* 164740

ETS PROTOONCOGENE 2, TRANSCRIPTION FACTOR; ETS2


Alternative titles; symbols

V-ETS AVIAN ERYTHROBLASTOSIS VIRUS E26 ONCOGENE HOMOLOG 2
ONCOGENE ETS2
ETS2 ONCOGENE
ETS2 INTRONIC TRANSCRIPT; ETS2IT1


HGNC Approved Gene Symbol: ETS2

Cytogenetic location: 21q22.2     Genomic coordinates (GRCh38): 21:38,805,183-38,824,955 (from NCBI)


TEXT

Description

ETS transcription factors, such as ETS2, 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 (Dwyer et al., 2007).


Cloning and Expression

Watson et al. (1988) sequenced human ETS1 (164720) cDNA and ETS2 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).

Dwyer et al. (2007) stated that the 469-amino acid ETS2 protein 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 thr72 that likely mediates transcriptional regulation.

Using 5-prime and 3-prime RACE, Owczarek et al. (2004) identified an unspliced polyadenylated ETS2 intronic transcript, which they designated ETS2IT1, extending from intron 1 to intron 2. Apart from exon 2, ETS2IT1 has no significant ORF, and it is not conserved in mouse. RT-PCR detected variable ETS2IT1 expression in placenta and in all human cell lines examined.


Gene Structure

Mavrothalassitis et al. (1990) demonstrated that the ETS2 gene has no TATA box or CAAT box in its promoter, but it has an alternative structure that serves a comparable function.

Owczarek et al. (2004) determined that the ETS2 gene spans 17.6 kb and has a major CpG island at its 5-prime end. It contains promoter regions upstream of exon 1 and within intron 1.


Mapping

By in situ hybridization, Watson et al. (1985) mapped the ETS2 gene to chromosome 21q22.1-q22.3.

Owczarek et al. (2004) mapped the mouse Ets2 gene to a region of chromosome 16 that shares incomplete homology of synteny with human chromosome 21q22.2-q22.3.


Gene Function

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.

The tumor suppressor PTEN (601728) possesses lipid and protein phosphatase activities. Its lipid phosphatase activity is essential for its tumor-suppressive function via the phosphoinositide 3-kinase (PIK3CG; 601232) and AKT1 (164730) pathways. Weng et al. (2002) demonstrated that overexpression of wildtype PTEN in the MCF-7 breast cancer line resulted in a phosphatase activity-dependent decrease in the phosphorylation of ETS2. Exposure of MCF-7 cells to insulin, insulin-like growth factor-1 (IGF1; 147440), or epidermal growth factor (EGF; 131530) can lead to the phosphorylation of ETS2. The MAP2K1 (176872) inhibitor PD590089 abrogated insulin-stimulated phosphorylation of ETS2. In contrast, the PI3K inhibitor LY492002 had no effect on insulin-stimulated phosphorylation of ETS2. Overexpression of PTEN abrogated activation of the uPA Ras-responsive enhancer (PLAU1; 191840), a target of ETS2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. The authors suggested that PTEN may block insulin-stimulated ETS2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS2 may be mediated through PTEN's protein phosphatase activity.

In Down syndrome (190685), expression of beta-amyloid precursor protein (APP; 104760) is 3- to 4-fold higher than what is expected from the trisomy-dependent 1.5-fold increase in gene load, suggesting that other genes on chromosome 21 further upregulate APP. Wolvetang et al. (2003) showed that ETS2 transactivated the APP gene via specific Ets-binding sites in the APP promoter. Brains and primary neuronal cultures from Ets2 transgenic mice, as well as mouse fibroblasts overexpressing human ETS2, showed molecular abnormalities consistent with Down syndrome, including elevated expression of APP and presenilin-1 (PSEN1; 104311) and increased beta-amyloid production.

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

Sussan et al. (2008) used mouse models of Down syndrome and of cancer in a biologic approach to investigate the relationship between trisomy and the incidence of intestinal tumors. Apc(Min) (611731)-mediated tumor number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr, and Ms1Rhr. Trisomy for orthologs of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumors. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumors. Further studies demonstrated that the Ets2 gene contributed most of the dosage-sensitive effect on intestinal tumor number. The action of Est2 as a repressor when it is overexpressed differs from tumor suppression, which requires normal gene function to prevent cellular transformation. Sussan et al. (2008) suggested that upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.


Cytogenetics

Sacchi et al. (1986) found that the ETS2 gene was translocated to chromosome 8 in the translocation t(8;21)(q22;q22), which is commonly found in patients with acute myeloid leukemia with morphology M2 (AML-M2). In a case of t(8;21)(q22;q22), Le Beau et al. (1986) found that the ETS2 gene was translocated to chromosome 8. The MOS oncogene (190060) was retained at the breakpoint on chromosome 8; thus, one or both of these genes may play a role in the pathogenesis of acute myelogenous leukemia.

Using genetic linkage analysis, Sacchi et al. (1988) demonstrated the location of the ETS2 gene relative to other loci and established that the breakpoint in acute myeloid leukemia is about 17 cM from ETS2. Thus, the breakpoint does not affect the ETS2 gene structure. The actual DNA sequence involved in the t(8;21) may reside in a 3-cM genetic region between 2 markers used in these studies. By family linkage studies using RFLPs, Sacchi et al. (1988) demonstrated that ERG (165080) is situated just proximal to ETS2.


Animal Model

Expression of ETS2, a protooncogene and transcription factor, occurs in a variety of cell types. During murine development it is highly expressed in newly formed cartilage, including skull precursor cells and vertebral primordia. Sumarsono et al. (1996) generated transgenic mice to investigate the consequences of overexpression of Ets2. They found that mice with less than 2-fold Ets2 overexpression in particular organs developed neurocranial, visceral cranial, and cervical skeletal abnormalities. These abnormalities had similarities with the skeletal anomalies found in trisomy-16 mice and in humans with Down syndrome (190685), in which the gene dosage of ETS2 is increased. The results were interpreted as indicating that ETS2 has a role in skeletal development and that overexpression is involved in the genesis of some skeletal abnormalities that occur in Down syndrome.

Wolvetang et al. (2003) demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome. Increased apoptosis correlated with increased expression of p53 (191170) and alterations in downstream factors in the p53 pathway. In the human HeLa cancer cell line, transfection with functional p53 enabled ETS2 overexpression to induce apoptosis. Furthermore, crossing the ETS2 transgenic mice with p53 -/- mice genetically rescued the thymic apoptosis phenotype. The authors concluded that overexpression of human ETS2 induces apoptosis that is dependent on p53.

Wen et al. (2007) generated an Ets2 conditional allele in mice. Ets2 inactivation resulted in a defect in trophoblast stem cell self-renewal and changes in gene expression normally associated with differentiation caused by growth factor withdrawal. Among the genes sensitive to Ets2 inactivation were Cdx2 (600297), Pace4 (167405), Eomes (604615), and Errb (ESRRB; 602167).


See Also:

REFERENCES

  1. Dwyer, J., Li, H., Xu, D., Liu, J.-P. Transcriptional regulation of telomerase activity: roles of the the (sic) Ets transcription factor family. Ann. New York Acad. Sci. 1114: 36-47, 2007. [PubMed: 17986575, related citations] [Full Text]

  2. Fujiwara, S., Fisher, R. J., Seth, A., Bhat, N. K., Showalter, S. D., Zweig, M., Papas, T. S. Characterization and localization of the products of the human homologs of the v-ets oncogene. Oncogene 2: 99-103, 1988. Note: Erratum: Oncogene 3: 235 only, 1988. [PubMed: 3285299, related citations]

  3. Le Beau, M. M., Rowley, J. D., Sacchi, N., Watson, D. K., Papas, T. S., Diaz, M. O. Hu-ets-2 is translocated to chromosome 8 in the t(8;21) in acute myelogenous leukemia. Cancer Genet. Cytogenet. 23: 269-274, 1986. [PubMed: 3021321, related citations] [Full Text]

  4. Mavrothalassitis, G. J., Watson, D. K., Papas, T. S. Molecular and functional characterization of the promoter of ETS2, the human c-ets-2 gene. Proc. Nat. Acad. Sci. 87: 1047-1051, 1990. [PubMed: 2405393, related citations] [Full Text]

  5. 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]

  6. Owczarek, C. M., Portbury, K. J., Hardy, M. P., O'Leary, D. A., Kudoh, J., Shibuya, K., Shimizu, N., Kola, I., Hertzog, P. J. Detailed mapping of the ERG-ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16. Gene 324: 65-77, 2004. [PubMed: 14693372, related citations] [Full Text]

  7. Sacchi, N., Cheng, S. V., Tanzi, R. E., Gusella, J. F., Drabkin, H. A., Patterson, D., Haines, J. H., Papas, T. S. The ETS genes on chromosome 21 are distal to the breakpoint of the acute myelogenous leukemia translocation (8;21). Genomics 3: 110-116, 1988. [PubMed: 3267212, related citations] [Full Text]

  8. 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]

  9. Sumarsono, S. H., Wilson, T. J., Tymms, M. J., Venter, D. J., Corrick, C. M., Kola, R., Lahoud, M. H., Papas, T. S., Seth, A., Kola, I. Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 379: 534-540, 1996. [PubMed: 8596630, related citations] [Full Text]

  10. Sussan, T. E., Yang, A., Li, F., Ostrowski, M. C., Reeves, R. H. Trisomy represses Apc(Min)-mediated tumours in mouse models of Down's syndrome. Nature 451: 73-75, 2008. [PubMed: 18172498, related citations] [Full Text]

  11. 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]

  12. 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]

  13. Watson, D. K., McWilliams-Smith, M. J., Nunn, M. F., Duesberg, P. H., O'Brien, S. J., Papas, T. S. The ets sequence from the transforming gene of avian erythroblastosis virus, E26, has unique domains on human chromosomes 11 and 21: both loci are transcriptionally active. Proc. Nat. Acad. Sci. 82: 7294-7298, 1985. [PubMed: 2997781, related citations] [Full Text]

  14. Wen, F., Tynan, J. A., Cecena, G., Williams, R., Munera, J., Mavrothalassitis, G., Oshima, R. G. Ets2 is required for trophoblast stem cell self-renewal. Dev. Biol. 312: 284-299, 2007. [PubMed: 17977525, images, related citations] [Full Text]

  15. Weng, L.-P., Brown, J. L., Baker, K. M., Ostrowski, M. C., Eng, C. PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum. Molec. Genet. 11: 1687-1696, 2002. Note: Erratum: Hum. Molec. Genet. 12: 1943 only, 2003. [PubMed: 12095911, related citations] [Full Text]

  16. Wolvetang, E. J., Wilson, T. J., Sanij, E., Busciglio, J., Hatzistavrou, T., Seth, A., Hertzog, P. J., Kola, I. ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Hum. Molec. Genet. 12: 247-255, 2003. [PubMed: 12554679, related citations] [Full Text]

  17. Wolvetang, E. W., Bradfield, O. M., Tymms, M., Zavarsek, S., Hatzistavrou, T., Kola, I., Hertzog, P. J. The chromosome 21 transcription factor ETS2 transactivates the beta-APP promoter: implications for Down syndrome. Biochim. Biophys. Acta 1628: 105-110, 2003. [PubMed: 12890557, related citations] [Full Text]


Ada Hamosh - updated : 3/7/2008
Patricia A. Hartz - updated : 1/14/2008
George E. Tiller - updated : 12/21/2004
George E. Tiller - updated : 6/18/2003
Ada Hamosh - updated : 3/6/2001
Creation Date:
Victor A. McKusick : 6/2/1986
alopez : 02/20/2024
carol : 01/25/2021
carol : 01/09/2013
terry : 6/7/2012
alopez : 3/21/2008
terry : 3/7/2008
mgross : 1/15/2008
terry : 1/14/2008
alopez : 3/28/2006
alopez : 12/21/2004
cwells : 6/18/2003
alopez : 3/6/2001
joanna : 11/5/1998
dkim : 7/24/1998
mark : 3/21/1996
terry : 3/7/1996
supermim : 3/16/1992
supermim : 3/23/1990
supermim : 3/20/1990
supermim : 3/7/1990
supermim : 3/1/1990
ddp : 10/27/1989

* 164740

ETS PROTOONCOGENE 2, TRANSCRIPTION FACTOR; ETS2


Alternative titles; symbols

V-ETS AVIAN ERYTHROBLASTOSIS VIRUS E26 ONCOGENE HOMOLOG 2
ONCOGENE ETS2
ETS2 ONCOGENE
ETS2 INTRONIC TRANSCRIPT; ETS2IT1


HGNC Approved Gene Symbol: ETS2

Cytogenetic location: 21q22.2     Genomic coordinates (GRCh38): 21:38,805,183-38,824,955 (from NCBI)


TEXT

Description

ETS transcription factors, such as ETS2, 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 (Dwyer et al., 2007).


Cloning and Expression

Watson et al. (1988) sequenced human ETS1 (164720) cDNA and ETS2 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).

Dwyer et al. (2007) stated that the 469-amino acid ETS2 protein 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 thr72 that likely mediates transcriptional regulation.

Using 5-prime and 3-prime RACE, Owczarek et al. (2004) identified an unspliced polyadenylated ETS2 intronic transcript, which they designated ETS2IT1, extending from intron 1 to intron 2. Apart from exon 2, ETS2IT1 has no significant ORF, and it is not conserved in mouse. RT-PCR detected variable ETS2IT1 expression in placenta and in all human cell lines examined.


Gene Structure

Mavrothalassitis et al. (1990) demonstrated that the ETS2 gene has no TATA box or CAAT box in its promoter, but it has an alternative structure that serves a comparable function.

Owczarek et al. (2004) determined that the ETS2 gene spans 17.6 kb and has a major CpG island at its 5-prime end. It contains promoter regions upstream of exon 1 and within intron 1.


Mapping

By in situ hybridization, Watson et al. (1985) mapped the ETS2 gene to chromosome 21q22.1-q22.3.

Owczarek et al. (2004) mapped the mouse Ets2 gene to a region of chromosome 16 that shares incomplete homology of synteny with human chromosome 21q22.2-q22.3.


Gene Function

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.

The tumor suppressor PTEN (601728) possesses lipid and protein phosphatase activities. Its lipid phosphatase activity is essential for its tumor-suppressive function via the phosphoinositide 3-kinase (PIK3CG; 601232) and AKT1 (164730) pathways. Weng et al. (2002) demonstrated that overexpression of wildtype PTEN in the MCF-7 breast cancer line resulted in a phosphatase activity-dependent decrease in the phosphorylation of ETS2. Exposure of MCF-7 cells to insulin, insulin-like growth factor-1 (IGF1; 147440), or epidermal growth factor (EGF; 131530) can lead to the phosphorylation of ETS2. The MAP2K1 (176872) inhibitor PD590089 abrogated insulin-stimulated phosphorylation of ETS2. In contrast, the PI3K inhibitor LY492002 had no effect on insulin-stimulated phosphorylation of ETS2. Overexpression of PTEN abrogated activation of the uPA Ras-responsive enhancer (PLAU1; 191840), a target of ETS2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. The authors suggested that PTEN may block insulin-stimulated ETS2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS2 may be mediated through PTEN's protein phosphatase activity.

In Down syndrome (190685), expression of beta-amyloid precursor protein (APP; 104760) is 3- to 4-fold higher than what is expected from the trisomy-dependent 1.5-fold increase in gene load, suggesting that other genes on chromosome 21 further upregulate APP. Wolvetang et al. (2003) showed that ETS2 transactivated the APP gene via specific Ets-binding sites in the APP promoter. Brains and primary neuronal cultures from Ets2 transgenic mice, as well as mouse fibroblasts overexpressing human ETS2, showed molecular abnormalities consistent with Down syndrome, including elevated expression of APP and presenilin-1 (PSEN1; 104311) and increased beta-amyloid production.

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

Sussan et al. (2008) used mouse models of Down syndrome and of cancer in a biologic approach to investigate the relationship between trisomy and the incidence of intestinal tumors. Apc(Min) (611731)-mediated tumor number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr, and Ms1Rhr. Trisomy for orthologs of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumors. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumors. Further studies demonstrated that the Ets2 gene contributed most of the dosage-sensitive effect on intestinal tumor number. The action of Est2 as a repressor when it is overexpressed differs from tumor suppression, which requires normal gene function to prevent cellular transformation. Sussan et al. (2008) suggested that upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.


Cytogenetics

Sacchi et al. (1986) found that the ETS2 gene was translocated to chromosome 8 in the translocation t(8;21)(q22;q22), which is commonly found in patients with acute myeloid leukemia with morphology M2 (AML-M2). In a case of t(8;21)(q22;q22), Le Beau et al. (1986) found that the ETS2 gene was translocated to chromosome 8. The MOS oncogene (190060) was retained at the breakpoint on chromosome 8; thus, one or both of these genes may play a role in the pathogenesis of acute myelogenous leukemia.

Using genetic linkage analysis, Sacchi et al. (1988) demonstrated the location of the ETS2 gene relative to other loci and established that the breakpoint in acute myeloid leukemia is about 17 cM from ETS2. Thus, the breakpoint does not affect the ETS2 gene structure. The actual DNA sequence involved in the t(8;21) may reside in a 3-cM genetic region between 2 markers used in these studies. By family linkage studies using RFLPs, Sacchi et al. (1988) demonstrated that ERG (165080) is situated just proximal to ETS2.


Animal Model

Expression of ETS2, a protooncogene and transcription factor, occurs in a variety of cell types. During murine development it is highly expressed in newly formed cartilage, including skull precursor cells and vertebral primordia. Sumarsono et al. (1996) generated transgenic mice to investigate the consequences of overexpression of Ets2. They found that mice with less than 2-fold Ets2 overexpression in particular organs developed neurocranial, visceral cranial, and cervical skeletal abnormalities. These abnormalities had similarities with the skeletal anomalies found in trisomy-16 mice and in humans with Down syndrome (190685), in which the gene dosage of ETS2 is increased. The results were interpreted as indicating that ETS2 has a role in skeletal development and that overexpression is involved in the genesis of some skeletal abnormalities that occur in Down syndrome.

Wolvetang et al. (2003) demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome. Increased apoptosis correlated with increased expression of p53 (191170) and alterations in downstream factors in the p53 pathway. In the human HeLa cancer cell line, transfection with functional p53 enabled ETS2 overexpression to induce apoptosis. Furthermore, crossing the ETS2 transgenic mice with p53 -/- mice genetically rescued the thymic apoptosis phenotype. The authors concluded that overexpression of human ETS2 induces apoptosis that is dependent on p53.

Wen et al. (2007) generated an Ets2 conditional allele in mice. Ets2 inactivation resulted in a defect in trophoblast stem cell self-renewal and changes in gene expression normally associated with differentiation caused by growth factor withdrawal. Among the genes sensitive to Ets2 inactivation were Cdx2 (600297), Pace4 (167405), Eomes (604615), and Errb (ESRRB; 602167).


See Also:

Watson et al. (1986)

REFERENCES

  1. Dwyer, J., Li, H., Xu, D., Liu, J.-P. Transcriptional regulation of telomerase activity: roles of the the (sic) Ets transcription factor family. Ann. New York Acad. Sci. 1114: 36-47, 2007. [PubMed: 17986575] [Full Text: https://doi.org/10.1196/annals.1396.022]

  2. Fujiwara, S., Fisher, R. J., Seth, A., Bhat, N. K., Showalter, S. D., Zweig, M., Papas, T. S. Characterization and localization of the products of the human homologs of the v-ets oncogene. Oncogene 2: 99-103, 1988. Note: Erratum: Oncogene 3: 235 only, 1988. [PubMed: 3285299]

  3. Le Beau, M. M., Rowley, J. D., Sacchi, N., Watson, D. K., Papas, T. S., Diaz, M. O. Hu-ets-2 is translocated to chromosome 8 in the t(8;21) in acute myelogenous leukemia. Cancer Genet. Cytogenet. 23: 269-274, 1986. [PubMed: 3021321] [Full Text: https://doi.org/10.1016/0165-4608(86)90189-5]

  4. Mavrothalassitis, G. J., Watson, D. K., Papas, T. S. Molecular and functional characterization of the promoter of ETS2, the human c-ets-2 gene. Proc. Nat. Acad. Sci. 87: 1047-1051, 1990. [PubMed: 2405393] [Full Text: https://doi.org/10.1073/pnas.87.3.1047]

  5. 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] [Full Text: https://doi.org/10.1038/35059131]

  6. Owczarek, C. M., Portbury, K. J., Hardy, M. P., O'Leary, D. A., Kudoh, J., Shibuya, K., Shimizu, N., Kola, I., Hertzog, P. J. Detailed mapping of the ERG-ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16. Gene 324: 65-77, 2004. [PubMed: 14693372] [Full Text: https://doi.org/10.1016/j.gene.2003.09.047]

  7. Sacchi, N., Cheng, S. V., Tanzi, R. E., Gusella, J. F., Drabkin, H. A., Patterson, D., Haines, J. H., Papas, T. S. The ETS genes on chromosome 21 are distal to the breakpoint of the acute myelogenous leukemia translocation (8;21). Genomics 3: 110-116, 1988. [PubMed: 3267212] [Full Text: https://doi.org/10.1016/0888-7543(88)90140-1]

  8. 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] [Full Text: https://doi.org/10.1126/science.3941901]

  9. Sumarsono, S. H., Wilson, T. J., Tymms, M. J., Venter, D. J., Corrick, C. M., Kola, R., Lahoud, M. H., Papas, T. S., Seth, A., Kola, I. Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 379: 534-540, 1996. [PubMed: 8596630] [Full Text: https://doi.org/10.1038/379534a0]

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Contributors:
Ada Hamosh - updated : 3/7/2008
Patricia A. Hartz - updated : 1/14/2008
George E. Tiller - updated : 12/21/2004
George E. Tiller - updated : 6/18/2003
Ada Hamosh - updated : 3/6/2001

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
alopez : 02/20/2024
carol : 01/25/2021
carol : 01/09/2013
terry : 6/7/2012
alopez : 3/21/2008
terry : 3/7/2008
mgross : 1/15/2008
terry : 1/14/2008
alopez : 3/28/2006
alopez : 12/21/2004
cwells : 6/18/2003
alopez : 3/6/2001
joanna : 11/5/1998
dkim : 7/24/1998
mark : 3/21/1996
terry : 3/7/1996
supermim : 3/16/1992
supermim : 3/23/1990
supermim : 3/20/1990
supermim : 3/7/1990
supermim : 3/1/1990
ddp : 10/27/1989