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.

  • Short Report
  • Published:

Overexpression of human βTrCP1 deleted of its F box induces tumorigenesis in transgenic mice

Oncogene volume 24, pages 2271–2276 (2005)Cite this article

Abstract

Genetic alterations affecting β-catenin, adenomatous polyposis coli or axin proteins are associated with the pathogenesis of numerous human tumors. All these mutations result in the synthesis of unphosphorylated β-catenin that escapes recognition by the β transducin repeat protein (βTrCP1), the receptor of an ubiquitin. The stabilized β-catenin translocates to the nucleus and activates the transcription of genes crucial for tumorigenesis. Recent evidence implicates mutations and overexpresssion of βTrCP1 in human prostate and colon tumors, respectively, suggesting that deregulated βTrCP1 may be involved in tumorigenesis. To explore this possibility further, we generated transgenic mice that specifically express a dominant-negative mutant of βTrCP1 (ΔFβTrCP1) or full-length βTrCP1 in intestine, liver and kidney. We found that 46% (16/35) of the transgenic mice that overexpressed the transgenes developed either intestinal adenomas (10/35) or hepatic (4/35) or urothelial (2/35) tumors. Immunohistological analysis of the tumors revealed that upregulation of cyclin D1, glutamine synthetase and chemotaxin 2 was associated with nuclear accumulation of β-catenin. These results show that the overexpression of ΔFβTrCP1 or βTrCP1 in vivo induce tumors through β-catenin activation.

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

Similar content being viewed by others

References

  • Besnard-Guérin C, Belaïdouini N, Lassot I, Segeral E, Jobart A, Marchal C and Benarous R . (2004). J. Biol. Chem., 279, 788–795.

  • Cadoret A, Ovejero C, Saadi-Kheddouci S, Souil E, Fabre M, Romagnolo B, Khan A and Perret C . (2001). Cancer Res., 61, 3245–3249.

  • Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers WH, Kitajewski J, Kahn A and Perret C . (2002). Oncogene, 21, 8293–8301.

  • De La Coste A, Romagnolo B, Billuart P, Renard C-A, Buendia M-A, Soubranne O, Fabre M, Chelly J, Beldjord C, Khan A and Perret C . (1998). Proc. Natl. Acad. Sci. USA, 95, 8847–8851.

  • Fuchs SY, Spiegelman VS and Kumar KG . (2004). Oncogene, 23, 2028–2036.

  • Gerstein AV, Almeida TA, Zhao G, Chess E, Shih Ie M, Buhler K, Pienta K, Rubin MA, Vessella R and Papadopoulos N . (2002). Genes Chromosomes Cancer, 34, 9–16.

  • Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L, Donzelli M, Margottin-Goguet F, Jackson PK, Yamasaki L and Pagano M . (2003). Dev. Cell, 4, 799–812.

  • Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M and Taketo MM . (1999). EMBO J., 18, 5931–5942.

  • Harada N, Miyoshi H, Murai N, Oshima H, Tamai Y, Oshima M and Taketo MM . (2002). Cancer Res., 62, 1971–1977.

  • Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R and Polakis P . (1999). Curr. Biol., 9, 207–210.

  • Kitagawa M, Hatakeyama S, Shirane M, Matsumoto M, Ishida N, Hattori K, Nakamichi I, Kikuchi A and Nakayama K . (1999). EMBO J., 18, 2401–2410.

  • Kroll M, Margottin F, Kohl A, Renard P, Durand H, Concordet JP, Bachelerie F, Arenzana-Seisdedos F and Benarous R . (1999). J. Biol. Chem., 274, 7941–7945.

  • Latres E, Chiaur DS and Pagano M . (1999). Oncogene, 18, 849–854.

  • Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K and Benarous R . (1998). Mol. Cell., 1, 565–574.

  • Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD and Jackson PK . (2003). Dev. Cell, 4, 813–826.

  • Nakayama K, Hatakeyama S, Maruyama S, Kikuchi A, Onoe K, Good RA and Nakayama KI . (2003). Proc. Natl. Acad. Sci. USA, 100, 8752–8757 (E-pub 3 July 2003).

  • Ovejero C, Cavard C, Périanin A, Hakvoort T, Vermeulen J, Godard C, Fabre M, Chafey P, Suzuki K, Romagnolo B, Yamagoe S and Perret C . (2004). Hepatology, 40, 167–176.

  • Polakis P . (2000). Genes Dev., 14, 1837–1851.

  • Romagnolo B, Berrebi D, Saadi-Keddoucci S, Porteu A, Pichard AL, Peuchmaur M, Vandewalle A, Kahn A and Perret C . (1999). Cancer Res., 59, 3875–3879.

  • Sadot E, Simcha I, Iwai K, Ciechanover A, Geiger B and Ben-Ze’ev A . (2000). Oncogene, 19, 1992–2001.

  • Spiegelman VS, Slaga TJ, Pagano M, Minamoto T, Ronai Z and Fuchs SY . (2000). Mol. Cell, 5, 877–882.

Download references

Acknowledgements

We thank Arlette Porteu at the Cochin Institute for transgenic injections and help with obtaining the transgenic mice, the animal staff of the Cochin Institute for skilful care of mice used in this study, and Frank Letourneur for sequence analysis. N Belaïdouni is supported by Sidaction, and C Besnard-Guérin by INSERM. This work was supported by grants from the ANRS, SIDACTION, ARC and Ligue nationale contre le Cancer.

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Department of INSERM U567, Institut Cochin, CNRS UMR8104, Université R Descartes Paris V, 27 rue du Faubourg Saint Jacques, 75014, Paris, France

    Nadia Belaïdouni, Richard Benarous & Corinne Besnard-Guérin

  2. Service d'Anatomapathologie, Hôpital Robert Debré, AP-HP et EA3102, 48 Bd Sérurier, 75019, Paris, France

    Michel Peuchmaur & Agnes Florentin

  3. Department of Genetic, Developement and Molecular Pathology, Department of INSERM U567, Institut Cochin, CNRS UMR 8104, Universite Paris V, 24 rue du Faubourg St-Jacques, 75014, Paris, France

    Christine Perret

Authors
  1. Nadia Belaïdouni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michel Peuchmaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine Perret
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Agnes Florentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard Benarous
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Corinne Besnard-Guérin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Richard Benarous or Corinne Besnard-Guérin.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Belaïdouni, N., Peuchmaur, M., Perret, C. et al. Overexpression of human βTrCP1 deleted of its F box induces tumorigenesis in transgenic mice. Oncogene 24, 2271–2276 (2005). https://doi.org/10.1038/sj.onc.1208418

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208418

Keywords

This article is cited by

Search

Advanced search

Quick links