Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas y Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
PLoS One. 2013 Jul 29;8(7):e69668. doi: 10.1371/journal.pone.0069668. Print 2013.
The unfolded protein response (UPR) and the Akt signaling pathway share several regulatory functions and have the capacity to determine cell outcome under specific conditions. However, both pathways have largely been studied independently. Here, we asked whether the Akt pathway regulates the UPR. To this end, we used a series of chemical compounds that modulate PI3K/Akt pathway and monitored the activity of the three UPR branches: PERK, IRE1 and ATF6. The antiproliferative and antiviral drug Akt-IV strongly and persistently activated all three branches of the UPR. We present evidence that activation of PERK/eIF2α requires Akt and that PERK is a direct Akt target. Chemical activation of this novel Akt/PERK pathway by Akt-IV leads to cell death, which was largely dependent on the presence of PERK and IRE1. Finally, we show that hypoxia-induced activation of eIF2α requires Akt, providing a physiologically relevant condition for the interaction between Akt and the PERK branch of the UPR. These data suggest the UPR and the Akt pathway signal to one another as a means of controlling cell fate.
未折叠蛋白反应（UPR）和 Akt 信号通路具有几个共同的调节功能，并在特定条件下有能力决定细胞的命运。然而，这两条通路在很大程度上都是独立研究的。在这里，我们想知道 Akt 通路是否调节 UPR。为此，我们使用了一系列调节 PI3K/Akt 通路的化学化合物，并监测了 UPR 的三个分支的活性：PERK、IRE1 和 ATF6。抗增殖和抗病毒药物 Akt-IV 强烈且持续地激活了 UPR 的所有三个分支。我们提供的证据表明，PERK/eIF2α 的激活需要 Akt，并且 PERK 是 Akt 的直接靶标。Akt-IV 通过化学激活这条新的 Akt/PERK 通路会导致细胞死亡，而这在很大程度上依赖于 PERK 和 IRE1 的存在。最后，我们表明缺氧诱导的 eIF2α 的激活需要 Akt，为 Akt 与 UPR 的 PERK 分支之间的相互作用提供了一种生理相关的条件。这些数据表明，UPR 和 Akt 通路通过相互信号传递来控制细胞命运。
