MiR-35 通过拮抗 MAPK 和核心细胞凋亡途径来缓冲秀丽隐杆线虫种系中的细胞凋亡阈值。,Cell Death and Differentiation

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MiR-35 通过拮抗 MAPK 和核心细胞凋亡途径来缓冲秀丽隐杆线虫种系中的细胞凋亡阈值。
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-04-05 , DOI: 10.1038/s41418-019-0325-6
Anh T Tran _{1,

2} , Eric M Chapman _{1,

3} , Mathieu N Flamand _{4,

5} , Bin Yu ₁ , Samuel J Krempel _{1,

3} , Thomas F Duchaine _{4,

6} , Matthew Eroglu _{1,

3} , W Brent Derry _{1,

3}

Affiliation

细胞凋亡是一种基因程序化的细胞死亡过程，在发育和疾病中具有深远的作用。MicroRNAs 调节许多蛋白质的表达，并且在人类疾病（如癌症）中经常失调。C. elegans 生殖细胞通过核心细胞凋亡和 MAPK 通路的联合活动响应基因毒性应激而发生细胞凋亡，但如何缓冲它们的信号阈值是一个悬而未决的问题。在这里，我们显示 mir-35-42 miRNA 家族在拮抗 MAPK 信号传导的正调节因子 NDK-1 和仅 BH3 的促凋亡蛋白 EGL-1 中发挥双重作用，以调节 DNA 损伤诱导的细胞凋亡的幅度在秀丽隐杆线虫种系中。我们表明，虽然 miR-35 通过促进转录物降解来抑制 EGL-1，但对 NDK-1 的抑制可能是通过隔离转录物来抑制翻译。重要的是，在即将死亡的细胞中观察到 NDK-1 表达的显着增加。在没有 miR-35 的情况下，增加的 NDK-1 活性增强了 MAPK 信号传导，导致生殖细胞死亡显着增加。我们的研究结果表明，NDK-1 作用于 EGL-1 的上游（或平行于），并且 miR-35 靶向 egl-1 和 ndk-1 以微调细胞杀伤以响应基因毒性应激。

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MiR-35 buffers apoptosis thresholds in the C. elegans germline by antagonizing both MAPK and core apoptosis pathways.

Apoptosis is a genetically programmed cell death process with profound roles in development and disease. MicroRNAs modulate the expression of many proteins and are often deregulated in human diseases, such as cancer. C. elegans germ cells undergo apoptosis in response to genotoxic stress by the combined activities of the core apoptosis and MAPK pathways, but how their signalling thresholds are buffered is an open question. Here we show mir-35-42 miRNA family play a dual role in antagonizing both NDK-1, a positive regulator of MAPK signalling, and the BH3-only pro-apoptotic protein EGL-1 to regulate the magnitude of DNA damage-induced apoptosis in the C. elegans germline. We show that while miR-35 represses EGL-1 by promoting transcript degradation, repression of NDK-1 may be through sequestration of the transcript to inhibit translation. Importantly, dramatic increase in NDK-1 expression was observed in cells about to die. In the absence of miR-35, increased NDK-1 activity enhanced MAPK signalling that lead to significant increases in germ cell death. Our findings demonstrate that NDK-1 acts upstream of (or in parallel to) EGL-1, and that miR-35 targets both egl-1 and ndk-1 to fine-tune cell killing in response to genotoxic stress.

更新日期：2019-05-16

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