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Cell Death Differ ; 26(12): 2637-2651, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30952991

RESUMO

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.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Núcleosídeo-Difosfato Quinase/metabolismo , Regiões 3' não Traduzidas , Animais , Apoptose/fisiologia , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Dano ao DNA , Regulação para Baixo , Células Germinativas , MicroRNAs/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Núcleosídeo-Difosfato Quinase/biossíntese , Núcleosídeo-Difosfato Quinase/genética , RNA Nucleotidiltransferases/genética , RNA Nucleotidiltransferases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
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