Journal
ONCOGENE
Volume 31, Issue 36, Pages 4022-4033Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.562
Keywords
Snail1; EMT; Akt; E-cadherin
Funding
- Ministerio de Ciencia e Innovacion [BFU2006-03203, BFU2009-07578, SAF2006-00339, SAF2010-16089]
- Fundacio La Marato de TV3
- Instituto Carlos III-Fondos FEDER (RTICCC) [C03710, RD06/0020/0040]
- Generalitat de Catalunya [2009SGR867]
- predoctoral fellowship from the Ministerio de Ciencia y Tecnologia
- predoctoral fellowship from the Instituto Carlos III
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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. Oncogene (2012) 31, 4022-4033; doi:10.1038/onc.2011.562; published online 12 December 2011
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