p53 mrNA controls p53 activity by managing Mdm2 functions
p53 mrNA controls p53 activity by managing Mdm2 functions
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DOI：
10.1038/ncb1770
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发表时间：
2008-09-01
影响因子：
21.3
通讯作者：
Fahraeus, Robin
中科院分区：
文献类型：
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作者：
Candeias, Marco M.;Malbert-Colas, Laurence;Fahraeus, Robin
E3 泛素连接酶 Mdm2 是 p53 肿瘤抑制活性的局部调节因子。它结合 p53，促进其多泛素化和降解，并控制 p53 合成。然而，尚不清楚 Mdm2 对 p53 合成和降解的双重功能是如何实现的。在这里，我们表明编码 Mdm2 结合位点的 p53 mRNA 区域直接与 Mdm2 的 RING 结构域相互作用。这会损害 Mdm2 的 E3 连接酶活性并促进 p53 mRNA 翻译。我们还表明，在 p53 mRNA 中引入癌症衍生的单沉默点突变会削弱其与 Mdm2 的结合，并导致 p53 活性降低。这些数据与沉默核苷酸的变化影响编码蛋白功能的机制一致，并表明 Mdm2 介导的 p53 合成和降解控制已在 p53 mRNA 序列及其编码氨基酸中进化。
The E3 ubiquitin ligase Mdm2 is a focal regulator of p53 tumour suppressor activity. It binds p53, promoting its polyubiquitination and degradation, and also controls p53 synthesis. However, it is not known how this dual function of Mdm2 on p53 synthesis and degradation is achieved. Here we show that the p53 mRNA region encoding the Mdm2-binding site interacts directly with the RING domain of Mdm2. This impairs the E3 ligase activity of Mdm2 and promotes p53 mRNA translation. We also show that introduction of cancer-derived single silent point-mutations in the p53 mRNA weakens its binding to Mdm2 and results in reduced p53 activity. These data are consistent with a mechanism by which changes in silent nucleotides can affect the function of the encoded protein, and indicate that Mdm2-mediated control of p53 synthesis and degradation has evolved in the p53 mRNA sequence and its encoded amino acids.