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:

Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells

Oncogene volume 23, pages 7345–7354 (2004)Cite this article

Abstract

Expression of Snail transcriptional factor is a determinant in the acquisition of a mesenchymal phenotype by epithelial tumor cells. However, the regulation of the transcription of this gene is still unknown. We describe here the characterization of a human SNAIL promoter that contains the initiation of transcription and regulates the expression of this gene in tumor cells. This promoter was activated in cell lines in response to agents that induce Snail transcription and the mesenchymal phenotype, as addition of the phorbol ester PMA or overexpression of integrin-linked kinase (ILK) or oncogenes such as Ha-ras or v-Akt. Although other regions of the promoter were required for a complete stimulation by Akt or ILK, a minimal fragment (−78/+59) was sufficient to maintain the mesenchymal specificity. Activity of this minimal promoter and SNAIL RNA levels were dependent on ERK signaling pathway. NFκB/p65 also stimulated SNAIL transcription through a region located immediately upstream the minimal promoter, between −194 and −78. These results indicate that Snail transcription is driven by signaling pathways known to induce epithelial to mesenchymal transition, reinforcing the role of Snail in this process.

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
Figure 7

Similar content being viewed by others

References

  • Ajenjo N, Aaronson DS, Cevallos E, Richard C, Leon J and Crespo P . (2000). J. Biol. Chem., 275, 7189–7197.

  • Bates RC and Mercurio AM . (2003). Mol. Biol. Cell, 14, 1790–1800.

  • Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J and García de Herreros A . (2000). Nat. Cell Biol., 2, 84–89.

  • Batlle E, Verdú J, Domínguez D, Llosas MM, Díaz V, Loukili N, Paciucci R, Alameda F and García de Herreros A . (1998). J. Biol. Chem., 273, 15091–15098.

  • Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F and Nieto MA . (2000). Nat. Cell Biol., 2, 78–83.

  • Carver EA, Rulang J, Lan Y, Oram KF and Gridley T . (2001). Mol. Cell. Biol., 21, 8184–8188.

  • Ciruna B and Rossant J . (2001). Dev. Cell, 1, 37–49.

  • Comijn J, Berx G, Vermassen P, Verschuren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroek D and van Roy F . (2001). Mol. Cell, 7, 1267–1278.

  • Conacci-Sorrell M, Simca I, BenYedida T, Blechman J, Savagner P and Ben-Ze'ev A . (2003). J. Cell. Biol., 163, 847–857.

  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T and Gutkind JS . (1995). Cell, 81, 1137–1146.

  • Christen B and Slack J . (1999). Development, 126, 119–125.

  • Domínguez D, Montserrat-Sentís B, Virgós-Soler A, Guaita S, Grueso J, Porta M, Puig I, Baulida J, Francí C and García de Herreros A . (2003). Mol. Cell. Biol., 23, 5078–5089.

  • Ellenrieder V, Gendler S, Boeck W, Seufferlein T, Menke A, Ruhland C, Adler G and Gress TM . (2001). Cancer Res., 61, 4222–4228.

  • Fambrough D, McClure K, Kazlauskas A and Lander ES . (1999). Cell, 97, 727–741.

  • Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS and Wade PA . (2003). Cell, 113, 207–219.

  • Gotzmann J, Huber H, Thallinger C, Wolschek M, Jansen B, Schulte-Hermann R, Beug H and Mikulitis W . (2002). J. Cell Sci., 115, 1189–1202.

  • Grande M, Franzen A, Karlsson O, Ericsson LE, Heldin NE and Nilsson M . (2002). J. Cell Sci., 115, 4227–4236.

  • Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, Van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN and Larue L . (2003). Cancer Res., 63, 2172–2178.

  • Grooteclaes M and Frisch SM . (2000). Oncogene, 19, 3823–3828.

  • Guaita S, Puig I, Franci C, Garrido M, Domínguez D, Batlle E, Sancho E, Dedhar S, Garcia de Herreros A and Baulida J . (2002). J. Biol. Chem., 277, 30209–39216.

  • Hajra KM, Chen DY and Fearon ER . (2002). Cancer Res., 62, 1613–1618.

  • Ip YT, Park RE, Kosman D, Yazdanbakhsh K and Levine M . (1992). Genes Dev., 6, 1518–1530.

  • Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H and Grünert S . (2002). J. Cell Biol., 156, 299–313.

  • Locascio A, Vega S, de Frutos CA, Manzanares M and Nieto MA . (2002). J. Biol. Chem., 277, 38803–38809.

  • Mayor R, Essex LJ, Bennett MF and Sargent MG . (1993). Development, 119, 661–671.

  • Nieto MA . (2002). Nat. Rev. Mol. Cell Biol., 3, 155–166.

  • Novak A, Hsu S, Leung-Hagsteijn CY, Radeva G, Papkoff J, Montesano R, Roskelly C, Grosschedl R and Dedhar S . (1998). Proc. Natl. Acad. Sci. USA, 95, 4374–4379.

  • Paznekas WA, Okajima K, Schertzer M, Wood S and Jabs EW . (1999). Genomics, 62, 42–49.

  • Peinado H, Quintanilla M and Cano A . (2003). J. Biol. Chem., 278, 21113–21123.

  • Pérez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA and Cano A . (2001). J. Biol. Chem., 276, 27424–27431.

  • Poser I, Dominguez D, García de Herreros A, Varnai A, Buettner R and Bosserhoff AK . (2001). J. Biol. Chem., 276, 24661–24666.

  • Spagnoli FM, Cicchino C, Tripodi M and Weiss MC . (2000). J. Cell Sci., 113, 3639–3647.

  • Tan C, Costello P, Sanghera J, Domínguez D, Baulida J, García de Herreros A and Dedhar S . (2001). Oncogene, 20, 133–140.

  • Thiery JP . (2002). Nat. Rev. Cancer, 2, 442–454.

  • Vleminckx K and Kemler R . (1999). BioEssays, 21, 211–220.

  • Yáñez-Mo M, Lara-Pezzi E, Selgas R, Ramírez-Huesca M, Domínguez-Jiménez C, Jiménez-Heffernan JA, Aguilera A, Sánchez-Tornero JA, Bajo MA, lvarez V, Castro MA, del Peso G, Cirujeda A, Gamallo C, Sánchez-Madrid F and López-Cabrera M . (2003). N Engl. J. Med., 348, 403–413.

  • Yao Y, Wu J, Germann U, Su MSS, Kuida K and Boucher D . (2003). Proc. Natl. Acad. Sci. USA, 100, 12759–12764.

Download references

Acknowledgements

This work was supported by Grants from Fundación Científica de la Asociación Española contra el Cáncer and Ministerio de Ciencia y Tecnología (PM99-0132 and SAF2003-02324) to AGH and by a grant from FEGEFLUC to LL. Partial support from a grant from Instituto Carlos III (RTICCC, C03710) is also appreciated. We thank Drs C Caelles, M Fresno, P Crespo, HG Pálmer and F Posas for the reagents. SG and IP are recipients of predoctoral fellowships from Ministerio de Ciencia y Tecnología and Ministerio de Educación, respectively. DD was a fellow from Instituto de Salud Carlos III. We are grateful to Dr Eduard Batlle for his initial work on the isolation of the promoter. The technical support of Judit Grueso is greatly appreciated.

Author information

Author notes

  1. Maria José Barberà

    Present address: Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Canada

  2. Maria José Barberà, Isabel Puig and David Domínguez: MJB, IP and DD contributed equally to this work and should be considered as co-first authors.

  3. David Domínguez: Currently works at the Institute for Cancer Genetics, Columbia University, New York, USA.

Authors and Affiliations

  1. Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Barcelona, Spain

    Maria José Barberà, Isabel Puig, David Domínguez, Sandra Guaita-Esteruelas, Sandra Peiró, Josep Baulida, Clara Francí & Antonio García de Herreros

  2. Developmental Genetics of Melanocytes, UMR146, CNRS-Institut Curie, Orsay Cedex, 91405, France

    Sylvia Julien-Grille & Lionel Larue

  3. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6H 3Z6, British Columbia, Canada

    Shoukat Dedhar

Authors
  1. Maria José Barberà
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isabel Puig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Domínguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sylvia Julien-Grille
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandra Guaita-Esteruelas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra Peiró
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Josep Baulida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Clara Francí
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shoukat Dedhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lionel Larue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Antonio García de Herreros
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonio García de Herreros.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barberà, M., Puig, I., Domínguez, D. et al. Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 23, 7345–7354 (2004). https://doi.org/10.1038/sj.onc.1207990

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207990

Keywords

This article is cited by

Search

Advanced search

Quick links