Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53
Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53
复制标题
DOI：
10.1038/sj.onc.1208648
复制
发表时间：
2005-07-14
期刊：
影响因子：
8
通讯作者：
Clemens, MJ
中科院分区：
文献类型：
--
作者：
Constantinou, C;Clemens, MJ
在小鼠红白血病细胞中，温度敏感型小鼠p53的激活迅速抑制蛋白质合成，并导致蛋白质合成起始因子eIF 4GI和eIF 4 E结合蛋白4 E-BP 1的早期去磷酸化和裂解。在这些条件下，去磷酸化的4 E-BP 1以及4 E-BP 1和eIF 4GI的切割产物与eIF 4 E结合，同时全长eIF 4GI与eIF 4 E的相互作用减少。这些变化可能在阻止eIF 4F复合物的形成，从而启动蛋白质合成中发挥重要作用。如先前对eIF 4GI观察到的，4 E-BP 1的裂解对一般半胱天冬酶抑制剂z-VAD.FMK不敏感，这与modi因子的半胱天冬酶非依赖性机制一致。阳离子和调节蛋白质合成。p53诱导的eIF 4GI和4 E-BP 1去磷酸化和切割模式与mTOR抑制剂雷帕霉素引起的模式的比较表明，p53活化和雷帕霉素具有不同的但累加的作用。此外，p53激活抑制雷帕霉素不敏感的蛋白激酶对4 E-BP 1的活性。P53和雷帕霉素对总蛋白合成的抑制具有累加效应。这些数据表明，在所研究的系统中，p53对蛋白质合成的抑制在很大程度上不依赖于雷帕霉素敏感性mTOR的调节。
Activation of a temperature-sensitive form of mouse p53 in murine erythroleukaemia cells rapidly inhibits protein synthesis and causes early dephosphorylation and cleavage of protein synthesis initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. Dephosphorylated 4E-BP1 and the cleaved products of 4E-BP1 and eIF4GI associate with eIF4E under these conditions, concomitant with decreased interaction of full-length eIF4GI with eIF4E. These changes may play an important role in preventing formation of the eIF4F complex and thus the initiation of protein synthesis. As observed previously for eIF4GI, the cleavage of 4E-BP1 is insensitive to the general caspase inhibitor z-VAD.FMK, consistent with a caspase-independent mechanism of factor modi. cation and regulation of protein synthesis. Comparison of the p53-induced patterns of eIF4GI and 4E-BP1 dephosphorylation and cleavage with those caused by the mTOR inhibitor rapamycin indicates that p53 activation and rapamycin have distinct but additive effects. Moreover, p53 activation inhibits rapamycin-insensitive protein kinase activity against 4E-BP1.P53 and rapamycin have additive effects on the inhibition of overall protein synthesis. These data suggest that the inhibition of protein synthesis by p53 is largely independent of the regulation of rapamycin-sensitive mTOR in the system under investigation.