Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Genes Dev. 2010 Oct 1;24(19):2146-56. doi: 10.1101/gad.1968910. Epub 2010 Sep 13.
Optimal induction of p53 protein after DNA damage requires RPL26-mediated increases in p53 mRNA translation. We report here the existence of a dsRNA region containing complementary sequences of the 5'- and 3'-untranslated regions (UTRs) of human p53 mRNA that is critical for its translational regulation by RPL26. Mutating as few as 3 bases in either of the two complementary UTR sequences abrogates the ability of RPL26 to bind to p53 mRNA and stimulate p53 translation, while compensatory mutations restore this binding and regulation. Short, single-strand oligonucleotides that target this 5'-3'-UTR base-pairing region blunt the binding of RPL26 to p53 mRNA in cells and reduce p53 induction and p53-mediated cell death after several different types of DNA damage and cellular stress. The ability to reduce stress induction of p53 with oligonucleotides or other small molecules has numerous potential therapeutic uses.
最佳的 p53 蛋白诱导作用需要在 DNA 损伤后通过 RPL26 介导的 p53 mRNA 翻译增加来实现。我们在此报告了一个 dsRNA 区域的存在，该区域包含人 p53 mRNA 的 5'和 3'非翻译区 (UTR) 的互补序列，对于 RPL26 对其翻译的调控至关重要。在这两个互补 UTR 序列中的任何一个中突变仅仅 3 个碱基，就会消除 RPL26 与 p53 mRNA 结合并刺激 p53 翻译的能力，而补偿性突变则恢复了这种结合和调控。靶向该 5'-3'-UTR 碱基配对区域的短单链寡核苷酸在细胞中削弱了 RPL26 与 p53 mRNA 的结合，并减少了几种不同类型的 DNA 损伤和细胞应激后 p53 的诱导和 p53 介导的细胞死亡。使用寡核苷酸或其他小分子来降低 p53 的应激诱导能力具有许多潜在的治疗用途。
