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  • Original Paper
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A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene

Oncogene volume 20, pages 4161–4168 (2001)Cite this article

Abstract

Chromosomal fusion of the N-terminal region of the Ewings Sarcoma Oncogene (EWS-activation-domain, EAD) to the DNA-binding domains of a variety of cellular transcription factors produce oncogenic proteins (EWS-fusion proteins (EFPs)) that cause distinct malignancies. In EFPs, the EAD acts as a potent transcriptional activation domain and this ability is repressed in the context of normal, non-tumorigenic, EWS. Trans-activation by the EAD is therefore a specific characteristic of EFPs and it is thought that EFPs induce tumorigenesis via improper transcriptional activation of cellular genes. Functional elements required for transcriptional activation are dispersed throughout the EAD, as are thirty-one copies of a Degenerate Hexapeptide Repeat (DHR, consensus SYGQQS). This suggests that the EAD contains a highly reiterated functional element related to DHRs. Here we show that in the context of EWS/ATF1, the EFP that causes malignant melanoma of soft parts, trans-cooperation by small regions of the EAD (∼30 residues) results in potent transcriptional activation dependent on the conserved tyrosine residues present in DHRs. These findings provide the first evidence for a role of DHRs in EAD-mediated trans-activation and demonstrate that the EAD represents a novel tyrosine-dependent transcriptional activation domain.

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References

  • Benuck ML, Li Z, Childs G . 1999 J. Biol. Chem. 274: 25419–25425

  • Bertolotti A, Melot T, Acker J, Vigneron M, Delattre O, Tora L . 1998 Mol. Cell. Biol. 18: 1489–1497

  • Blair WS, Bogerd HP, Madore SJ, Cullen BR . 1994 Mol. Cell. Biol. 14: 7226–7234

  • Brown AD, Lopez-Terrada D, Denny CT, Lee KAW . 1995 Oncogene 10: 1749–1756

  • Carey M . 1998 Cell 92: 5–8

  • Carey M, Kolman J, Katz DA, Gradoville L, Barberis L, Miller G . 1992 J. Virol. 66: 4803–4813

  • Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G, Aurias A, Thomas G . 1992 Nature 359: 162–165

  • Deloulme JC, Prichard L, Delattre O, Storm DR . 1997 J. Biol. Chem. 272: 27369–27377

  • Felsch JS, Lane WS, Peralta EG . 1999 Curr. Biol. 9: 485–488

  • Fujimura Y, Ohno T, Siddique H, Lee L, Rao VN, Reddy ESP . 1996 Oncogene 12: 159–167

  • Gill G, Pascal E, Tseng ZH, Tjian R . 1994 Proc. Natl. Acad. Sci. 91: 192–196

  • Guinamard R, Fougereau M, Seckinger P . 1997 Scand. J. Immunol. 45: 587–595

  • Kim TK, Roeder RG . 1994 Nucleic Acids Res. 22: 251

  • Kim J, Lee KAW, Pelletier J . 1998 Oncogene 16: 1021–1030

  • Kim J, Lee JM, Branton PE, Pelletier J . 1999 Proc. Natl. Acad. Sci., USA 96: 14300–14305

  • Kovar H, Aryee D, Zoubek A . 1999 Curr. Op. Oncol. 11: 275–284

  • Krajewski W, Lee KAW . 1994 Mol. Cell. Biol. 14: 7204–7210

  • Lee KAW, Masson N . 1993 Biochem. Biophys. Acta. 1174: 221–233

  • Lessnick SL, Braun BS, Denny CT, May WA . 1995 Oncogene 10: 423–431

  • Li KKC, Lee KAW . 2000 J. Biol. Chem. 275: 23053–23058

  • MacArthur H, Walter G . 1984 J. Virol. 52: 483–491

  • May WA, Lessnick SL, Braun BS, Klemsz M, Lewis BC, Lunsford LB, Hromas R, Denny CT . 1993 Mol. Cell. Biol. 13: 7393–7398

  • May WA, Denny CT . 1997 Curr. Top. Micro. Immun. 220: 143–150

  • Mayer BJ, Jackson PK, Van ER, Baltimore D . 1992 Mol. Cell. Biol. 12: 609–618

  • Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH . 1986 Proc. Natl. Acad. Sci., USA 83: 6682–6686

  • Netzer WJ, Hartl FU . 1997 Nature 388: 343–349

  • Nyanguile O, Uesugi M, Austin DJ, Verdine GL . 1997 Proc. Natl. Acad. Sci., USA 94: 13402–13406

  • Ohno T, Rao VN, Reddy ESP . 1993 Cancer Res. 53: 5859–5863

  • Pan S, Ming KY, Dunn TA, Li KKC, Lee KAW . 1998 Oncogene 16: 1625–1631

  • Petermann R, Mossier BM, Aryee DNT, Khazak V, Golemis EA, Kovar H . 1998 Oncogene 17: 603–610

  • Pollock R, Gilman M . 1997 Proc. Natl. Acad. Sci., USA 94: 13388–13389

  • Prasad DDK, Ouchida M, Lee L, Rao VN, Reddy ESP . 1994 Oncogene 9: 3717–3729

  • Rauscher III FJ . 1997 Curr. Top. Micro. Immun. 220: 151–162

  • Regier JL, Shen F, Triezenberg SJ . 1993 Proc. Natl. Acad. Sci., USA 90: 883–887

  • Ribeiro A, Brown AD, Lee KAW . 1994 J. Biol. Chem. 269: 31124–31128

  • Ron D . 1997 Curr. Top. Micro. Immun. 220: 131–142

  • Sanchez-Garcia I, Rabbitts TH . 1994 Proc. Natl. Acad. Sci., USA 91: 7869–7873

  • Seipel K, Georgiev O, Schaffner W . 1992 EMBO J. 11: 4961–4968

  • Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG, Birge RB, Fajardom JE, Chou MM, Hanafusa H, Schaffhausen B, Cantley LC . 1993 Cell 72: 767–778

  • Songyang Z, Carraway III KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, Mayer BJ, Cantley LC . 1995 Nature 373: 536–539

  • Tanaka M, Herr W . 1994 Mol. Cell. Biol. 14: 6056–6067

  • Triezenberg SJ . 1995 Curr. Opin. Genet. Dev. 5: 190–196

  • Zhang D, Paley AJ, Childs G . 1998 J. Biol. Chem. 273: 18086–18091

  • Zhou H, Lee KAW . 2001 Oncogene 20: 1519–1524

  • Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CDM, Aurias A, Thomas G . 1993 Nature Genetics 4: 341–345

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Acknowledgements

We thank Dr Zhang Mingjie for many discussions during the course of this work, Dr Chris Rock for helpful comments on the manuscript and Kim KC Li for excellent technical assistance. This work was supported by a Hong Kong Government Research Grants Council grant (award HKUST 6106/98M) to KAW Lee.

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  1. Department of Biology, Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, S.A.R., China

    Liang Feng & Kevin A W Lee

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  1. Liang Feng
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Correspondence to Kevin A W Lee.

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Feng, L., Lee, K. A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene. Oncogene 20, 4161–4168 (2001). https://doi.org/10.1038/sj.onc.1204522

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