Mutant p53 inhibits miRNA biogenesis by interfering with the microprocessor complex
Mutant p53 inhibits miRNA biogenesis by interfering with the microprocessor complex
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DOI：
10.1038/onc.2016.51
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发表时间：
2016-07-01
期刊：
影响因子：
8
通讯作者：
Gurtner, A.
中科院分区：
文献类型：
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作者：
Garibaldi, F.;Falcone, E.;Gurtner, A.
microRNA（miRNAs）的下调通常在癌症中观察到，并且促进肿瘤发生，这表明miRNAs可能起肿瘤抑制剂的作用。然而，miRNA在癌症中的调节机制以及癌基因和miRNA生物发生之间的联系仍然知之甚少。TP 53肿瘤抑制基因在一半的人类癌症中发生突变，导致具有功能获得活性的癌基因。在这里，我们证明了突变型p53（mutp 53）癌蛋白调节癌细胞中的一个小分子RNA子集的生物发生，抑制其转录后成熟。有趣的是，在这些miRNAs中，有几种在人类肿瘤中也下调。通过共聚焦、免疫共沉淀和RNA-染色质免疫沉淀实验，我们发现内源性mutp 53结合并从微处理器复合物中隔离RNA解旋酶p72/82，干扰Drosha-pri-miRNAs的结合。与此一致，p72的过表达导致成熟miRNA水平的增加。此外，功能实验证明了mutp 53依赖性miRNA（miR-517 a、-519 a、-218、-105）的肿瘤抑制作用。我们的研究强调了一种以前未描述的机制，通过这种机制，mutp 53干扰Drosha-p72/82相关性，至少部分导致在癌症中观察到的miRNA失调。
Downregulation of microRNAs (miRNAs) is commonly observed in cancers and promotes tumorigenesis suggesting that miRNAs may function as tumor suppressors. However, the mechanism through which miRNAs are regulated in cancer, and the connection between oncogenes and miRNA biogenesis remain poorly understood. The TP53 tumor-suppressor gene is mutated in half of human cancers resulting in an oncogene with gain-of-function activities. Here we demonstrate that mutant p53 (mutp53) oncoproteins modulate the biogenesis of a subset of miRNAs in cancer cells inhibiting their post-transcriptional maturation. Interestingly, among these miRNAs several are also downregulated in human tumors. By confocal, co-immunoprecipitation and RNA-chromatin immunoprecipitation experiments, we show that endogenous mutp53 binds and sequesters RNA helicases p72/82 from the microprocessor complex, interfering with Drosha-pri-miRNAs association. In agreement with this, the overexpression of p72 leads to an increase of mature miRNAs levels. Moreover, functional experiments demonstrate the oncosuppressive role of mutp53-dependent miRNAs (miR-517a, -519a, -218, -105). Our study highlights a previously undescribed mechanism by which mutp53 interferes with Drosha-p72/82 association leading, at least in part, to miRNA deregulation observed in cancer.