The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro
The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro
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DOI：
10.1038/sj.onc.1202620
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发表时间：
1999-04-29
期刊：
影响因子：
8
通讯作者：
Koromilas, AE
中科院分区：
文献类型：
--
作者：
Cuddihy, AR;Wong, AHT;Koromilas, AE
肿瘤抑制因子p53是一种多功能蛋白，在调节细胞对DNA损伤或其他应激的反应中起着关键作用，p53的这些功能受到蛋白-蛋白相互作用和磷酸化的调节，双链RNA激活的蛋白激酶PKR是一种丝氨酸/苏氨酸激酶，通过翻译起始因子eIF-2 α的磷酸化来调节蛋白质合成。PKR是一种干扰素（IFN）诱导蛋白，被认为通过其抑制蛋白合成的能力介导IFN的抗病毒和抗增殖作用。在p53获得野生型构象的条件下，ifn增强了PKR与p53的相互作用。体外形成PKR/p53复合物需要PKR的n端调控结构域和人类p53的c端最后30个氨基酸。此外，p53可能作为PKR的底物，因为在体外激活的PKR诱导人p53在丝氨酸（392）上的磷酸化。这些新发现提高了PKR和p53在体内功能相互作用的可能性，这可能至少部分解释了每种蛋白质在转录和翻译水平上调节基因表达的能力。
The tumor suppressor p53 is a multifunctional protein that plays a critical role in modulating cellular responses upon DNA damage or other stresses, These functions of p53 are regulated both by protein-protein interactions and phosphorylation, The double-stranded RNA activated protein kinase PKR is a serine/threonine kinase that modulates protein synthesis through the phosphorylation of translation initiation factor eIF-2 alpha. PKR is an interferon (IFN)-inducible protein that is thought to mediate the anti-viral and anti-proliferative effects of IFN via its capacity to inhibit protein synthesis, Here we report that PKR physically associates with p53. The interaction of PKR with p53 is enhanced by IFNs and upon conditions that p53 acquires a wild type conformation. PKR/p53 complex formation in vitro requires the N-terminal regulatory domain of PKR and the last 30 amino acids of the C-terminus of human p53. In addition, p53 may function as a substrate of PKR since phosphorylation of human p53 on serine(392) is induced by activated PKR in vitro. These novel findings raise the possibility of a functional interaction between PKR and p53 in vivo, which may account, at least in part, for the ability of each protein to regulate gene expression at both the transcriptional and the translational levels.