ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR-30b-3p and miR-573 binding.
ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR-30b-3p and miR-573 binding.
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ADAR1通过破坏miR-30b-3p和miR-573结合来调节ARHGAP26基因表达。
DOI：
10.1261/rna.041533.113
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发表时间：
2013-11
期刊：
影响因子：
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通讯作者：
Wang L
中科院分区：
文献类型：
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作者：
Wang Q;Hui H;Guo Z;Zhang W;Hu Y;He T;Tai Y;Peng P;Wang L
本文描述了在Rho GTPase激活蛋白26 (ARHGAP26) mRNA的3 ' UTR中广泛的adar1介导的RNA编辑。这导致miR-30b-3p和miR-573两种mirna的结合位点被破坏，从而导致ARHGAP26 mRNA和蛋白水平上调。Wang和合著者进一步将这种调节与肿瘤发生联系起来，他们发现癌症期间ADAR1表达的改变会导致ARHGAP26的下调，而ARHGAP26是一种肿瘤抑制因子。Rho GTPase激活蛋白26 （ARHGAP26）是Rho家族的负调控因子，可将小G蛋白RhoA和Cdc42转化为无活性的gdp结合形式。它对CLIC/GEEC内吞途径、细胞扩散和肌肉发育至关重要。本研究表明，ARHGAP26 mRNA在ADAR1特异性催化的3 ' UTR中经历了广泛的A-to-I RNA编辑。此外，在ADAR1被敲除的细胞中，ARHGAP26的mRNA和蛋白水平降低。相反，ADAR1过表达增加了ARHGAP26 mRNA和蛋白的丰度。此外，我们发现miR-30b-3p和miR-573都靶向ARHGAP26基因，并且ADAR1介导的ARHGAP26的RNA编辑消除了miR-30b-3p或miR-573对其表达的抑制。当ADAR1过表达时，挽救miR-30b-3p或miR-573介导的ARHGAP26蛋白丰度降低。重要的是，我们还发现，敲低ADAR1会提高RhoA活性，这与ARHGAP26水平的降低是一致的。相反，当ADAR1过表达时，RhoA-GTP的量减少。ARHGAP26和ADAR1在人体组织样本中的相似表达模式进一步证实了我们的发现。综上所述，我们的研究结果表明，ADAR1通过破坏ARHGAP26的3 ' UTR内miR-30b-3p和miR-573的结合，通过A-to-I RNA编辑调节ARHGAP26的表达。这项研究为ADAR1及其RNA编辑功能调控microrna介导的靶基因调控的机制提供了新的见解。
This paper describes extensive ADAR1-mediated RNA editing in the 3′ UTR of the Rho GTPase activating protein 26 (ARHGAP26) mRNA. This results in the disruption of binding sites for two miRNAs, miR-30b-3p and miR-573, and consequently leads to an up-regulation of the ARHGAP26 mRNA and protein levels. Wang and coauthors further connect this regulation to tumorigenesis by showing that alterations in ADAR1 expression during cancer lead to down-regulation of ARHGAP26, which behaves as a tumor suppressor. Rho GTPase activating protein 26 (ARHGAP26) is a negative regulator of the Rho family that converts the small G proteins RhoA and Cdc42 to their inactive GDP-bound forms. It is essential for the CLIC/GEEC endocytic pathway, cell spreading, and muscle development. The present study shows that ARHGAP26 mRNA undergoes extensive A-to-I RNA editing in the 3′ UTR that is specifically catalyzed by ADAR1. Furthermore, the mRNA and protein levels of ARHGAP26 were decreased in cells in which ADAR1 was knocked down. Conversely, ADAR1 overexpression increased the abundance of ARHGAP26 mRNA and protein. In addition, we found that both miR-30b-3p and miR-573 target the ARHGAP26 gene and that RNA editing of ARHGAP26 mediated by ADAR1 abolished the repression of its expression by miR-30b-3p or miR-573. When ADAR1 was overexpressed, the reduced abundance of ARHGAP26 protein mediated by miR-30b-3p or miR-573 was rescued. Importantly, we also found that knocking down ADAR1 elevated RhoA activity, which was consistent with the reduced level of ARHGAP26. Conversely, when ADAR1 was overexpressed, the amount of RhoA-GTP decreased. The similar expression patterns of ARHGAP26 and ADAR1 in human tissue samples further confirmed our findings. Taken together, our results suggest that ADAR1 regulates the expression of ARHGAP26 through A-to-I RNA editing by disrupting the binding of miR-30b-3p and miR-573 within the 3′ UTR of ARHGAP26. This study provides a novel insight into the mechanism by which ADAR1 and its RNA editing function regulate microRNA-mediated modulation of target genes.