miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signalling.
miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signalling.
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DOI：
10.1371/journal.pone.0069090
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Stevenson NJ
中科院分区：
文献类型：
--
作者：
Collins AS;McCoy CE;Lloyd AT;O'Farrelly C;Stevenson NJ
细胞因子信号传导抑制因子（SOCS）蛋白是Janus激酶信号转导和转录激活因子（JAK-STAT）途径的典型抑制剂。许多细胞因子和致病介质诱导SOCS的表达，SOCS在负反馈回路中抑制进一步的信号转导。SOCS mRNA的表达受STAT蛋白的DNA结合调控，然而，其转录后调控尚不清楚。microRNAs （miRNAs）是一种小的非编码rna，与靶mrna上的互补序列结合，通常沉默基因表达。miR-19a已被证明在多发性骨髓瘤中调节SOCS1的表达，并被抗病毒细胞因子干扰素-(IFN)-α诱导，提示其参与调控JAK-STAT通路。本研究旨在确定miR-19a在JAK-STAT通路中的靶点，并阐明其功能后果。生物信息学分析在多个JAK-STAT相关基因（包括SOCS1、SOCS3、SOCS5和Cullin (Cul) 5）中鉴定出高度保守的3'UTR miR-19a靶序列。功能研究显示，miR-19a显著降低SOCS3 mRNA和蛋白，而miR-19a拮抗剂特异性地逆转了其抑制作用。此外，mir -19a介导的SOCS3的减少通过STAT3增强了IFN-α和白细胞介素(IL)-6信号转导。这些结果揭示了一种新的机制，miR-19a可能通过控制SOCS3表达来增强JAK-STAT信号转导，这是理解炎症调节的基础。
Suppressors of cytokine signalling (SOCS) proteins are classic inhibitors of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Many cytokines and pathogenic mediators induce expression of SOCS, which act in a negative feedback loop to inhibit further signal transduction. SOCS mRNA expression is regulated by DNA binding of STAT proteins, however, their post-transcriptional regulation is poorly understood. microRNAs (miRNAs) are small non-coding RNAs that bind to complementary sequences on target mRNAs, often silencing gene expression. miR-19a has been shown to regulate SOCS1 expression during mutiple myeloma and be induced by the anti-viral cytokine interferon-(IFN)-α, suggesting a role in the regulation of the JAK-STAT pathway. This study aimed to identify targets of miR-19a in the JAK-STAT pathway and elucidate the functional consequences. Bioinformatic analysis identified highly conserved 3’UTR miR-19a target sequences in several JAK-STAT associated genes, including SOCS1, SOCS3, SOCS5 and Cullin (Cul) 5. Functional studies revealed that miR-19a significantly decreased SOCS3 mRNA and protein, while a miR-19a antagomir specifically reversed its inhibitory effect. Furthermore, miR-19a-mediated reduction of SOCS3 enhanced IFN-α and interleukin (IL)-6 signal transduction through STAT3. These results reveal a novel mechanism by which miR-19a may augment JAK-STAT signal transduction via control of SOCS3 expression and are fundamental to the understanding of inflammatory regulation.
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影响因子：
32.4
作者：
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通讯作者：
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