Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

EWS-ATF-1 chimeric protein in soft tissue clear cell sarcoma associates with CREB-binding protein and interferes with p53-mediated trans-activation function

Abstract

The recurrent t(12;22) (q13;q12) chromosomal translocation associated with soft tissue clear cell sarcoma results in a chimeric protein EWS-ATF-1 that acts as a constitutive transcriptional activator. The CBP/p300 transcriptional coactivator, which links various transcriptional factors to basal transcription apparatus, participates in transcriptional activation, growth and cell cycle control and differentiation. In this study, we show that EWS-ATF-1 associates constitutively with CBP both in vitro and in vivo. Both EWS and ATF-1 fusion domains are needed for this interaction. Here, we demonstrate that EWS-ATF-1 represses p53/CBP-mediated trans-activation function. Overexpression of CBP can counteract this repressive effect of EWS-ATF-1. Taken together, these findings suggest that one of the mechanisms by which EWS-ATF-1 may cause tumors is through targeting CBP/p300 resulting in the loss of function of p53. This novel mechanism may be responsible for the development of these and other related solid tumors.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  • Arias J, Alberts AS, Brindle P, Claret FX, Smeal T, Karin M, Feramisco J, Montminy M . 1994 Nature 370: 226–229

  • Ariumi Y, Kaida A, Lin JY, Hirota M, Masui O, Yamaoka S, Taya Y, Shimotohno K . 2000 Oncogene 19: 1491–1499

  • Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS, Kelly K . 1997 Cell 89: 1175–1184

  • Bailly RA, Bosselut R, Zucman J, Cormier F, Delattre O, Roussel M, Thomas G, Ghysdael J . 1994 Mol. Cell Biol. 14: 3230–3241

  • Ben-David Y, Giddens EB, Letwin K, Bernstein A . 1991 Genes Dev. 5: 908–918

  • Bertolotti A, Lutz Y, Heard DJ, Chambon P, Tora L . 1996 EMBO J. 15: 5022–5031

  • Borrow J, Stanton Jr VP, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dube I, Frischauf AM, Horsman D, Mitelman F, Volinia S, Watmore AE, Housman DE . 1996 Nat. Genet. 14: 33–41

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

  • Burd CG, Dreyfuss G . 1994 Science 265: 615–621

  • Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH . 1993 Nature 365: 855–859

  • Crozat A, Aman P, Mandahl N, Ron D . 1993 Nature 363: 640–644

  • 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

  • Epstein AL, Martin AO, Kempson R . 1984 Cancer Res. 44: 1265–1274

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

  • Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF, Daigo Y, Russell P, Wilson A, Sowter HM, Delhanty JD, Ponder BA, Kouzarides T, Caldas C . 2000 Nat. Genet. 24: 300–303

  • Gerald WL, Rosai J, Ladanyi M . 1995 Proc. Natl. Acad. Sci. USA 92: 1028–1032

  • Giles RH, Peters DJ, Breuning MH . 1998 Trends Genet. 14: 178–183

  • Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, Croce CM, Canaani E . 1992 Cell 71: 701–708

  • Gu W, Roeder RG . 1997 Cell 90: 595–606

  • Gu W, Shi XL, Roeder RG . 1997 Nature 387: 819–823

  • Ichikawa H, Shimizu K, Hayashi Y, Ohki M . 1994 Cancer Res. 54: 2865–2868

  • Immanuel D, Zinszner H, Ron D . 1995 Mol. Cell Biol. 15: 4562–4571

  • Jeon IS, Davis JN, Braun BS, Sublett JE, Roussel MF, Denny CT, Shapiro DN . 1995 Oncogene 10: 1229–1234

  • Kaneko Y, Yoshida K, Handa M, Toyoda Y, Nishihira H, Tanaka Y, Sasaki Y, Ishida S, Higashino F, Fujinaga K . 1996 Genes Chromosomes Cancer 15: 115–121

  • Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace Jr AJ . 1992 Cell 71: 587–597

  • Kern SE, Pietenpol JA, Thiagalingam S, Seymour A, Kinzler KW, Vogelstein B . 1992 Science 256: 827–830

  • Kung AL, Rebel VI, Bronson RT, Ch'ng LE, Sieff CA, Livingston DM, Yao TP . 2000 Genes Dev. 14: 272–277

  • Labelle Y, Zucman J, Stenman G, Kindblom LG, Knight J, Turc-Carel C, Dockhorn-Dworniczak B, Mandahl N, Desmaze C, Peter M . 1995 Hum. Mol. Genet. 4: 2219–2226

  • Levine AJ . 1997 Cell 88: 323–331

  • Lill NL, Grossman SR, Ginsberg D, DeCaprio J, Livingston DM . 1997 Nature 387: 823–827

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

  • Miller RW, Rubinstein JH . 1995 Am. J. Med. Genet. 56: 112–115

  • Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES . 1994 Oncogene 9: 3087–3097

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

  • Ouchida M, Ohno T, Fujimura Y, Rao VN, Reddy ES . 1995 Oncogene 11: 1049–1054

  • Panagopoulos I, Aman P, Fioretos T, Hoglund M, Johansson B, Mandahl N, Heim S, Behrendtz M, Mitelman F . 1994 Genes Chromosomes Cancer 11: 256–262

  • Panagopoulos I, Hoglund M, Mertens F, Mandahl N, Mitelman F, Aman P . 1996 Oncogene 12: 489–494

  • Peter M, Couturier J, Pacquement H, Michon J, Thomas G, Magdelenat H, Delattre O . 1997 Oncogene 14: 1159–1164

  • Prasad DD, Rao VN, Reddy ES . 1992 Cancer Res. 52: 5833–5837

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

  • Rabbitts TH, Forster A, Larson R, Nathan P . 1993 Nat, Genet. 4: 175–180

  • Rao VN, Papas TS, Reddy ES . 1987 Science 237: 635–639

  • Reddy ES, Rao VN, Papas TS . 1987 Proc. Natl. Acad. Sci. USA 84: 6131–6135

  • Satake N, Ishida Y, Otoh Y, Hinohara S, Kobayashi H, Sakashita A, Maseki N, Kaneko Y . 1997 Genes Chromosomes Cancer 20: 60–63

  • Shimomura A, Ogawa Y, Kitani T, Fujisawa H, Hagiwara M . 1996 J. Biol. Chem. 271: 17957–17960

  • Somasundaram K, El-Deiry WS . 1997 Oncogene 14: 1047–1057

  • Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ, Denny CT . 1994 Nat. Genet. 6: 146–151

  • Stolow DT, Haynes SR . 1995 Nucleic Acids Res. 23: 835–843

  • Urano F, Umezawa A, Hong W, Kikuchi H, Hata J . 1996 Biochem. Biophys. Res. Commun. 219: 608–612

  • Van Orden K, Giebler HA, Lemasson I, Gonzales M, Nyborg JK . 1999 J. Biol. Chem. 274: 26321–26328

  • Yi H, Fujimura Y, Ouchida M, Prasad DD, Rao VN, Reddy ES . 1997 Oncogene 14: 1259–1268

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

Download references

Acknowledgements

We thank other colleagues of Reddy and Rao's laboratories for their kind cooperation. This work is supported in part by NIH grants RO1 CA 85343, RO1 CA 58642 and US Army medical research and command grant DAMD-17-99-1-9060 to ESP Reddy and CA 57322 to VN Rao.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fujimura, Y., Siddique, H., Lee, L. et al. EWS-ATF-1 chimeric protein in soft tissue clear cell sarcoma associates with CREB-binding protein and interferes with p53-mediated trans-activation function. Oncogene 20, 6653–6659 (2001). https://doi.org/10.1038/sj.onc.1204684

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204684

Keywords

  • EWS-ATF-1
  • CBP
  • p53
  • Ewing's sarcoma
  • clear cell sarcoma

Further reading

Search

Quick links