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Akt2 interacts with Snail1 in the E-cadherin promoter

Oncogene volume 31, pages 4022–4033 (2012)Cite this article

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Abstract

Snail1 is a transcriptional factor essential for triggering epithelial-to-mesenchymal transition. Moreover, Snail1 promotes resistance to apoptosis, an effect associated to PTEN gene repression and Akt stimulation. In this article we demonstrate that Snail1 activates Akt at an additional level, as it directly binds to and activates this protein kinase. The interaction is observed in the nucleus and increases the intrinsic Akt activity. We determined that Akt2 is the isoform interacting with Snail1, an association that requires the pleckstrin homology domain in Akt2 and the C-terminal half in Snail1. Snail1 enhances the binding of Akt2 to the E-cadherin (CDH1) promoter and Akt2 interference prevents Snail1 repression of CDH1 gene. We also show that Snail1 binding increases Akt2 intrinsic activity on histone H3 and have identified Thr45 as a residue modified on this protein. Phosphorylation of Thr45 in histone H3 is sensitive to Snail1 and Akt2 cellular levels; moreover, Snail1 upregulates the binding of phosphoThr45 histone H3 to the CDH1 promoter. These results uncover an unexpected role of Akt2 in transcriptional control and point out to phosphorylation of Thr45 in histone H3 as a new epigenetic mark related to Snail1 and Akt2 action.

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Acknowledgements

We are grateful to Neus Ontiveros for technical help; Dr David Casagolda for assistance with confocal microscopy; and Drs Lionel Larue and Alberto Muñoz for reagents. This study was supported by grants awarded by the Ministerio de Ciencia e Innovación (BFU2006-03203 and BFU2009-07578 to MD and SAF2006-00339 and SAF2010-16089 to AGH) and Fundació La Marató de TV3 (to AGH). The partial support from the Instituto Carlos III-Fondos FEDER (RTICCC, C03710, RD06/0020/0040) and the Generalitat de Catalunya (2009SGR867) is also appreciated. PV and RV-C were supported by predoctoral fellowships from the Ministerio de Ciencia y Tecnología and Instituto Carlos III, respectively.

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Authors and Affiliations

  1. Programa de Recerca en Càncer, IMIM-Hospital del Mar, Barcelona, Spain

    P Villagrasa, V M Díaz, R Viñas-Castells, S Peiró, N Dave & A García de Herreros

  2. Unitat de Biofísica-CEB, Facultat de Medicina, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain

    P Villagrasa, B Del Valle-Pérez & M Duñach

  3. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    V M Díaz & A García de Herreros

  4. Institut de Neurociència i Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain

    A Rodríguez-Asiain & J M Lizcano

  5. Centro de Investigaciones Biológicas (CSIC), Madrid, Spain

    J I Casal

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  1. P Villagrasa
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Correspondence to M Duñach or A García de Herreros.

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Villagrasa, P., Díaz, V., Viñas-Castells, R. et al. Akt2 interacts with Snail1 in the E-cadherin promoter. Oncogene 31, 4022–4033 (2012). https://doi.org/10.1038/onc.2011.562

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