MicroRNA-34a is dispensable for p53 function as teratogenesis inducer.
MicroRNA-34a is dispensable for p53 function as teratogenesis inducer.
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DOI：
10.1007/s00204-014-1223-9
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发表时间：
2014-09
影响因子：
6.1
通讯作者：
Shomron N
中科院分区：
文献类型：
--
作者：
Mor E;He L;Torchinsky A;Shomron N
肿瘤抑制蛋白p53是胚胎对多种致畸刺激的敏感性的强有力的调节剂，既作为致畸诱导剂又作为抑制剂。然而，p53参与实现其功能的靶点在很大程度上仍然不确定。我们询问被鉴定为p53的主要靶点之一的miR-34家族是否介导其作为致畸诱导剂的功能。为此，将妊娠ICR、p53和miR-34 a杂合子小鼠和Spargue-Dowley大鼠暴露于5-aza-2 '-脱氧胞苷（5-aza），这是一种致畸剂，可诱导小鼠后肢的肢体减少异常（LRA）和大鼠后肢或前肢的LRA。使用5-氮杂暴露胚胎的后肢和前肢芽，我们发现miR-34家族成员是小鼠和大鼠肢芽中上调最多的miRNA，其表达水平在注定表现出LRA的肢芽中显著更高。还观察到Met和Gas 1在胚胎肢芽中被miR-34 a靶向，并且p53介导5-aza诱导的转录miR-34家族激活和miR-34 a靶向抑制。最后，我们发现p53调节对5-aza的致畸反应，作为致畸诱导剂，并且miR-34 a基因缺失不影响小鼠对5-aza的易感性。总体而言，这项研究支持了证明miR-34家族作为p53的调节靶点的早期观察结果，但首次表明miR-34家族在p53参与的通路中发挥冗余功能，作为致畸诱导剂。
The tumor suppressor protein p53 is a powerful regulator of the embryo’s susceptibility to diverse teratogenic stimuli, functioning both as a teratogenesis inducer and suppressor. Targets which p53 engages to fulfill its functions remains largely undefined, though. We asked whether the miR-34 family, identified as one of the main targets of p53, mediates its function as a teratogenesis inducer. For this, pregnant ICR, p53 and miR-34a heterozygous mice and Spargue-Dowley rats were exposed to 5-aza-2’-deoxycytidin (5-aza), a teratogen inducing limb reduction anomalies (LRA) of the hindlimbs in mice and LRA of either the hindlimbs or forelimbs in rats. Using Hind- and forelimb buds of 5-aza-exposed embryos, we found that the miR-34 family members are the most upregulated miRNAs in mouse and rat limb buds, with their expression level being significantly higher in limb buds destined to exhibit LRA. It was also observed that Met and Gas1 are targeted by miR-34a in embryonic limb buds and that p53 mediates the 5-aza-induced transcriptional miR-34 family activation and miR-34a targets suppression. Finally, we showed that p53 regulates the teratogenic response to 5-aza acting as a teratogenesis inducer and that miR-34a gene deletion do not affect the susceptibility of mice to 5-aza. Overall, this study supports earlier observations demonstrating miR-34 family as a regulatory target of p53 but suggests for the first time that miR-34 family play a redundant function in the pathway(s) engaged by p53 acting as a teratogenesis inducer.
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