Modulation of the Akt pathway reveals a novel link with PERK/eIF2α, which is relevant during hypoxia.
Modulation of the Akt pathway reveals a novel link with PERK/eIF2α, which is relevant during hypoxia.
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DOI：
10.1371/journal.pone.0069668
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Colman-Lerner A
中科院分区：
文献类型：
--
作者：
Blaustein M;Pérez-Munizaga D;Sánchez MA;Urrutia C;Grande A;Risso G;Srebrow A;Alfaro J;Colman-Lerner A
未折叠蛋白反应（UPR）和Akt信号通路共享几个调节功能，并具有在特定条件下决定细胞结果的能力。然而，这两种途径在很大程度上是独立研究的。在这里，我们询问Akt通路是否调节UPR。为此，我们使用了一系列调节PI 3 K/Akt通路的化合物，并监测了三个UPR分支：PERK，IRE 1和ATF 6的活性。抗增殖和抗病毒药物Akt-IV强烈而持久地激活了UPR的所有三个分支。我们提供的证据表明，PERK/eIF 2 α的激活需要Akt，PERK是Akt的直接靶点。这种新的Akt/PERK途径被Akt-IV化学激活导致细胞死亡，这在很大程度上取决于PERK和IRE 1的存在。最后，我们发现缺氧诱导的eIF 2 α激活需要Akt，这为Akt和UPR的PERK分支之间的相互作用提供了生理相关条件。这些数据表明，UPR和Akt途径相互传递信号，作为控制细胞命运的手段。
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.
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