Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway.
Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway.
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DOI：
10.1126/scisignal.2001630
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发表时间：
2011-09-27
影响因子：
7.3
通讯作者：
Koromilas AE
中科院分区：
文献类型：
--
作者：
Mounir Z;Krishnamoorthy JL;Wang S;Papadopoulou B;Campbell S;Muller WJ;Hatzoglou M;Koromilas AE
后生动物通过诱导翻译起始因子eIF 2 α亚基丝氨酸51位磷酸化（eIF 2 αP）对各种形式的环境应激做出反应，这种修饰导致mRNA翻译的全面抑制。在此，我们证明eIF 2 αP是通过药理学抑制磷酸肌醇-3-激酶（PI 3 K）-Akt通路以及通过遗传或小干扰（si）RNA介导的Akt消融诱导的。eIF 2 αP增加是一个进化保守过程，涉及内质网（ER）驻留蛋白激酶PERK，其受苏氨酸799处Akt依赖性磷酸化负调控。在小鼠乳腺肿瘤以及暴露于ER应激或氧化应激的细胞中，激活的Akt下调PERK活性和eIF 2 αP，分别诱导细胞存活或死亡。在未应激的细胞中，PERK-eIF 2 αP通路保护存活并促进对PI 3 K或Akt失活的有害影响的适应。因此，PERK-eIF 2 αP臂的失活增加了肿瘤细胞对PI 3 K或Akt药理学抑制剂死亡的易感性。因此，除了mTOR之外，PERK-eIF 2 αP通路还提供了Akt信号传导和翻译控制之间的联系，这在肿瘤形成和治疗中具有意义。
Metazoans respond to various forms of environmental stress by inducing the phosphorylation of the α subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP), a modification that leads to a global inhibition of mRNA translation. Herein, we demonstrate that eIF2αP is induced by pharmacological inhibition of the phosphoinositide-3-kinase (PI3K)-Akt pathway as well as by genetic or small interfering (si)RNA-mediated ablation of Akt. Increased eIF2αP is an evolutionary conserved process that involves the endoplasmic reticulum (ER)-resident protein kinase PERK, which is negatively regulated by Akt-dependent phosphorylation at threonine 799. PERK activity and eIF2αP are downregulated by activated Akt in mouse mammary gland tumors as well as in cells exposed to ER stress or oxidative stress leading to the induction of cell survival or death respectively. In unstressed cells, the PERK-eIF2αP pathway guards survival and facilitates adaptation to the deleterious effects of PI3K or Akt inactivation. As such, inactivation of the PERK-eIF2αP arm increases the susceptibility of tumor cells to death by pharmacological inhibitors of PI3K or Akt. Thus, in addition to mTOR the PERK-eIF2αP pathway provides a link between Akt signaling and translational control with implications in tumor formation and treatment.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
10.5
作者：
Cherkasova, VA;Hinnebusch, AG
通讯作者：
Hinnebusch, AG
DOI：
10.1073/pnas.92.17.7686
发表时间：
1995-08-15
影响因子：
11.1
作者：
DUDLEY, DT;PANG, L;SALTIEL, AR
通讯作者：
SALTIEL, AR
影响因子：
4.3
作者：
Krishnamoorthy, Jothilatha;Mounir, Zineb;Koromilas, Antonis E.
通讯作者：
Koromilas, Antonis E.
影响因子：
9.2
作者：
Deng, J;Harding, HP;Sonenberg, N
通讯作者：
Sonenberg, N