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  • Original Paper
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The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice

Oncogene volume 19, pages 2413–2422 (2000)Cite this article

Abstract

The characteristic t(12;16)(q13;p11) chromosomal translocation, which leads to gene fusion that encodes the FUS-CHOP chimeric protein, is associated with human liposarcomas. The altered expression of FUS-CHOP has been implicated in a characteristic subgroup of human liposarcomas. We have introduced the FUS-CHOP transgene into the mouse genome in which the expression of the transgene is successfully driven by the elongation factor 1α (EF1α) promoter to all tissues. The consequent overexpression of FUS-CHOP results in most of the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation of intracellular lipid, induction of adipocyte-specific genes and a concordant block in the differentiation program. We have demonstrated that liposarcomas in the FUS-CHOP transgenic mice express high levels of the adipocyte regulatory protein PPARγ, whereas it is not expressed in embryonic fibroblasts from these animals following induction to differentiation toward the adipocyte lineage, indicating that the in vitro system does not really reflect the in vivo situation and the developmental defect is downstream of PPARγ expression. No tumors of other tissues were found in these transgenic mice despite widespread activity of the EF1α promoter. This establishes FUS-CHOP overexpression as a key determinant of human liposarcomas and provide the first in vivo evidence for a link between a fusion gene created by a chromosomal translocation and a solid tumor.

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References

  • Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD and Brinster RL . 1985 Nature 318: 533–538

  • Adelmant G, Gilbert JD and Freytag SO . 1998 J Biol Chem 273: 15574–15581

  • Ailhaud G, Grimaldi P and Negrel R . 1992 Annu Rev Nutr 12: 207–233

  • Altabef M, Garcia M, Lavau C, Bae S-C, Dejean A and Samarut J . 1996 EMBO J 15: 2707–2716

  • Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, Hoglund M, Forster A, Rabbitts TH, Ron D, Mandahl N and Mitelman F . 1996 Genomics 37: 1–8

  • Batchvarova N, Wang XZ and Ron D . 1995 EMBO J 14: 4654–4661

  • Benneth JH, Shousha S, Puddle B and Athanasou NA . 1995 J Clin Pathol 48: 950–954

  • Cao Z, Umek RM and McKnight SL . 1991 Genes Dev 5: 1538–1552

  • Carlson SG, Fawcett TW, Bartlett JD, Bernier M and Holbrook NJ . 1993 Mol Cell Biol 13: 4736–4744

  • Castellanos A, Pintado B, Wuruaga E, Arévalo R, López A, Orfao A and Sánchez-García I . 1997 Blood 90: 2168–2174

  • Chang HR, Hajdu SI, Collin C and Brennan MP . 1989 Cancer 64: 1514–1520

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

  • Fornace Jr AJ, Nebert DW, Hollander MC, Luethy JD, Papathanasiou M, Fargnoli J and Holbrook N-J . 1989 Mol Cell Biol 9: 4196–4203

  • Freytag SO and Geddes TJ . 1992 Science 256: 379–382

  • Hwang C-S, Loftus TM, Mandrup S and Lane MD . 1997 Annu Rev Cell Dev Biol 13: 231–259

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

  • Kliewer SA, Umesono K, Noonan DJ, Heyman RA and Evans RM . 1992 Nature 358: 771–774

  • Knight JC, Renwick PJ, Cin PD, Van den Berghe H and Fletcher CD . 1995 Cancer Res 55: 24–27

  • Kuroda M, Ishida T, Takanashi M, Satoh M, Machinami R and Watanabe T . 1997 Am J Pathol 151: 735–744

  • Leder A, Pattengale PK, Kuo A, Stewart TA and Leder P . 1986 Cell 45: 485–495

  • Mack TM . 1995 Cancer 75: 211–244

  • Mizushima S and Nagata S . 1990 Nucleic Acid Research 18: 4322

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

  • Panagopoulos I, Mandahl N, Mitelman F and Aman P . 1995 Oncogene 11: 1133–1137

  • Prasad DD, Ouchida M, Lee L, Rao VN and Peddy ESP . 1994 Oncogene 9: 3717–3729

  • Price BD and Calderwood SK . 1992 Cancer Res 52: 3814–3817

  • Quiafe CJ, Pinkert CA, Ornitz DM, Palmiter RD and Brinster R . 1987 Cell 48: 1023–1034

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

  • Rabbitts TH . 1994 Nature 372: 143–149

  • Ron D and Habener JF . 1992 Genes Dev 6: 439–453

  • Ruther U, Garbner C, Komitowski D, Muller R and Wagner EF . 1987 Nature 325: 412–416

  • Samuelsson L, Stromberg K, Vikman K, Bjursell G and Enerback S . 1991 EMBO J 10: 3787–3793

  • Sánchez-García I and Rabbitts TH . 1994 Proc Natl Acad Sci USA 91: 7869–7873

  • Sánchez-García I . 1997 Annu Rev Genetics 31: 429–453

  • Shimizu K, Ichikawa H, Tojo A, Kaneko Y, Maseki N et al. 1993 Proc Natl Acad Sci USA 90: 10280–10284

  • Sinn E, Muller W, Pattengale P, Tepler I, Wallace R and Leder P . 1987 Cell 49: 465–475

  • Takada T, Iida K, Awaji T, Itoh K, Takahashi R, Shibui A, Yoshida K, Sugano S and Tsujimoto G . 1997 Nature Biotech 15: 458–461

  • Tanaka T, Yoshida N, Kishimoto T and Akira S . 1997 EMBO J 16: 7432–7443

  • Tontonoz P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher CDM, Brun RP, Mueller E, Altiok S, Oppenheim H, Evans RM and Spiegelman BM . 1997 Proc Natl Acad Sci USA 94: 237–241

  • Umek RM, Friedman AD and McKnight SL . 1991 Science 251: 288–292

  • Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR and Wilson DR . 1995 Science 269: 1108–1112

  • Wang XZ, Lawson B, Brewer JW, Zinszner H, Sanjay A, Mi LJ, Boorstein R, Kreibich G, Hendershot LM and Ron D . 1996 Mol Cell Biol 16: 4273–4280

  • Yeh WC, Cao Z, Classon M and McKnight SL . 1995 Genes Dev 9: 168–181

  • Zinszner H, Albalat R and Ron D . 1994 Genes Dev 8: 2513–2526

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Acknowledgements

We are grateful to Dr R Arévalo for providing the histological facilities. We are indebted to Dr C Cobaleda for help in the preparation of the manuscript, and specific thanks to JC Villoria-Terrón and JF Martín-Martín for excellent technical advice. This work has been supported by European Commission (BMH4-CT96-0375), DGCYT (UE96-0041, PB96-0816 and 1FD97-0360), Fundación Científica of the AECC, FIS (99/0935) and NIH grant (1 R01 CA79955-01).

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Authors and Affiliations

  1. Departamento de Proliferación y Diferenciacion Celular, Instituto de Microbiología Bioquímica, CSIC/Universidad de Salamanca, Edificio Departamental, Avda del Campo Charro s/n, Salamanca, 37007, Spain

    J Pérez-Losada, J F Martín-Martín & I Sánchez-García

  2. Area de Reproducción Animal, Centro de Investigación y Tecnología, Ctra de la Coruña km 5.9, Madrid, 28040, Spain

    B Pintado & A Gutiérrez-Adán

  3. Servicio de Anatomía Patológica, Universidad de Salamanca, Spain

    T Flores

  4. Servicio de Radiodiagnóstico, Universidad de Salamanca, Spain

    B Bañares-González & J Calabia del Campo

  5. Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Spain

    E Battaner

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  1. J Pérez-Losada
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  2. B Pintado
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Pérez-Losada, J., Pintado, B., Gutiérrez-Adán, A. et al. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Oncogene 19, 2413–2422 (2000). https://doi.org/10.1038/sj.onc.1203572

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