RNA-binding protein EWS explained

RNA-binding protein EWS is a protein that in humans is encoded by the EWSR1 gene on human chromosome 22, specifically 22q12.2.^{[1] [2]} It is one of 3 proteins in the FET protein family.^[3]

Clinical significance

The q22.2 region of chromosome 22 encodes the N-terminal transactivation domain of the EWS protein and that region may become joined to one of several other chromosomes which encode various transcription factors; see EWS/FLI and OMIM-133450.^[4] The expression of a chimeric protein with the EWS transactivation domain fused to the DNA binding region of a transcription factor generates a powerful oncogenic protein causing Ewing sarcoma and other members of the Ewing family of tumors. These translocations can occur due to chromoplexy, a burst of complex chromosomal rearrangements seen in cancer cells. ^[5] The normal EWS gene encodes an RNA binding protein closely related to FUS (gene) and TAF15, all of which have been associated to amyotrophic lateral sclerosis.^[6]

Interactions

The EWS protein has been shown to interact with:

• ATF1,^[7]
• BARD1,^[8]
• ERG,^[9]
• POU4F1,^[10]
• PTK2B^[11]
• SF1,^[12]
• SNRPC,^[13] and
• ZNF165.^[14]

Further reading

• Ohno T, Rao VN, Reddy ES . EWS/Fli-1 chimeric protein is a transcriptional activator . Cancer Res. . 53 . 24 . 5859–63 . December 1993 . 7503813 .
• Ouchida M, Ohno T, Fujimura Y, Rao VN, Reddy ES . Loss of tumorigenicity of Ewing's sarcoma cells expressing antisense RNA to EWS-fusion transcripts . Oncogene . 11 . 6 . 1049–54 . September 1995 . 7566963 .
• Book: Ban J, Siligan C, Kreppel M, Aryee D, Kovar H . Ews-Fli1 in Ewing's Sarcoma: Real Targets and Collateral Damage . New trends in cancer for the 21st century . 587 . 41–52 . 17163154 . 10.1007/978-1-4020-5133-3_4 . Advances in Experimental Medicine and Biology . 2006 . 978-1-4020-4966-8 .
• Meister HP . [Morphological findings of chronic constipation in childhood] . Monatsschrift für Kinderheilkunde . 124 . 5 . 354–6 . 1976 . 934118 .
• Guthrie GM, Verstraete A, Deines MM, Stern RM . Symptoms of stress in four societies . The Journal of Social Psychology . 95 . Second half . 165–72 . 1975 . 1127890 . 10.1080/00224545.1975.9918699 .
• Bhagirath T, Abe S, Nojima T, Yoshida MC . Molecular analysis of a t(11;22) translocation junction in a case of Ewing's sarcoma . Genes Chromosomes Cancer . 13 . 2 . 126–32 . 1995 . 7542907 . 10.1002/gcc.2870130209 . 36929552 .
• Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES . The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains . Oncogene . 9 . 10 . 3087–97 . 1994 . 8084618 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Plougastel B, Zucman J, Peter M, Thomas G, Delattre O . Genomic structure of the EWS gene and its relationship to EWSR1, a site of tumor-associated chromosome translocation . Genomics . 18 . 3 . 609–15 . 1994 . 8307570 . 10.1016/S0888-7543(05)80363-5 .
• Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G . EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts . Nat. Genet. . 4 . 4 . 341–5 . 1993 . 8401579 . 10.1038/ng0893-341 . 10944105 .
• Brodie SG, Stocker SJ, Wardlaw JC, Duncan MH, McConnell TS, Feddersen RM, Williams TM . EWS and WT-1 gene fusion in desmoplastic small round cell tumor of the abdomen . Hum. Pathol. . 26 . 12 . 1370–4 . 1996 . 8522311 . 10.1016/0046-8177(95)90303-8 .
• Fujimura Y, Ohno T, Siddique H, Lee L, Rao VN, Reddy ES . The EWS-ATF-1 gene involved in malignant melanoma of soft parts with t(12;22) chromosome translocation, encodes a constitutive transcriptional activator . Oncogene . 12 . 1 . 159–67 . 1996 . 8552387 .
• Clark J, Benjamin H, Gill S, Sidhar S, Goodwin G, Crew J, Gusterson BA, Shipley J, Cooper CS . Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma . Oncogene . 12 . 2 . 229–35 . 1996 . 8570200 .
• Magnaghi-Jaulin L, Masutani H, Robin P, Lipinski M, Harel-Bellan A . SRE elements are binding sites for the fusion protein EWS-FLI-1 . Nucleic Acids Res. . 24 . 6 . 1052–8 . 1996 . 8604338 . 145748 . 10.1093/nar/24.6.1052 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .
• Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, Höglund M, Forster A, Rabbitts TH, Ron D, Mandahl N, Mitelman F . Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS . Genomics . 37 . 1 . 1–8 . 1997 . 8921363 . 10.1006/geno.1996.0513 . free .
• Morohoshi F, Arai K, Takahashi EI, Tanigami A, Ohki M . Cloning and mapping of a human RBP56 gene encoding a putative RNA binding protein similar to FUS/TLS and EWS proteins . Genomics . 38 . 1 . 51–7 . 1997 . 8954779 . 10.1006/geno.1996.0591 .
• Zucman-Rossi J, Legoix P, Thomas G . Identification of new members of the Gas2 and Ras families in the 22q12 chromosome region . Genomics . 38 . 3 . 247–54 . 1997 . 8975699 . 10.1006/geno.1996.0625 .
• Guinamard R, Fougereau M, Seckinger P . The SH3 domain of Bruton's tyrosine kinase interacts with Vav, Sam68 and EWS . Scand. J. Immunol. . 45 . 6 . 587–95 . 1997 . 9201297 . 10.1046/j.1365-3083.1997.d01-447.x . 23303841 .
• Deloulme JC, Prichard L, Delattre O, Storm DR . The prooncoprotein EWS binds calmodulin and is phosphorylated by protein kinase C through an IQ domain . J. Biol. Chem. . 272 . 43 . 27369–77 . 1997 . 9341188 . 10.1074/jbc.272.43.27369 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .

External links

• Ewing sarcoma breakpoint region 1 on the Atlas of Genetics and Oncology

Notes and References

1. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G . Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours . Nature . 359 . 6391 . 162–5 . October 1992 . 1522903 . 10.1038/359162a0 . 1992Natur.359..162D . 4331584 .
2. Web site: Entrez Gene: EWSR1 Ewing sarcoma breakpoint region 1.
3. Flucke U, van Noesel MM, Siozopoulou V, Creytens D, Tops BB, van Gorp JM, Hiemcke-Jiwa LS . EWSR1-The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review . Diagnostics (Basel, Switzerland) . 11 . 6 . June 2021 . 1093 . 34203801 . 8232650 . 10.3390/diagnostics11061093 . free .
4. Web site: EWS family fusion genes - OMIM.
5. Anderson ND, de Borja R, Young MD, Fuligni F, Rosic A, Roberts ND, Hajjar S, Layeghifard M, Novokmet A, Kowalski PE, Anaka M . Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. . Science . 361 . 6405 . eaam8419 . August 2018 . 30166462 . 6176908 . 10.1126/science.aam8419 .
6. Couthouis J, Hart MP, Erion R, King OD, Diaz Z, Nakaya T, Ibrahim F, Kim HJ, Mojsilovic-Petrovic J, Panossian S, Kim CE, Frackelton EC, Solski JA, Williams KL, Clay-Falcone D, Elman L, McCluskey L, Greene R, Hakonarson H, Kalb RG, Lee VM, Trojanowski JQ, Nicholson GA, Blair IP, Bonini NM, Van Deerlin VM, Mourelatos Z, Shorter J, Gitler AD . Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis . Hum. Mol. Genet. . 21 . 13 . 2899–911 . 2012 . 22454397 . 3373238 . 10.1093/hmg/dds116 .
7. Fujimura Y, Ohno T, Siddique H, Lee L, Rao VN, Reddy ES . The EWS-ATF-1 gene involved in malignant melanoma of soft parts with t(12;22) chromosome translocation, encodes a constitutive transcriptional activator . Oncogene . 12 . 1 . 159–67 . January 1996 . 8552387 .
8. Spahn L, Petermann R, Siligan C, Schmid JA, Aryee DN, Kovar H . Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway . Cancer Res. . 62 . 16 . 4583–7 . August 2002 . 12183411 .
9. Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES . The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains . Oncogene . 9 . 10 . 3087–97 . Oct 1994 . 8084618 .
10. Thomas GR, Latchman DS . The pro-oncoprotein EWS (Ewing's Sarcoma protein) interacts with the Brn-3a POU transcription factor and inhibits its ability to activate transcription . Cancer Biol. Ther. . 1 . 4 . 428–32 . 12432261 . 10.4161/cbt.1.4.23. 2002 . free .
11. Felsch JS, Lane WS, Peralta EG . Tyrosine kinase Pyk2 mediates G-protein-coupled receptor regulation of the Ewing sarcoma RNA-binding protein EWS . Curr. Biol. . 9 . 9 . 485–8 . May 1999 . 10322114 . 10.1016/s0960-9822(99)80214-0. free . 1999CBio....9..485F .
12. Zhang D, Paley AJ, Childs G . The transcriptional repressor ZFM1 interacts with and modulates the ability of EWS to activate transcription . J. Biol. Chem. . 273 . 29 . 18086–91 . July 1998 . 9660765 . 10.1074/jbc.273.29.18086. free .
13. Knoop LL, Baker SJ . The splicing factor U1C represses EWS/FLI-mediated transactivation . J. Biol. Chem. . 275 . 32 . 24865–71 . August 2000 . 10827180 . 10.1074/jbc.M001661200 . free .
14. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .