Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin
Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin
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DOI：
10.1016/j.cell.2005.07.034
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发表时间：
2005-10-07
期刊：
影响因子：
64.5
通讯作者：
Kastan, MB
中科院分区：
文献类型：
--
作者：
Takagi, M;Absalon, MJ;Kastan, MB
DNA损伤后p53蛋白水平的增加主要归因于p53蛋白半衰期的增加。在这里，我们证明，增加翻译的p53 mRNA也是一个关键步骤，在诱导p53蛋白在辐射细胞。核糖体蛋白L26（RPL 26）和核仁素与p53 mRNA的5'非翻译区（UTR）结合，控制DNA损伤后p53的翻译和诱导。RPL 26在DNA损伤后优先结合于5'UTR，并且其过表达增强了p53 mRNA与较重的多核糖体的结合，增加了p53翻译的速率，诱导G1细胞周期停滞，并增强辐射诱导的细胞凋亡。当RPL 26表达被抑制时，观察到相反的效果。相反，核仁素过表达抑制p53的翻译和DNA损伤后的诱导，而核仁素下调促进p53的表达。这些发现证明了DNA损伤反应中p53翻译增加的重要性，并表明RPL 26和核仁素在影响p53诱导中的关键作用。
Increases in p53 protein levels after DNA damage have largely been attributed to an increase in the half-life of p53 protein. Here we demonstrate that increased translation of p53 mRNA is also a critical step in the induction of p53 protein in irradiated cells. Ribosomal protein L26 (RPL26) and nucleolin were found to bind to the 5' untranslated region (UTR) of p53 mRNA and to control p53 translation and induction after DNA damage. RPL26 preferentially binds to the 5'UTR after DNA damage, and its overexpression enhances association of p53 mRNA with heavier polysomes, increases the rate of p53 translation, induces G1 cell-cycle arrest, and augments irradiation-induced apoptosis. Opposite effects were seen when RPL26 expression was inhibited. In contrast, nucleolin overexpression suppresses p53 translation and induction after DNA damage, whereas nucleolin downregulation promotes p53 expression. These findings demonstrate the importance of increased translation of p53 in DNA-damage responses and suggest critical roles for RPL26 and nucleolin in affecting p53 induction.