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.

  • Original Paper
  • Published:

The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium

Oncogene volume 19, pages 5729–5735 (2000)Cite this article

Abstract

Genetic analysis of human papillary thyroid carcinomas (PTC) has revealed unique chromosomal translocations that form oncogenic fusion proteins and promote thyroid tumorigenesis in up to 60% of tumors examined. Although, the majority of thyroid specific translocations involve the growth factor receptor c-RET, variant rearrangements of the receptor for nerve growth factor, NTRK1 have also been described. One such translocation, TRK-T1, forms a fusion protein composed of the carboxyl terminal tyrosine kinase domain of NTRK1 and the amino terminal portion of TPR (Translocated Promoter Region). To determine if TRK-T1 expression can cause thyroid cancer in vivo, we developed transgenic mice that express the human TRK-T1 fusion protein in the thyroid. Immunohistochemical analysis of TRK-T1 transgenic mouse thyroids revealed TRK-T1 staining within the thyroid follicular epithelium. In contrast to nontransgenic littermates, 54% of transgenic mice developed thyroid abnormalities that included follicular hyperplasia and papillary carcinoma. Furthermore, all transgenic mice examined greater than 7 months of age developed thyroid hyperplasia and/or carcinoma. These data support the conclusion that TRK-T1 is oncogenic in vivo and contributes to the neoplastic transformation of the thyroid.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Ausubel F, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA and Struhl K. . 1995 Short Protocols in Molecular Biology, ed. John Wiley and Sons, Inc: New York.

  • Beimfohr C, Klugbauer S, Demidchik EP, Lengfelder E and Rabes HM. . 1999 Int. J. Cancer 80: 842–847.

  • Bongarzone I, Fugazzola L, Vigneri P, Mariani L, Mondellini P, Pacini F, Basolo F, Pinchera A, Pilotti S and Pierotti MA. . 1996 J. Clin. Endocrinol. Metab. 81: 2006–2009.

  • Bongarzone I, Pierotti MA, Monzini N, Mondellini P, Manenti G, Donghi R, Pilotti S, Grieco M, Santoro M, Fusco A and et al. 1989 Oncogene 4: 1457–1462.

  • Bongarzone I, Vigano E, Alberti L, Borrello MG, Pasini B, Greco A, Mondellini P, Smith DP, Ponder BA, Romeo G and Pierotti MA. . 1998a Oncogene 16: 2295–2301.

  • Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S and Pierrotti MA. . 1998b Clin. Cancer Res. 4: 223–228.

  • Delvincourt C, Patey M, Flament JB, Suarez HG, Larbre H, Jardillier JC and Delisle MJ. . 1996 Clin. Biochem. 29: 267–271.

  • Fugazzola L, Pilotti S, Pinchera A, Vorontsova TV, Mondellini P, Bongarzone I, Greco A, Astakhova L, Butti MG, Demidchik EP and et al. 1995 Cancer Res. 55: 5617–5620.

  • Fusco A, Berlingieri MT, Di Fiore PP, Portella G, Grieco M and Vecchio G. . 1987 Mol. Cell. Biol. 7: 3365–3370.

  • Greco A, Fusetti L, Miranda C, Villa R, Zanotti S, Pagliardini S and Pierotti MA. . 1998 Oncogene 16: 809–816.

  • Greco A, Mariani C, Miranda C, Lupas A, Pagliardini S, Pomati M and Pierotti MA. . 1995 Mol. Cell. Biol. 15: 6118–6127.

  • Greco A, Pierotti MA, Bongarzone I, Pagliardini S, Lanzi C and Della Porta G . 1992 Oncogene 7: 237–242.

  • Hogan B, Constantini F and Lacy E. . 1986 Manipulating the Mouse Embryo. A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Sping Harbor, NY.

  • Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY, Xing S and Ledent C. . 1996 Endocrinology 137: 375–378.

  • Klugbauer S, Lengfelder E, Demidchik EP and Rabes HM. . 1995 Oncogene 11: 2459–2467.

  • Klugbauer S, Lengfelder E, Demidchik EP and Rabes HM. . 1996 Oncogene 13: 1099–1102.

  • Martin-Zanca D, Hughes SH and Barbacid M. . 1986 Nature 319: 743–748.

  • Pierotti MA, Bongarzone I, Borello MG, Greco A, Pilotti S and Sozzi G. . 1996 Genes Chromosomes Cancer 16: 1–14.

  • Portella G, Vitagliano D, Borselli C, Melillo RM, Salvatore D, Rothstein JL, Vecchio G, Fusco A and Santoro M. . 1999 Oncol. Res. 11: 421–427.

  • Powell Jr DJ, Russell J, Nibu, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M, Fusco A and Rothstein JL. . 1998 Cancer Res. 58: 5523–5528.

  • Rabes HM and Klugbauer S. . 1998 Recent Results Cancer Res. 154: 248–264.

  • Rochefort P, Caillou B, Michiels FM, Ledent C, Talbot M, Schlumberger M, Lavelle F, Monier R and Feunteun J. . 1996 Oncogene 12: 111–118.

  • Rosai J, Carcangiu ML and Delellis RA. . 1990 Tumors of the Thyroid Gland, 3rd Edn. Armed Forces Institute of Pathology, Washington, D.C.

  • Sagartz JE, Jhiang SM, Tong Q and Capen CC. . 1997 Lab. Invest. 76: 307–318.

  • Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli G, Vecchio G and Fusco A. . 1996 Oncogene 12: 1821–1826.

  • Sozzi G, Bongarzone I, Miozzo M, Cariani CT, Mondellini P, Calderone C, Pilotti S, Pierotti MA and Della Porta G. . 1992 Genes Chromosomes Cancer 5: 212–218.

  • Wajjwalku W, Nakamura S, Hasegawa Y, Miyazaki K, Satoh Y, Funahashi H, Matsuyama M and Takahashi M. . 1992 Jpn. J. Cancer Res. 83: 671–675.

  • Wynford-Thomas D. . 1997 Horm. Res. 47: 145–157.

Download references

Acknowledgements

We thank the Kimmel Cancer Institute Transgenic Animal Facility for assistance in the development of transgenic mice and the Nucleic Acid Facility for oligonucleotide synthesis and DNA sequencing. This work was supported by grants from the National Institute of Health CA21124 and CA76259 (JL Rothstein), T32-AI07492 (DJ Powell) and T32-CA09678 (JP Russell) and the Italian Association for Cancer Research (M Santoro).

Author information

Authors and Affiliations

  1. Department of Otolaryngology (Head & Neck Surgery), Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, Pennsylvania, USA

    John P Russell, Daniel J Powell & Jay L Rothstein

  2. Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, Pennsylvania, USA

    Mary Cunnane

  3. Division of Experimental Oncology A, Instituto Nazionale Tumori, Milan, Italy

    Angela Greco

  4. Dipartimento di Biologia e Patologia Cellulare e Molecolare, Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Facolta di Medicina e Chirurgia, Universita di Napoli, Naples, 80131, Italy

    Giuseppe Portella & Massimo Santoro

  5. Dipartimento di Medicina Sperimentale e Clinica, Facolta de Medicina e Chirugia, di Catanzaro, T. Campanella 5, Cantanzaro, 88100, Italy

    Alfredo Fusco

Authors
  1. John P Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel J Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary Cunnane
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angela Greco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giuseppe Portella
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Massimo Santoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alfredo Fusco
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jay L Rothstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Russell, J., Powell, D., Cunnane, M. et al. The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium. Oncogene 19, 5729–5735 (2000). https://doi.org/10.1038/sj.onc.1203922

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203922

Keywords

This article is cited by

Search

Advanced search

Quick links