Rox8 promotes microRNA-dependent yki messenger RNA decay
Rox8 promotes microRNA-dependent yki messenger RNA decay
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Rox8 促进 microRNA 依赖性 yki 信使 RNA 衰变。
DOI：
10.1073/pnas.2013449117
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发表时间：
2020-12-01
影响因子：
11.1
通讯作者：
Xue, Lei
中科院分区：
文献类型：
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作者：
Guo, Xiaowei;Sun, Yihao;Xue, Lei
河马途径是器官生长和肿瘤发生的进化保守的调节因子。在果蝇中，致癌的RAS(V12)与细胞极性丧失协同作用，促进河马途径依赖性肿瘤的生长。为了确定调节这一信号的其他因素，我们利用果蝇RAS(V12)/LGL(-/-)在体内肿瘤模型中进行了遗传筛选，并确定Rox8，一种RNA结合蛋白(RBP)，作为河马途径的正调控因子。我们发现，Rox8的过度表达抑制了组织的过度生长，而Rox8的缺失则增强了河马依赖的组织过度生长，并伴随着yki蛋白水平和靶基因表达的改变。在机制上，Rox8直接结合位于yki 3‘非编码区的靶点，招募并稳定装载miR-8的RISC的靶向，从而加速yki信使RNA(MRNA)的衰退。此外，Rox8的人类同源基因Tiar在被导入果蝇后，能够促进yki mRNA的降解，并破坏人类细胞中Yap mRNA的稳定。因此，我们的研究提供了体内证据，证明Hippo途径受RBP和microRNA(MiRNA)协同作用的转录后调控，这可能为调节Hippo途径介导的肿瘤发生提供一种途径。
The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In Drosophila, oncogenic Ras(V12) cooperates with loss-of-cell polarity to promote Hippo pathway dependent tumor growth. To identify additional factors that modulate this signaling, we performed a genetic screen utilizing the Drosophila Ras(V12)/lgl(-/-) in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway. We found that Rox8 overexpression suppresses whereas Rox8 depletion potentiates Hippo-dependent tissue overgrowth, accompanied by altered Yki protein level and target gene expression. Mechanistically, Rox8 directly binds to a target site located in the yki 3' UTR, recruits and stabilizes the targeting of miR-8-loaded RISC, which accelerates the decay of yki messenger RNA (mRNA). Moreover, TIAR, the human ortholog of Rox8, is able to promote the degradation of yki mRNA when introduced into Drosophila and destabilizes YAP mRNA in human cells. Thus, our study provides in vivo evidence that the Hippo pathway is posttranscriptionally regulated by the collaborative action of RBP and microRNA (miRNA), which may provide an approach for modulating Hippo pathway mediated tumorigenesis.