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Gene Review

EWSR1  -  EWS RNA-binding protein 1

Homo sapiens

Synonyms: EWS, EWS oncogene, Ewing sarcoma breakpoint region 1 protein, RNA-binding protein EWS, bK984G1.4
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Disease relevance of EWSR1


Psychiatry related information on EWSR1

  • OBJECTIVES: To explore and test methods for the operation of a national Early Warning System (EWS) in Denmark and to support decision making by the Danish Centre for Evaluation and Health Technology Assessment on this issue [5].
  • BACKGROUND: While cognitive formulations of eating disorders emphasise the role of dysfunctional assumptions regarding eating, weight and shape (EWS), less is known about the role of dysfunctional assumptions that are unrelated to EWS and those linking beliefs about EWS with negative beliefs about the self or the world [6].

High impact information on EWSR1

  • This indicates that the EWS-FLI1 fusion protein may act as an aberrant transcription factor, but the exact mechanism of oncogenesis remains unknown [7].
  • Our results implicate TGF-beta RII as a direct target of EWS-FLI1 [7].
  • Ewing sarcoma and related peripheral primitive neuroectodermal tumours share recurrent translocations that fuse the gene EWSR1 (formerly EWS) from 22q-12 to FLI1 and genes encoding other ETS transcription factors (which bind DNA through the conserved ETS domain) [7].
  • We have found that EWS/FLI1 and structurally related fusion proteins upregulate manic fringe (MFNG), a recently described member of the Fringe gene family instrumental in somatic development [8].
  • EWS/FLI1, a fusion gene found in Ewing's sarcoma, encodes a transcriptional regulator and promotes cellular transformation by modulating the transcription of specific target genes [8].

Chemical compound and disease context of EWSR1


Biological context of EWSR1

  • Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation [14].
  • This study thus has demonstrated that the EWSR1-ATF1 chimera represents a fusion gene that can be associated with different tumor types [2].
  • In this article, we report that POU5F1 was fused to EWSR1 in a case of undifferentiated sarcoma derived from pelvic bone with chromosomal translocation t(6;22)(p21;q12) [15].
  • Activation of the EWSR1-ATF1 oncogene is probably an early step in the transformation process, but the overall gene expression patterns are likely to vary considerably between AFH and CCS, in keeping with their clinicopathologic differences [2].
  • Furthermore, fluorescence in situ hybridization (FISH) with cosmid probes corresponding to loci flanking the EWSR1 region demonstrated no split of chromosome 22 in all analyzed interphase nuclei [16].

Anatomical context of EWSR1


Associations of EWSR1 with chemical compounds


Physical interactions of EWSR1

  • The region on EWS which interacts with ZFM1 maps to 37 amino acids within its NTD [20].
  • Following a scheme similar to previously described translocations in Ewing tumors, a t(2;22) chromosome translocation fuses the N-terminal domain of EWS to the ETS DNA binding domain of FEV [24].
  • Employing yeast two-hybrid cloning we isolated the seventh largest subunit of human RNA polymerase II (hsRPB7) as a protein that specifically interacts with the amino terminus of EWS [25].
  • Here, we show that EWS interacts with Pyk2, a protein tyrosine kinase implicated in a variety of signal transduction processes [23].
  • Desmoplastic small round cell tumor (DSRCT) is a malignant human cancer that is associated with a specific t(11;22) chromosome translocation, where 265 amino acids from the EWS amino-terminus are fused to the DNA binding domain of the WT1 tumor suppressor gene [26].

Enzymatic interactions of EWSR1

  • STAT3 activation was assessed by immunohistochemistry using a monoclonal antibody specific for tyrosine(705)-phosphorylated STAT3 (pSTAT3(tyr705)) and a tissue microarray containing 49 paraffin-embedded ESFT tumours with known EWS translocations [27].

Regulatory relationships of EWSR1

  • Based on this hypothesis, we investigated the effect of EWS on the activation of nuclear receptors that are activated by CBP [19].
  • EWS/ETS fusions activate telomerase in Ewing's tumors [28].
  • The splicing factor U1C represses EWS/FLI-mediated transactivation [29].
  • Exogenous IGFBP-3 remarkably inhibits EWS growth, both in monolayer and anchorage-independent conditions, and significantly reduces cell motility [30].
  • We have previously reported that cyclin E expression was upregulated in EFT cells and in EWS-Fli1 transformed fibroblastic cells [31].

Other interactions of EWSR1


Analytical, diagnostic and therapeutic context of EWSR1


  1. Expression profiling of t(12;22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3. Schaefer, K.L., Brachwitz, K., Wai, D.H., Braun, Y., Diallo, R., Korsching, E., Eisenacher, M., Voss, R., Van Valen, F., Baer, C., Selle, B., Spahn, L., Liao, S.K., Lee, K.A., Hogendoorn, P.C., Reifenberger, G., Gabbert, H.E., Poremba, C. Cancer Res. (2004) [Pubmed]
  2. Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma. Hallor, K.H., Mertens, F., Jin, Y., Meis-Kindblom, J.M., Kindblom, L.G., Behrendtz, M., Kalén, A., Mandahl, N., Panagopoulos, I. Genes Chromosomes Cancer (2005) [Pubmed]
  3. Absence of mutations of the BRAF gene in malignant melanoma of soft parts (clear cell sarcoma of tendons and aponeuroses). Panagopoulos, I., Mertens, F., Isaksson, M., Mandahl, N. Cancer Genet. Cytogenet. (2005) [Pubmed]
  4. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Zucman, J., Delattre, O., Desmaze, C., Epstein, A.L., Stenman, G., Speleman, F., Fletchers, C.D., Aurias, A., Thomas, G. Nat. Genet. (1993) [Pubmed]
  5. "The future should not take us by surprise": preparation of an early warning system in Denmark. Douw, K., Vondeling, H., Sørensen, J., Jørgensen, T., Sigmund, H. International journal of technology assessment in health care. (2004) [Pubmed]
  6. Development and preliminary validation of the testable assumptions questionnaire--eating disorders (TAQ-ED). Hinrichsen, H., Garry, J., Waller, G. Eating behaviors. (2006) [Pubmed]
  7. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Hahm, K.B., Cho, K., Lee, C., Im, Y.H., Chang, J., Choi, S.G., Sorensen, P.H., Thiele, C.J., Kim, S.J. Nat. Genet. (1999) [Pubmed]
  8. EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic. May, W.A., Arvand, A., Thompson, A.D., Braun, B.S., Wright, M., Denny, C.T. Nat. Genet. (1997) [Pubmed]
  9. Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway. Spahn, L., Petermann, R., Siligan, C., Schmid, J.A., Aryee, D.N., Kovar, H. Cancer Res. (2002) [Pubmed]
  10. Exposure on cell surface and extensive arginine methylation of ewing sarcoma (EWS) protein. Belyanskaya, L.L., Gehrig, P.M., Gehring, H. J. Biol. Chem. (2001) [Pubmed]
  11. Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma. Clark, J., Benjamin, H., Gill, S., Sidhar, S., Goodwin, G., Crew, J., Gusterson, B.A., Shipley, J., Cooper, C.S. Oncogene (1996) [Pubmed]
  12. A practical approach to the clinical diagnosis of Ewing's sarcoma/primitive neuroectodermal tumour and other small round cell tumours sharing EWS rearrangement using new fluorescence in situ hybridisation probes for EWSR1 on formalin fixed, paraffin wax embedded tissue. Yamaguchi, U., Hasegawa, T., Morimoto, Y., Tateishi, U., Endo, M., Nakatani, F., Kawai, A., Chuman, H., Beppu, Y., Endo, M., Kurotaki, H., Furuta, K. J. Clin. Pathol. (2005) [Pubmed]
  13. A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene. Feng, L., Lee, K.A. Oncogene (2001) [Pubmed]
  14. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Delattre, O., Zucman, J., Plougastel, B., Desmaze, C., Melot, T., Peter, M., Kovar, H., Joubert, I., de Jong, P., Rouleau, G. Nature (1992) [Pubmed]
  15. EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12). Yamaguchi, S., Yamazaki, Y., Ishikawa, Y., Kawaguchi, N., Mukai, H., Nakamura, T. Genes Chromosomes Cancer (2005) [Pubmed]
  16. Synovial sarcoma with a secondary chromosome change der(22)t(17;22)(q12;q12). Nishio, J., Iwasaki, H., Ishiguro, M., Ohjimi, Y., Isayama, T., Naito, M., Kaneko, Y., Kamada, N., Kikuchi, M. Cancer Genet. Cytogenet. (2002) [Pubmed]
  17. Arrangement of chromosome 11 and 22 territories, EWSR1 and FLI1 genes, and other genetic elements of these chromosomes in human lymphocytes and Ewing sarcoma cells. Taslerová, R., Kozubek, S., Lukásová, E., Jirsová, P., Bártová, E., Kozubek, M. Hum. Genet. (2003) [Pubmed]
  18. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma. Riggi, N., Cironi, L., Provero, P., Suvà, M.L., Stehle, J.C., Baumer, K., Guillou, L., Stamenkovic, I. Cancer Res. (2006) [Pubmed]
  19. Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4-mediated transcription. Araya, N., Hirota, K., Shimamoto, Y., Miyagishi, M., Yoshida, E., Ishida, J., Kaneko, S., Kaneko, M., Nakajima, T., Fukamizu, A. J. Biol. Chem. (2003) [Pubmed]
  20. The transcriptional repressor ZFM1 interacts with and modulates the ability of EWS to activate transcription. Zhang, D., Paley, A.J., Childs, G. J. Biol. Chem. (1998) [Pubmed]
  21. The SH3 domain of Bruton's tyrosine kinase interacts with Vav, Sam68 and EWS. Guinamard, R., Fougereau, M., Seckinger, P. Scand. J. Immunol. (1997) [Pubmed]
  22. The COOH-terminal domain of FLI-1 is necessary for full tumorigenesis and transcriptional modulation by EWS/FLI-1. Arvand, A., Welford, S.M., Teitell, M.A., Denny, C.T. Cancer Res. (2001) [Pubmed]
  23. Tyrosine kinase Pyk2 mediates G-protein-coupled receptor regulation of the Ewing sarcoma RNA-binding protein EWS. Felsch, J.S., Lane, W.S., Peralta, E.G. Curr. Biol. (1999) [Pubmed]
  24. A new member of the ETS family fused to EWS in Ewing tumors. Peter, M., Couturier, J., Pacquement, H., Michon, J., Thomas, G., Magdelenat, H., Delattre, O. Oncogene (1997) [Pubmed]
  25. Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II. Petermann, R., Mossier, B.M., Aryee, D.N., Khazak, V., Golemis, E.A., Kovar, H. Oncogene (1998) [Pubmed]
  26. Modulation of EWS/WT1 activity by the v-Src protein tyrosine kinase. Kim, J., Lee, J.M., Branton, P.E., Pelletier, J. FEBS Lett. (2000) [Pubmed]
  27. STAT3 is activated in a subset of the Ewing sarcoma family of tumours. Lai, R., Navid, F., Rodriguez-Galindo, C., Liu, T., Fuller, C.E., Ganti, R., Dien, J., Dalton, J., Billups, C., Khoury, J.D. J. Pathol. (2006) [Pubmed]
  28. EWS/ETS fusions activate telomerase in Ewing's tumors. Takahashi, A., Higashino, F., Aoyagi, M., Yoshida, K., Itoh, M., Kyo, S., Ohno, T., Taira, T., Ariga, H., Nakajima, K., Hatta, M., Kobayashi, M., Sano, H., Kohgo, T., Shindoh, M. Cancer Res. (2003) [Pubmed]
  29. The splicing factor U1C represses EWS/FLI-mediated transactivation. Knoop, L.L., Baker, S.J. J. Biol. Chem. (2000) [Pubmed]
  30. Insulin-like growth factor binding protein 3 as an anticancer molecule in Ewing's sarcoma. Benini, S., Zuntini, M., Manara, M.C., Cohen, P., Nicoletti, G., Nanni, P., Oh, Y., Picci, P., Scotlandi, K. Int. J. Cancer (2006) [Pubmed]
  31. Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor cells. Li, X., Tanaka, K., Nakatani, F., Matsunobu, T., Sakimura, R., Hanada, M., Okada, T., Nakamura, T., Iwamoto, Y. Int. J. Cancer (2005) [Pubmed]
  32. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Prieur, A., Tirode, F., Cohen, P., Delattre, O. Mol. Cell. Biol. (2004) [Pubmed]
  33. EWS-FLI1, EWS-ERG, and EWS-ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor beta type II receptor gene. Im, Y.H., Kim, H.T., Lee, C., Poulin, D., Welford, S., Sorensen, P.H., Denny, C.T., Kim, S.J. Cancer Res. (2000) [Pubmed]
  34. Inhibition of platelet-derived growth factor-induced cell growth signaling by a short interfering RNA for EWS-Fli1 via down-regulation of phospholipase D2 in Ewing sarcoma cells. Nozawa, S., Ohno, T., Banno, Y., Dohjima, T., Wakahara, K., Fan, D.G., Shimizu, K. J. Biol. Chem. (2005) [Pubmed]
  35. A novel zinc finger gene is fused to EWS in small round cell tumor. Mastrangelo, T., Modena, P., Tornielli, S., Bullrich, F., Testi, M.A., Mezzelani, A., Radice, P., Azzarelli, A., Pilotti, S., Croce, C.M., Pierotti, M.A., Sozzi, G. Oncogene (2000) [Pubmed]
  36. Esophageal extraskeletal Ewing's sarcoma. Maesawa, C., Iijima, S., Sato, N., Yoshinori, N., Suzuki, M., Tarusawa, M., Ishida, K., Tamura, G., Saito, K., Masuda, T. Hum. Pathol. (2002) [Pubmed]
  37. Induction of the interleukin-2/15 receptor beta-chain by the EWS-WT1 translocation product. Wong, J.C., Lee, S.B., Bell, M.D., Reynolds, P.A., Fiore, E., Stamenkovic, I., Truong, V., Oliner, J.D., Gerald, W.L., Haber, D.A. Oncogene (2002) [Pubmed]
  38. Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses. Panagopoulos, I., Mertens, F., Dêbiec-Rychter, M., Isaksson, M., Limon, J., Kardas, I., Domanski, H.A., Sciot, R., Perek, D., Crnalic, S., Larsson, O., Mandahl, N. Int. J. Cancer (2002) [Pubmed]
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