The let-7 microRNA interfaces extensively with the translation machinery to regulate cell differentiation.
The let-7 microRNA interfaces extensively with the translation machinery to regulate cell differentiation.
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DOI：
10.4161/cc.7.19.6778
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Grosshans H
中科院分区：
文献类型：
--
作者：
Ding XC;Slack FJ;Grosshans H
MicroRNAs(MiRNAs)是一种非编码RNA，通过转录后机制调节大量的靶基因，从而控制主要的发育途径。在系统发育上保守的let-7miRNA调节细胞的增殖和分化，因此在线虫中起着关键的发育时机调节作用，在人类中也是一个肿瘤抑制基因。利用反向遗传筛选，我们已经确定了线虫let-7的遗传相互作用伙伴，包括已知和新的潜在靶基因。最初发现几个翻译启动因子是let-7突变的抑制因子，这使我们系统地研究了let-7与翻译机制之间的遗传相互作用，我们发现这种相互作用是普遍存在的。在野生型let-7存在的情况下，翻译起始因子eIF3的缺失导致了性早熟细胞的分化，这表明发育时间受到翻译调控，可能是由let-7调控的。由于eIF3在人类中的过表达促进了同时也是let-7介导的抑制靶的mRNAs的翻译，我们认为eIF3可能直接或间接地对抗let-7的活性。这可能为let-7和eIF3在调节肿瘤发生中相反的功能提供了解释。
MicroRNAs (miRNAs) are noncoding RNAs that regulate numerous target genes through a posttranscriptional mechanism and thus control major developmental pathways. The phylogenetically conserved let-7 miRNA regulates cell proliferation and differentiation, thus functioning as a key regulator of developmental timing in C. elegans and a tumor suppressor gene in humans. Using a reverse genetic screen, we have identified genetic interaction partners of C. elegans let-7, including known and novel potential target genes. Initial identification of several translation initiation factors as suppressors of a let-7 mutation led us to systematically examine genetic interaction between let-7 and the translational machinery, which we found to be widespread. In the presence of wild-type let-7, depletion of the translation initiation factor eIF3 resulted in precocious cell differentiation, suggesting that developmental timing is translationally regulated, possibly by let-7. As overexpression of eIF3 in humans promotes translation of mRNAs that are also targets of let-7-mediated repression, we suggest that eIF3 may directly or indirectly oppose let-7 activity. This might provide an explanation for the opposite functions of let-7 and eIF3 in regulating tumorigenesis.
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