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Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat.
Genes & development Pub Date : 2019-11-07 , DOI: 10.1101/gad.330134.119
Verena Labi 1, 2, 3 , Siying Peng 2 , Filippos Klironomos 1, 4 , Mathias Munschauer 1, 4 , Nicolai Kastelic 1, 4 , Tirtha Chakraborty 2 , Katia Schoeler 3 , Emmanuel Derudder 1, 2, 5 , Manuela Martella 6 , Guido Mastrobuoni 1, 4 , Luis R Hernandez-Miranda 1 , Ines Lahmann 1 , Christine Kocks 1, 4 , Carmen Birchmeier 1 , Stefan Kempa 1, 4 , Leticia Quintanilla-Martinez de Fend 6 , Markus Landthaler 1, 4 , Nikolaus Rajewsky 1, 4 , Klaus Rajewsky 1, 2
Affiliation  

Knockout of the ubiquitously expressed miRNA-17∼92 cluster in mice produces a lethal developmental lung defect, skeletal abnormalities, and blocked B lymphopoiesis. A shared target of miR-17∼92 miRNAs is the pro-apoptotic protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17∼92:Bim interactions to the complex miR-17∼92 knockout phenotype, we used a system of conditional mutagenesis of the nine Bim 3' UTR miR-17∼92 seed matches. Blocking miR-17∼92:Bim interactions early in development phenocopied the lethal lung phenotype of miR-17∼92 ablation and generated a skeletal kinky tail. In the hematopoietic system, instead of causing the predicted B cell developmental block, it produced a selective inability of B cells to resist cellular stress; and prevented B and T cell hyperplasia caused by Bim haploinsufficiency. Thus, the interaction of miR-17∼92 with a single target is essential for life, and BIM regulation by miRNAs serves as a rheostat controlling cell survival in specific physiological contexts.

中文翻译:

通过 miRNA 控制的 BIM 变阻器对细胞存活的上下文特定调节。

在小鼠中敲除普遍表达的 miRNA-17∼92 簇会导致致命的发育性肺缺陷、骨骼异常和 B 淋巴细胞生成受阻。miR-17∼92 miRNA 的共同目标是促凋亡蛋白 BIM,它是哺乳动物细胞生死决定的核心。为了阐明 miR-17∼92:Bim 相互作用对复杂的 miR-17∼92 敲除表型的贡献,我们使用了九个 Bim 3' UTR miR-17∼92 种子匹配的条件诱变系统。在发育早期阻断 miR-17∼92:Bim 相互作用表型复制了 miR-17∼92 消融的致命肺表型,并产生了骨骼卷曲的尾巴。在造血系统中,它并没有引起预测的 B 细胞发育阻滞,而是导致 B 细胞选择性地无法抵抗细胞应激;并防止由 Bim 单倍体不足引起的 B 和 T 细胞增生。因此,miR-17∼92 与单个靶标的相互作用对生命至关重要,miRNA 对 BIM 的调节可作为特定生理环境中控制细胞存活的变阻器。
更新日期:2019-11-01
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