miR-34 and p53: New Insights into a Complex Functional Relationship.
miR-34 and p53: New Insights into a Complex Functional Relationship.
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DOI：
10.1371/journal.pone.0132767
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lieberman J
中科院分区：
文献类型：
--
作者：
Navarro F;Lieberman J
miR-34是一个由p53转录激活的肿瘤抑制miRNA家族，被认为是p53功能的关键介质。然而，敲除小鼠miR-34家族对p53应答的影响很小或没有影响。在人类细胞中，不同miR-34家族成员对p53功能的相对贡献以及p53对miR-34的依赖程度尚不清楚。在这里，我们表明miR-34a对人类细胞中的p53反应具有复杂的影响。在HCT116细胞中，miR-34a过表达可增强p53的转录活性，而与之密切相关的家族成员miR-34b和miR-34c即使过表达也几乎没有作用。TP53本身和强p53转激活抑制剂MDM4都是miR-34a的直接靶点。miR-34a调控的基因还包括其他四种p53翻译后抑制剂。miR-34a过表达导致p53充足的人类癌细胞系中p53水平的可变影响。在HCT116中，miR-34a过表达增加p53蛋白水平和稳定性。参与人类p53网络的所有mrna中约有四分之一与生物素化的miR-34a结合，这表明许多mrna是miR-34a的直接靶点。然而，只有约五分之一与miR-34a结合的mrna也与miR-34b或miR-34c结合。敲除miR-34a的两种人类细胞系与小鼠细胞一样，对基因毒性应激具有未受损的p53介导的反应。miR-34对p53网络复杂的正面和负面影响表明，miR-34a可能不是简单地促进p53反应，而是在系统水平上稳定p53对基因毒性应激反应的稳健性。
miR-34, a tumor suppressor miRNA family transcriptionally activated by p53, is considered a critical mediator of p53 function. However, knockout of the mouse miR-34 family has little or no effect on the p53 response. The relative contribution of different miR-34 family members to p53 function or how much p53 relies on miR-34 in human cells is unclear. Here we show that miR-34a has a complex effect on the p53 response in human cells. In HCT116 cells miR-34a overexpression enhances p53 transcriptional activity, but the closely related family members, miR-34b and miR-34c, even when over-expressed, have little effect. Both TP53 itself and MDM4, a strong p53 transactivation inhibitor, are direct targets of miR-34a. The genes regulated by miR-34a also include four other post-translational inhibitors of p53. miR-34a overexpression leads to variable effects on p53 levels in p53-sufficient human cancer cell lines. In HCT116, miR-34a overexpression increases p53 protein levels and stability. About a quarter of all mRNAs that participate in the human p53 network bind to biotinylated miR-34a, suggesting that many are direct miR-34a targets. However, only about a fifth of the mRNAs that bind to miR-34a also bind to miR-34b or miR-34c. Two human cell lines knocked out for miR-34a have unimpaired p53-mediated responses to genotoxic stress, like mouse cells. The complex positive and negative effects of miR-34 on the p53 network suggest that rather than simply promoting the p53 response, miR-34a might act at a systems level to stabilize the robustness of the p53 response to genotoxic stress.