Cuddihy A R, Wong A H, Tam N W, Li S, Koromilas A E
Department of Oncology, McGill University, Montreal, Quebec, Canada.
Oncogene. 1999 Apr 29;18(17):2690-702. doi: 10.1038/sj.onc.1202620.
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-2alpha. 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 serine392 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.
肿瘤抑制蛋白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关键作用。p53的这些功能通过蛋白质-蛋白质相互作用和磷酸化来调节。双链RNA激活蛋白激酶PKR是一种丝氨酸/苏氨酸激酶，通过翻译起始因子eIF-2α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质合成的能力介导IFN的抗病毒和抗增殖作用。在此我们报告PKR与p53存在物理关联。IFN以及在p53获得野生型构象的条件下，PKR与p53的相互作用会增强。体外PKR/p53复合物的形成需要PKR的N端调节结构域和人p53 C端的最后30个氨基酸。此外，p53可能作为PKR的底物，因为在体外活化的PKR可诱导人p53的丝氨酸392发生磷酸化。这些新发现增加了PKR与p53在体内存在功能相互作用的可能性，这可能至少部分解释了每种蛋白在转录和翻译水平调节基因表达的能力。
