The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation.
The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation.
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DOI：
10.1371/journal.pone.0107016
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gupta M
中科院分区：
文献类型：
--
作者：
Hu G;Lou Z;Gupta M
长链非编码rna （lncRNAs）是重要的转录调控因子；然而，它们在蛋白质翻译中的作用并不为人所知。在这里，我们探讨了lncRNA GAS5是否与翻译起始机制相关并调节翻译。在淋巴瘤细胞系的rna免疫沉淀试验中，GAS5富含真核翻译起始因子- 4e （eIF4E）。我们在eIF4E蛋白中发现了两个RNA结合基序，每个基序的缺失都抑制了GAS5与eIF4E的结合。为了证实GAS5在翻译调控中的作用，我们分别用GAS5 siRNA和体外转录的GAS5 RNA敲低或过表达GAS5。GAS5 siRNA对全局蛋白翻译没有影响，但特异性地增加了c-Myc蛋白水平，而对c-Myc mRNA没有影响。c-Myc蛋白增加的机制是增强了c-Myc mRNA与多体的关联，但不影响蛋白质的稳定性。相比之下，体外转录的GAS5 RNA过表达抑制了c-Myc蛋白，但不影响c-Myc mRNA。有趣的是，GAS5被发现与c-Myc mRNA结合，表明GAS5通过lncRNA-mRNA相互作用调节c-Myc翻译。我们的发现揭示了GAS5 lncRNA通过其与eIF4E和c-Myc mRNA的相互作用在翻译调控中的作用。
Long noncoding RNAs (lncRNAs) are important regulators of transcription; however, their involvement in protein translation is not well known. Here we explored whether the lncRNA GAS5 is associated with translation initiation machinery and regulates translation. GAS5 was enriched with eukaryotic translation initiation factor-4E (eIF4E) in an RNA-immunoprecipitation assay using lymphoma cell lines. We identified two RNA binding motifs within eIF4E protein and the deletion of each motif inhibited the binding of GAS5 with eIF4E. To confirm the role of GAS5 in translation regulation, GAS5 siRNA and in vitro transcribed GAS5 RNA were used to knock down or overexpress GAS5, respectively. GAS5 siRNA had no effect on global protein translation but did specifically increase c-Myc protein level without an effect on c-Myc mRNA. The mechanism of this increase in c-Myc protein was enhanced association of c-Myc mRNA with the polysome without any effect on protein stability. In contrast, overexpression of in vitro transcribed GAS5 RNA suppressed c-Myc protein without affecting c-Myc mRNA. Interestingly, GAS5 was found to be bound with c-Myc mRNA, suggesting that GAS5 regulates c-Myc translation through lncRNA-mRNA interaction. Our findings have uncovered a role of GAS5 lncRNA in translation regulation through its interactions with eIF4E and c-Myc mRNA.
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