Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53
Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53
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DOI：
10.1038/sj.cdd.4402045
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发表时间：
2007-03-01
影响因子：
12.4
通讯作者：
Clemens, M. J.
中科院分区：
文献类型：
--
作者：
Constantinou, C.;Clemens, M. J.
肿瘤抑制蛋白 p53 的激活迅速抑制蛋白质合成。这与起始因子 eIF4GI 和 eIF4E 结合蛋白 4E-BP1 的去磷酸化和裂解有关。当 p53 的激活在 16 小时内逆转，4E-BP1 重新磷酸化时，完整的 eIF4GI 水平缓慢增加，蛋白质合成逐渐恢复。蛋白质合成的恢复被雷帕霉素和渥曼青霉素部分阻断，但不被蛋白激酶抑制剂 PD98059 和 CGP74514A 阻断。雷帕霉素和渥曼青霉素均可延迟 eIF4GI 的再现，但 PD98059 或 CGP74514A 则不然。相比之下，全长 4E-BP1 迅速重新磷酸化，并且该过程被雷帕霉素、PD98059 和 CGP74514A 部分抑制。因此，p53的激活导致针对eIF4GI的不同雷帕霉素和渥曼青霉素敏感途径以及针对4E-BP1的雷帕霉素敏感和不敏感途径的抑制。 p53 失活后的逐渐恢复很大程度上取决于 eIF4GI 恢复的动力学，而不是全长 4E-BP1 的再磷酸化。这些发现表明，细胞在 p53 失活后重新磷酸化 4E-BP1、重新合成 eIF4GI 和恢复蛋白质合成速率的能力是生理应激缓解后恢复的一个重要方面。
Activation of the tumour suppressor protein p53 rapidly inhibits protein synthesis. This is associated with dephosphorylation and cleavage of initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. When the activation of p53 is reversed within 16 h 4E-BP1 becomes rephosphorylated, the level of intact eIF4GI slowly increases and protein synthesis gradually recovers. The recovery of protein synthesis is partially blocked by rapamycin and wortmannin but not by the protein kinase inhibitors PD98059 and CGP74514A. Both rapamycin and wortmannin, but not PD98059 or CGP74514A, delay the reappearance of eIF4GI. In contrast, full-length 4E-BP1 rapidly becomes rephosphorylated and this process is partially inhibited by rapamycin, PD98059 and CGP74514A. Thus, activation of p53 results in the inhibition of distinct rapamycin-and wortmannin-sensitive pathways that target eIF4GI, and rapamycin-sensitive and -insensitive pathways that target 4E-BP1. Following inactivation of p53 the gradual recovery is determined largely by the kinetics of restoration of eIF4GI rather than by the rephosphorylation of full-length 4E-BP1. These findings suggest that the ability of cells to rephosphorylate 4E-BP1, resynthesise eIF4GI and restore the rate of protein synthesis after inactivation of p53 is an important aspect of recovery following the relief of physiological stress.