretic mobility shift assays, Laitem et al. (2009) showed that recombinant ETS1-p27 bound the palindromic ETS-binding site (EBS) of the stromelysin-1 (MMP3; 185250) promoter in vitro. Like ETS1-p51, ETS1-p27 bound the EBS in a cooperative ternary complex. ETS1-p27 disrupted binding of ETS1-p51 to the EBS in a dose-dependent manner and induced translocation of ETS1-p51 from the nucleus to the cytoplasm. ETS1-p27 also inhibited transactivation of the stromelysin-1 promoter by ETS2 and PEA3 (ETV4; 600711), which bind the EBS. Furthermore, ETS1-p27 blocked synergistic activation of the collagenase-1 (MMP8; 120355) promoter by ETS1-p51 and the JUN (165160)/FOS (164810) complex. ETS1-p27 repressed the tumoral properties of the MDA-MB-231 breast carcinoma cell line, including proliferation, transformation, and invasion in vitro and tumor growth in nude mice. Laitem et al. (2009) concluded that ETS1-p27 is an endogenous dominant-negative inhibitor of ETS1 transcriptional activity.


Cytogenetics

In 3 patients with acute monocytic leukemia (AMoL) and t(9;11)(p22;q23), Diaz et al. (1986) showed that the breakpoint on 9p split the interferon genes and that the interferon-beta-1 gene was translocated to chromosome 11. The ETS1 gene was translocated from chromosome 11 to 9p adjacent to interferon genes. They suggested that juxtaposition of interferon and ETS1 genes may be involved in the pathogenesis of AMoL. Diaz et al. (1986) concluded that the fibroblast interferon gene (at least beta-1) is located in 9p22, distal to alpha-interferon.

Sacchi et al. (1986) showed that the ETS1 gene is translocated to chromosome 4 in the translocation t(4;11)(q21;q23), which is characteristic of a subtype of leukemia that represents the expansion of a myeloid/lymphoid precursor cell.

Rovigatti et al. (1986) found that the ETS1 oncogene was rearranged and amplified 30-fold in a case of acute myelomonocytic leukemia in which a homogeneously stained region (HSR) occurred on 11q23; the oncogene was also rearranged and amplified approximately 10-fold in a case of small lymphocytic cell lymphoma with an inverted insert that also involved band 11q23. In situ hybridization (their Figure 3) suggested localization in 11q23.3.

Goyns et al. (1987) found that the ETS1 gene was rearranged in some cases of acute lymphoblastic leukemia.

Gollin et al. (1986) described a patient with Ewing sarcoma (612219) who was heterozygous for FRA11B and had a translocation t(11;22)(q23;q11) in the malignant cells. The localization of ETS1 to 11q24 indicates that the chromosomes of the patient reported by Gollin et al. (1986) did not rearrange at this fragile site to give rise to Ewing sarcoma. Simmers and Sutherland (1988) suggested that this can be added to the 'mounting evidence against individuals with fragile sites being predisposed to developing cancer.'

Thrombocytopenia or pancytopenia is frequently reported in patients with partial 11q deletion. Gangarossa et al. (1996) described a patient with deletion of the terminal portion of 11q: del(11)(q24.2qter). The classic clinical manifestations including chronic thrombocytopenic purpura were present. They reported for the first time the presence of micromegakaryocytes in the bone marrow aspirate of the patient. Noting that the ETS1 gene maps to the approximate site of the deletion and that nuclear factor related to kappa-B binding protein (164013) maps to 11q24-q25, Gangarossa et al. (1996) raised the possibility that the presence of 1 or both of these DNA-binding proteins that are likely to be involved in hematopoiesis may result, when present in only 1 copy, in thrombocytopenia or pancytopenia.


Animal Model

T cells pass through a number of stages before final differentiation into single-positive (SP) CD4 (186940)-positive or CD8 (186910)-positive alpha (TCRA; see 186880)/beta (TCRB; see 186930) T lymphocytes. The pre-T-cell receptor (TCR) stages include 4 CD4-negative/CD8-negative double-negative (DN) stages, DN1 (CD44 (107269)-positive/CD25 (147730)-negative), DN2 (CD44-positive/CD25-positive), DN3 (CD44-negative/CD25-positive), and DN4 (CD44-negative/CD25-negative), before differentiation to the double-positive (DP) CD4-positive/CD8-positive stage. Eyquem et al. (2004) generated mice deficient in the Ets1 transcription factor to determine its role in transition from DN3 to DN4, inhibition of DN cell apoptosis, cellular expansion, and allelic exclusion at the TCRB locus. Although Ets1 -/- embryos were present up to day 18.5 postcoitus in a mendelian ratio, by 3 weeks of age only 2% of mice were Ets1 -/-. At 4 weeks, the mutant mice weighed 50% less than heterozygous or wildtype mice. Among DN thymocytes, the mutation diminished the number of alpha/beta T cells, but not gamma/delta T cells. The numbers of DP and SP T cells were severely reduced. FACS analysis demonstrated a marked reduction in the number of DN4 cells and an increase in the number of DN2 cells, as well as a reduced efficiency of the allelic exclusion process, with an increased percentage of coexpression of 2 different TCRB chains. Eyquem et al. (2004) concluded that ETS1 is a critical transcription factor for pre-TCR functioning and for allelic exclusion at the TCRB locus.

In Ets1-null mice, Zhan et al. (2005) observed significantly reduced arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy compared to wildtype mice in response to angiotensin II (see 106150). The induction of 2 known targets of ETS1, CDKN1A (116899) and PAI1 (173360), by angiotensin II was markedly blunted in the aorta of Ets1-null mice compared with wildtype controls. Expression of MCP1 (CCL2; 158105) was similarly reduced, resulting in significantly diminished recruitment of T cells and macrophages to the vessel wall. Zhan et al. (2005) concluded that ETS1 has a critical role as a transcriptional mediator of vascular inflammation and remodeling in response to angiotensin II.

Ye et al. (2010) stated that an approximately 7-Mb cardiac critical region in distal chromosome 11q contained a putative causative gene(s) for congenital heart disease (see Jacobsen syndrome, 147791). The authors used chromosomal microarray mapping to characterize 3 patients with congenital heart defects and distal interstitial 11q deletions that overlap the 7-Mb cardiac critical region. The 1.2-Mb region of overlap contains 6 genes, including the ETS1 gene, which is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of Ets1 in C57/B6 mice caused large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle. Ye et al. (2010) proposed an important role for ETS1 in mammalian heart development, and suggested that hemizygosity for this locus may be responsible for the cardiac lesions seen in Jacobsen syndrome.


REFERENCES

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  9. Fisher, R. J., Koizumi, S., Kondoh, A., Mariano, J. M., Mavrothalassitis, G., Bhat, N. K., Papas, T. S. Human ETS1 oncoprotein: purification, isoforms, -SH modification, and DNA sequence-specific binding. J. Biol. Chem. 267: 17957-17965, 1992. [PubMed: 1517230, related citations]

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  11. Gangarossa, S., Mattina, T., Romano, V., Milana, G., Mollica, F., Schiliro, G. Micromegakaryocytes in a patient with partial deletion of the long arm of chromosome 11 (del(11)(q24.2qter)) and chronic thrombocytopenic purpura. Am. J. Med. Genet. 62: 120-123, 1996. [PubMed: 8882392, related citations] [Full Text]

  12. Gold, D. P., van Dongen, J. J. M., Morton, C. C., Bruns, G. A. P., van den Elsen, P., Geurts van Kessel, A. H. M., Terhorst, C. The gene encoding the epsilon subunit of the T3/T-cell receptor complex maps to chromosome 11 in humans and to chromosome 9 in mice. Proc. Nat. Acad. Sci. 84: 1664-1668, 1987. [PubMed: 2882512, related citations] [Full Text]

  13. Gollin, S. M., Perrot, L. J., Gray, B. A., Kletzel, M. Spontaneous expression of fra(11)(q23) in a patient with Ewing's sarcoma and t(11;22)(q23;q11). Cancer Genet. Cytogenet. 20: 331-339, 1986. [PubMed: 3943071, related citations] [Full Text]

  14. Goyns, M. H., Hann, I. M., Stewart, J., Gegonne, A., Birnie, G. D. The c-ets-1 proto-oncogene is rearranged in some cases of acute lymphoblastic leukaemia. Brit. J. Cancer 56: 611-613, 1987. [PubMed: 3480753, related citations] [Full Text]

  15. Griffin, C. A., McKeon, C., Israel, M. A., Gegonne, A., Ghysdael, J., Stehelin, D., Douglass, E. C., Green, A. A., Emanuel, B. S. Comparison of constitutional and tumor-associated 11;22 translocations: nonidentical breakpoints on chromosomes 11 and 22. Proc. Nat. Acad. Sci. 83: 6122-6126, 1986. [PubMed: 3461479, related citations] [Full Text]

  16. Hashiya, N., Jo, N., Aoki, M., Matsumoto, K., Nakamura, T., Sato, Y., Ogata, N., Ogihara, T., Kaneda, Y., Morishita, R. In vivo evidence of angiogenesis induced by transcription factor Ets-1: Ets-1 is located upstream of angiogenesis cascade. Circulation 109: 3035-3041, 2004. [PubMed: 15173033, related citations] [Full Text]

  17. Hollenhorst, P. C., Shah, A. A., Hopkins, C., Graves, B. J. Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev. 21: 1882-1894, 2007. [PubMed: 17652178, images, related citations] [Full Text]

  18. Laitem, C., Leprivier, G., Choul-Li, S., Begue, A., Monte, D., Larsimont, D., Dumont, P., Duterque-Coquillaud, M., Aumercier, M. Ets-1 p27: a novel Ets-1 isoform with dominant-negative effects on the transcriptional properties and the subcellular localization of Ets-1 p51. Oncogene 28: 2087-2099, 2009. [PubMed: 19377509, related citations] [Full Text]

  19. Ohtani, N., Zebedee, Z., Huot, T. J. G., Stinson, J. A., Sugimoto, M., Ohashi, Y., Sharrocks, A. D., Peters, G., Hara, E. Opposing effects of Ets and Id proteins on p16(INK4A) expression during cellular senescence. Nature 409: 1067-1070, 2001. [PubMed: 11234019, related citations] [Full Text]

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  21. Sacchi, N., Watson, D. K., Geurts van Kessel, A. H. M., Hagemeijer, A., Kersey, J., Drabkin, H. D., Patterson, D., Papas, T. S. Hu-ets-1 and Hu-ets-2 genes are transposed in acute leukemias with (4;11) and (8;21) translocations. Science 231: 379-382, 1986. [PubMed: 3941901, related citations] [Full Text]

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  24. Simmers, R. N., Sutherland, G. R. Further localization of ETS1 indicates that the chromosomal rearrangement in Ewing sarcoma does not occur at fra(11)(q23). Hum. Genet. 78: 144-147, 1988. [PubMed: 3422214, related citations] [Full Text]

  25. Suzuki, H., Romano-Spica, V., Papas, T. S., Bhat, N. K. ETS1 suppresses tumorigenicity of human colon cancer cells. Proc. Nat. Acad. Sci. 92: 4442-4446, 1995. [PubMed: 7753825, related citations] [Full Text]

  26. Watson, D. K., McWilliams, M. J., Lapis, P., Lautenberger, J. A., Schweinfest, C. W., Papas, T. S. Mammalian ets-1 and ets-2 genes encode highly conserved proteins. Proc. Nat. Acad. Sci. 85: 7862-7866, 1988. [PubMed: 2847145, related citations] [Full Text]

  27. Watson, D. K., McWilliams-Smith, M. J., Kozak, C., Reeves, R., Gearhart, J., Nunn, M. F., Nash, W., Fowle, J. R., III, Duesberg, P., Papas, T. S., O'Brien, S. J. Conserved chromosomal positions of dual domains of the ets protooncogene in cats, mice, and humans. Proc. Nat. Acad. Sci. 83: 1792-1796, 1986. [PubMed: 3513188, related citations] [Full Text]

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  30. Zhan, Y., Brown, C., Maynard, E., Anshelevich, A., Ni, W., Ho, I.-C., Oettgen, P. Ets-1 is a critical regulator of Ang II-medicated vascular inflammation and remodeling. J. Clin. Invest. 115: 2508-2516, 2005. [PubMed: 16138193, images, related citations] [Full Text]


George E. Tiller - updated : 2/8/2011
Patricia A. Hartz - updated : 8/30/2010
Patricia A. Hartz - updated : 1/14/2008
Patricia A. Hartz - updated : 8/31/2007
Patricia A. Hartz - updated : 5/3/2006
Patricia A. Hartz - updated : 1/17/2006
Marla J. F. O'Neill - updated : 11/16/2005
Paul J. Converse - updated : 12/17/2004
Ada Hamosh - updated : 3/6/2001
Creation Date:
Victor A. McKusick : 6/2/1986
alopez : 02/20/2024
carol : 01/25/2021
carol : 08/22/2016
mgross : 10/04/2013
carol : 1/9/2013
wwang : 3/14/2011
terry : 2/8/2011
mgross : 9/24/2010
terry : 8/30/2010
carol : 8/5/2008
mgross : 1/15/2008
terry : 1/14/2008
carol : 9/7/2007
carol : 9/6/2007
carol : 9/6/2007
terry : 8/31/2007
mgross : 6/7/2006
terry : 5/3/2006
mgross : 1/18/2006
mgross : 1/17/2006
terry : 1/17/2006
wwang : 11/18/2005
wwang : 11/18/2005
terry : 11/16/2005
terry : 10/12/2005
mgross : 12/17/2004
mgross : 12/17/2004
alopez : 3/6/2001
dkim : 12/10/1998
joanna : 11/5/1998
dkim : 10/28/1998
mark : 4/25/1996
terry : 4/18/1996
mark : 10/2/1995
mimadm : 4/14/1994
carol : 3/1/1993
carol : 1/15/1993
carol : 1/13/1993
carol : 12/8/1992

* 164720

ETS PROTOONCOGENE 1, TRANSCRIPTION FACTOR; ETS1


Alternative titles; symbols

V-ETS AVIAN ERYTHROBLASTOSIS VIRUS E26 ONCOGENE HOMOLOG 1
ONCOGENE ETS1
ETS1 ONCOGENE


HGNC Approved Gene Symbol: ETS1

Cytogenetic location: 11q24.3     Genomic coordinates (GRCh38): 11:128,458,765-128,587,558 (from NCBI)


TEXT

Description

ETS transcription factors, such as ETS1, regulate numerous genes and are involved in stem cell development, cell senescence and death, and tumorigenesis. The conserved ETS domain within these proteins is a winged helix-turn-helix DNA-binding domain that recognizes the core consensus DNA sequence GGAA/T of target genes (summary by Dwyer et al., 2007).


Cloning and Expression

Watson et al. (1988) sequenced human ETS1 cDNA and ETS2 (164740) cDNA clones obtained from human and mouse. The human ETS1 gene encodes a deduced 441-amino acid protein that is more than 95% identical to the chicken Ets1 gene product. Human and mouse ETS2 cDNA clones are closely related and encode proteins of 469 and 468 residues, respectively. The equivalent of the ETS1 and ETS2 genes are contiguous, i.e., located on the same chromosome, and are coordinately transcribed in birds (Watson et al., 1985). Whereas the chicken ETS protein, which contains both the ETS1 and ETS2 domains, distributes equally between the cytoplasm and nucleus, in the human and other mammals, the ETS1 protein is cytoplasmic and the ETS2 protein is nuclear. This, together with their noncoordinate expression, suggests that ETS1 and ETS2 have different biologic functions (Fujiwara et al., 1988).

Fisher et al. (1992) isolated the ETS1 protooncogene protein by immunoaffinity chromatography and obtained 4 isoforms ranging in size from 39 to 52 kD.

Dwyer et al. (2007) stated that ETS1 is a 441-amino acid protein that contains an N-terminal pointed domain and a C-terminal ETS DNA-binding domain. It also has a MAPK (see MAPK1; 176948) phosphorylation site at thr38 that likely mediates transcriptional regulation.

Laitem et al. (2009) noted that 2 ETS1 transcripts had been characterized: full-length ETS1, which encodes a 51-kD protein (ETS1-p51), and ETS1-delta(VII), which lacks exon 7 and encodes ETS1-p42. ETS-p42 lacks the N-terminal inhibitory domain found in ETS1-p51, and it has unique DNA-binding and transcriptional properties and regulates different target genes. By RT-PCR of rabbit synovial fibroblasts and human osteosarcoma and mammary adenocarcinoma cell lines, Laitem et al. (2009) cloned an ETS1 splice variant that lacks exons 3 through 6, which they called ETS1-delta(III-VI). ETS1-delta(III-VI) encodes a deduced 225-amino acid protein, ETS1-p27, that contains only the N-terminal sequence and C-terminal DNA-binding domain flanked by inhibitory domains of full-length ETS1-p51. It lacks thr38, the pointed domain, and the transactivation domain, all of which are required for transactivation of ETS1 target genes. RT-PCR analysis detected variable expression of full-length ETS1 and ETS1-delta(III-VI) in all fetal tissues examined and in adult spleen, thymus, placenta, and ovary, but not in adult brain or kidney. Both transcripts were expressed in tumor mammary tissues, but not in normal breast tissue. Western blot analysis detected endogenous ETS1-p27 at an apparent molecular mass of 27 kD in rabbit and human cell lines. Fluorescence-tagged ETS1-p27 localized to both the nucleus and cytoplasm of transfected HEK293 cells.


Mapping

By in situ hybridization, de Taisne et al. (1984) assigned human oncogene ETS to chromosome 11q23-q24. Watson et al. (1985) identified 2 distinct DNA segments homologous to the ETS region of the transforming gene of avian erythroblastosis virus, E26. ETS1, located on chromosome 11, encodes a single mRNA of 6.8 kb; ETS2, on chromosome 21, encodes 3 mRNAs of 4.7, 3.2, and 2.7 kb. Mapping was done by somatic cell hybridization.

By in situ hybridization in cells from a person with an 11q23.3-qter deletion, Griffin et al. (1986) refined the assignment of ETS1 to 11q23.3-q24.

By in situ hybridization to pachytene bivalents, Bello et al. (1989) provided sublocalization to 11q23.3.

Simmers and Sutherland (1988) refined the assignment of the ETS1 gene to demonstrate that it is separate from fragile site FRA11B (600651) which is just distal to the midpoint of band 11q23.3. They specifically assigned ETS1 to 11q24.

On the basis of multipoint linkage analysis of CEPH families, Concannon et al. (1990) concluded that ETS1 is located approximately 19.2 cM telomeric to THY1.


Gene Family

The ETS family of transcription factors was originally defined on the basis of the conserved primary sequence of their DNA-binding domains. ETS domain proteins function as either transcriptional activators or repressors and their activities are often regulated by signal transduction pathways, including MAP kinase pathways (Sharrocks et al., 1997).


Evolution

The oncogene v-ets was originally discovered as a component of a chimeric genome, along with a truncated v-myb (189990) gene, present in the genome of E26, an avian leukosis virus. Members of the ETS gene family have been cloned and sequenced from a variety of species ranging from human to Drosophila; their encoded products are highly conserved, more so than other known nuclear protooncogene products. The several classes of ETS family members could be due to an ancestral gene duplication, followed by genetic recombination(s) or divergence; however, since all of the classes are present in both invertebrates and vertebrates, such an ancestral duplication must predate the emergence of chordates more than 500 million years ago (review by Seth et al., 1992).


Gene Function

Bhat et al. (1990) found that, on T-cell activation, ETS2 mRNA and proteins are induced, whereas ETS1 gene expression decreases to very low levels.

Suzuki et al. (1995) found that when ETS1 was ectopically expressed in 2 highly tumorigenic human colon cancer cell lines devoid of endogenous ETS1 protein, the ETS1 transcription factor reversed the transformed phenotype and tumorigenicity of the cells in a dose-dependent manner. In contrast, expression in 1 cell line of a variant form of ETS1 lacking its native transcriptional activity did not alter the tumorigenic properties of the cells, suggesting that the reduction in tumorigenicity was specific for the wildtype ETS1 gene product. Since these colon cancer cells have multiple genetic alterations, Suzuki et al. (1995) suggested that the system could be a good model for studying suppression of tumorigenicity at a transcriptional level, leading to the design and development of novel drugs for cancer treatment.

The p16(INK4A) cyclin-dependent kinase inhibitor (CDKN2A; 600160) is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signaling in somatic cells. Ohtani et al. (2001) demonstrated a role for the ETS1 and ETS2 transcription factors in regulating the expression of p16(INK4A) in these different contexts based on their ability to activate the p16(INK4A) promoter through an ETS binding site and their patterns of expression during the life span of human diploid fibroblasts. The induction of p16(INK4A) by ETS2, which is abundant in young human diploid fibroblasts, is potentiated by signaling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein ID1 (600349). In senescent cells, where the ETS2 levels and MEK signaling decline, the marked increase in p16(INK4A) expression is consistent with the reciprocal reduction of ID1 and accumulation of ETS1.

Hashiya et al. (2004) transfected human ETS1 into rat hindlimb and found that it stimulated angiogenesis, as measured by increased capillary density and blood flow. Overexpression of ETS1 upregulated the concentrations of Hgf (142409) and Vegf (192240) in rat hindlimb, and administration of neutralizing antibodies against Hgf and Vegf attenuated the increases in blood flow and endothelial cells induced by ETS1. Hashiya et al. (2004) found a similar upregulation of HGF and VEGF following overexpression of ETS1 in human vascular smooth muscle cells.

Drane et al. (2004) found that ETS1 was phosphorylated by the multisubunit transcription/repair factor TFIIH, of which ERCC2 (126340) is a subunit. Phosphorylation of ETS1 enhanced vitamin D receptor (VDR; 601769)-mediated transactivation.

Using chromatin immunoprecipitation coupled with genomewide promoter microarrays to query endogenous promoter occupancy by 3 ETS proteins, ETS1, ELF1 (189973), and GABPA (600609), in the Jurkat human T-cell line, Hollenhorst et al. (2007) found frequent redundant promoter occupancy and less frequent specific promoter occupancy. Redundant binding correlated with housekeeping classes of genes, whereas specific binding examples represented more specialized genes. Redundant binding correlated with consensus ETS-binding sequences near transcription start sites, whereas specific binding sites diverged dramatically from the consensus and were further from transcription start sites. A subset of ETS1-binding events correlated with an ETS-RUNX composite site that differed dramatically from ETS1 or RUNX1 consensus sites.

Dwyer et al. (2007) reviewed the roles of ETS proteins in regulating telomerase (see TERT; 187270) activity and telomere length.

Using electrophoretic mobility shift assays, Laitem et al. (2009) showed that recombinant ETS1-p27 bound the palindromic ETS-binding site (EBS) of the stromelysin-1 (MMP3; 185250) promoter in vitro. Like ETS1-p51, ETS1-p27 bound the EBS in a cooperative ternary complex. ETS1-p27 disrupted binding of ETS1-p51 to the EBS in a dose-dependent manner and induced translocation of ETS1-p51 from the nucleus to the cytoplasm. ETS1-p27 also inhibited transactivation of the stromelysin-1 promoter by ETS2 and PEA3 (ETV4; 600711), which bind the EBS. Furthermore, ETS1-p27 blocked synergistic activation of the collagenase-1 (MMP8; 120355) promoter by ETS1-p51 and the JUN (165160)/FOS (164810) complex. ETS1-p27 repressed the tumoral properties of the MDA-MB-231 breast carcinoma cell line, including proliferation, transformation, and invasion in vitro and tumor growth in nude mice. Laitem et al. (2009) concluded that ETS1-p27 is an endogenous dominant-negative inhibitor of ETS1 transcriptional activity.


Cytogenetics

In 3 patients with acute monocytic leukemia (AMoL) and t(9;11)(p22;q23), Diaz et al. (1986) showed that the breakpoint on 9p split the interferon genes and that the interferon-beta-1 gene was translocated to chromosome 11. The ETS1 gene was translocated from chromosome 11 to 9p adjacent to interferon genes. They suggested that juxtaposition of interferon and ETS1 genes may be involved in the pathogenesis of AMoL. Diaz et al. (1986) concluded that the fibroblast interferon gene (at least beta-1) is located in 9p22, distal to alpha-interferon.

Sacchi et al. (1986) showed that the ETS1 gene is translocated to chromosome 4 in the translocation t(4;11)(q21;q23), which is characteristic of a subtype of leukemia that represents the expansion of a myeloid/lymphoid precursor cell.

Rovigatti et al. (1986) found that the ETS1 oncogene was rearranged and amplified 30-fold in a case of acute myelomonocytic leukemia in which a homogeneously stained region (HSR) occurred on 11q23; the oncogene was also rearranged and amplified approximately 10-fold in a case of small lymphocytic cell lymphoma with an inverted insert that also involved band 11q23. In situ hybridization (their Figure 3) suggested localization in 11q23.3.

Goyns et al. (1987) found that the ETS1 gene was rearranged in some cases of acute lymphoblastic leukemia.

Gollin et al. (1986) described a patient with Ewing sarcoma (612219) who was heterozygous for FRA11B and had a translocation t(11;22)(q23;q11) in the malignant cells. The localization of ETS1 to 11q24 indicates that the chromosomes of the patient reported by Gollin et al. (1986) did not rearrange at this fragile site to give rise to Ewing sarcoma. Simmers and Sutherland (1988) suggested that this can be added to the 'mounting evidence against individuals with fragile sites being predisposed to developing cancer.'

Thrombocytopenia or pancytopenia is frequently reported in patients with partial 11q deletion. Gangarossa et al. (1996) described a patient with deletion of the terminal portion of 11q: del(11)(q24.2qter). The classic clinical manifestations including chronic thrombocytopenic purpura were present. They reported for the first time the presence of micromegakaryocytes in the bone marrow aspirate of the patient. Noting that the ETS1 gene maps to the approximate site of the deletion and that nuclear factor related to kappa-B binding protein (164013) maps to 11q24-q25, Gangarossa et al. (1996) raised the possibility that the presence of 1 or both of these DNA-binding proteins that are likely to be involved in hematopoiesis may result, when present in only 1 copy, in thrombocytopenia or pancytopenia.


Animal Model

T cells pass through a number of stages before final differentiation into single-positive (SP) CD4 (186940)-positive or CD8 (186910)-positive alpha (TCRA; see 186880)/beta (TCRB; see 186930) T lymphocytes. The pre-T-cell receptor (TCR) stages include 4 CD4-negative/CD8-negative double-negative (DN) stages, DN1 (CD44 (107269)-positive/CD25 (147730)-negative), DN2 (CD44-positive/CD25-positive), DN3 (CD44-negative/CD25-positive), and DN4 (CD44-negative/CD25-negative), before differentiation to the double-positive (DP) CD4-positive/CD8-positive stage. Eyquem et al. (2004) generated mice deficient in the Ets1 transcription factor to determine its role in transition from DN3 to DN4, inhibition of DN cell apoptosis, cellular expansion, and allelic exclusion at the TCRB locus. Although Ets1 -/- embryos were present up to day 18.5 postcoitus in a mendelian ratio, by 3 weeks of age only 2% of mice were Ets1 -/-. At 4 weeks, the mutant mice weighed 50% less than heterozygous or wildtype mice. Among DN thymocytes, the mutation diminished the number of alpha/beta T cells, but not gamma/delta T cells. The numbers of DP and SP T cells were severely reduced. FACS analysis demonstrated a marked reduction in the number of DN4 cells and an increase in the number of DN2 cells, as well as a reduced efficiency of the allelic exclusion process, with an increased percentage of coexpression of 2 different TCRB chains. Eyquem et al. (2004) concluded that ETS1 is a critical transcription factor for pre-TCR functioning and for allelic exclusion at the TCRB locus.

In Ets1-null mice, Zhan et al. (2005) observed significantly reduced arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy compared to wildtype mice in response to angiotensin II (see 106150). The induction of 2 known targets of ETS1, CDKN1A (116899) and PAI1 (173360), by angiotensin II was markedly blunted in the aorta of Ets1-null mice compared with wildtype controls. Expression of MCP1 (CCL2; 158105) was similarly reduced, resulting in significantly diminished recruitment of T cells and macrophages to the vessel wall. Zhan et al. (2005) concluded that ETS1 has a critical role as a transcriptional mediator of vascular inflammation and remodeling in response to angiotensin II.

Ye et al. (2010) stated that an approximately 7-Mb cardiac critical region in distal chromosome 11q contained a putative causative gene(s) for congenital heart disease (see Jacobsen syndrome, 147791). The authors used chromosomal microarray mapping to characterize 3 patients with congenital heart defects and distal interstitial 11q deletions that overlap the 7-Mb cardiac critical region. The 1.2-Mb region of overlap contains 6 genes, including the ETS1 gene, which is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of Ets1 in C57/B6 mice caused large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle. Ye et al. (2010) proposed an important role for ETS1 in mammalian heart development, and suggested that hemizygosity for this locus may be responsible for the cardiac lesions seen in Jacobsen syndrome.


See Also:

Gold et al. (1987); Watson et al. (1986)

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Contributors:
George E. Tiller - updated : 2/8/2011
Patricia A. Hartz - updated : 8/30/2010
Patricia A. Hartz - updated : 1/14/2008
Patricia A. Hartz - updated : 8/31/2007
Patricia A. Hartz - updated : 5/3/2006
Patricia A. Hartz - updated : 1/17/2006
Marla J. F. O'Neill - updated : 11/16/2005
Paul J. Converse - updated : 12/17/2004
Ada Hamosh - updated : 3/6/2001

Creation Date:
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