Inhibition of Protein Synthesis Alters Protein Degradation through Activation of Protein Kinase B (AKT)
Inhibition of Protein Synthesis Alters Protein Degradation through Activation of Protein Kinase B (AKT)
复制标题
抑制蛋白质合成通过激活蛋白激酶 B (AKT) 改变蛋白质降解
DOI：
10.1074/jbc.m112.445148
复制
发表时间：
2013-08-16
影响因子：
4.8
通讯作者：
Gong, Cheng-Xin
中科院分区：
文献类型：
--
作者：
Dai, Chun-Ling;Shi, Jianhua;Gong, Cheng-Xin
蛋白质代谢的稳态是由生物系统中蛋白质的生物合成和降解速率来维持和调节的。蛋白质降解的改变可以通过反馈机制调节蛋白质的生物合成。蛋白质生物合成的变化是否调节蛋白质降解尚未报道。在这项研究中，我们发现蛋白质生物合成的抑制诱导AKT的磷酸化/活化，并导致AKT靶底物的磷酸化，包括FoxO 1，GSK 3 α/β，p70 S6 K，AS 160和E3泛素连接酶MDM 2。核糖体蛋白S6的磷酸化也受到蛋白质生物合成抑制的调节。AKT磷酸化/活化主要通过PI 3 K途径介导，因为它被PI 3 K抑制剂LY 294002阻断。活化的AKT使MDM 2的Ser（166）磷酸化，并促进肿瘤抑制因子p53的降解。这些发现表明，蛋白质生物合成的抑制可以通过激活AKT来改变一些蛋白质的降解。这项研究揭示了一种新的蛋白质降解调节机制，并呼吁在阻断蛋白质生物合成以研究蛋白质半衰期时要谨慎。
The homeostasis of protein metabolism is maintained and regulated by the rates of protein biosynthesis and degradation in living systems. Alterations of protein degradation may regulate protein biosynthesis through a feedback mechanism. Whether a change in protein biosynthesis modulates protein degradation has not been reported. In this study, we found that inhibition of protein biosynthesis induced phosphorylation/activation of AKT and led to phosphorylation of AKT target substrates, including FoxO1, GSK3 alpha/beta, p70S6K, AS160, and the E3 ubiquitin ligase MDM2. Phosphorylation of ribosomal protein S6 was also modulated by inhibition of protein biosynthesis. The AKT phosphorylation/activation was mediated mainly through the PI3K pathway because it was blocked by the PI3K inhibitor LY294002. The activated AKT phosphorylated MDM2 at Ser(166) and promoted degradation of the tumor suppressor p53. These findings suggest that inhibition of protein biosynthesis can alter degradation of some proteins through activation of AKT. This study reveals a novel regulation of protein degradation and calls for caution in blocking protein biosynthesis to study the half-life of proteins.