MicroRNA-125b is a novel negative regulator of p53
MicroRNA-125b is a novel negative regulator of p53
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DOI：
10.1101/gad.1767609
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发表时间：
2009-04-01
影响因子：
10.5
通讯作者：
Lim, Bing
中科院分区：
文献类型：
--
作者：
Le, Minh T. N.;Teh, Cathleen;Lim, Bing
p53转录因子是一种关键的肿瘤抑制因子，也是应激反应的中心调节因子。为了确保对细胞信号的鲁棒和精确的响应，必须从转录到翻译后水平严格调控p53基因的表达。计算预测表明，一些microRNA参与p53的转录后调节。在这里，我们证明了miR-125 b，一种脑富集的microRNA，是斑马鱼和人类中p53的真正负调节因子。miR-125 b介导的p53下调严格依赖于miR-125 b与p53 mRNA非翻译区中microRNA反应元件的结合。miR-125 b的过表达抑制了人神经母细胞瘤细胞和人肺成纤维细胞中p53蛋白的内源性水平并抑制了细胞凋亡。相反，miR-125 b的敲低提高了p53蛋白的水平，并诱导人肺成纤维细胞和斑马鱼脑中的细胞凋亡。这种表型可以通过内源性p53功能的消融或miR-125 b在斑马鱼中的异位表达来显著地拯救。有趣的是，当斑马鱼胚胎用γ射线或喜树碱处理时，miR-125 b下调，对应于DNA损伤引起的p53蛋白快速增加。miR-125 b的异位表达抑制p53的增加和应激诱导的细胞凋亡。总之，我们的研究表明，miR-125 b是一个重要的负调节p53和p53诱导的细胞凋亡过程中的发展和应激反应。
The p53 transcription factor is a key tumor suppressor and a central regulator of the stress response. To ensure a robust and precise response to cellular signals, p53 gene expression must be tightly regulated from the transcriptional to the post-translational levels. Computational predictions suggest that several microRNAs are involved in the post-transcriptional regulation of p53. Here we demonstrate that miR-125b, a brain-enriched microRNA, is a bona fide negative regulator of p53 in both zebrafish and humans. miR-125b-mediated down-regulation of p53 is strictly dependent on the binding of miR-125b to a microRNA response element in the 39 untranslated region of p53 mRNA. Overexpression of miR-125b represses the endogenous level of p53 protein and suppresses apoptosis in human neuroblastoma cells and human lung fibroblast cells. In contrast, knockdown of miR-125b elevates the level of p53 protein and induces apoptosis in human lung fibroblasts and in the zebrafish brain. This phenotype can be rescued significantly by either an ablation of endogenous p53 function or ectopic expression of miR-125b in zebrafish. Interestingly, miR-125b is down-regulated when zebrafish embryos are treated with gamma-irradiation or camptothecin, corresponding to the rapid increase in p53 protein in response to DNA damage. Ectopic expression of miR-125b suppresses the increase of p53 and stress-induced apoptosis. Together, our study demonstrates that miR-125b is an important negative regulator of p53 and p53-induced apoptosis during development and during the stress response.