Programa de Recerca en Càncer, IMIM-Hospital del Mar, Barcelona, Spain.
Oncogene. 2012 Sep 6;31(36):4022-33. doi: 10.1038/onc.2011.562. Epub 2011 Dec 12.
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.
蜗牛 1 是一种转录因子，对于触发上皮细胞-间充质转化是必不可少的。此外，蜗牛 1 促进抗细胞凋亡，这种作用与 PTEN 基因抑制和 Akt 刺激有关。在本文中，我们证明蜗牛 1 在额外的水平上激活 Akt，因为它直接结合并激活这种蛋白激酶。这种相互作用发生在细胞核中，并增加了 Akt 的内在活性。我们确定 Akt2 是与蜗牛 1 相互作用的同工型，这种关联需要 Akt2 的 pleckstrin 同源结构域和蜗牛 1 的 C 端半部分。蜗牛 1 增强了 Akt2 与 E-钙粘蛋白（CDH1）启动子的结合，而 Akt2 的干扰阻止了蜗牛 1 对 CDH1 基因的抑制。我们还表明，蜗牛 1 结合增加了 Akt2 对组蛋白 H3 的内在活性，并确定 Thr45 是该蛋白上修饰的残基。组蛋白 H3 上 Thr45 的磷酸化对蜗牛 1 和 Akt2 的细胞水平敏感；此外，蜗牛 1 上调了磷酸化 Thr45 组蛋白 H3 与 CDH1 启动子的结合。这些结果揭示了 Akt2 在转录控制中的一个意外作用，并指出组蛋白 H3 上 Thr45 的磷酸化是与蜗牛 1 和 Akt2 作用相关的一个新的表观遗传标记。
