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Ribosomal stress induces L11- and p53-dependent apoptosis in mouse pluripotent stem cells

机译:核糖体应激诱导小鼠多能干细胞中L11和p53依赖性凋亡

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摘要

Ribosome biogenesis is the most demanding energetic process in proliferating cells, and it is emerging as a critical sensor of cellular homeostasis. Upon disturbance of ribosome biogenesis, specific free ribosomal proteins, most notably, L11, bind and inhibit Mdm2, resulting in activation of the tumor suppressor p53. This pathway has been characterized in somatic and cancer cells, but its function in embryonic pluripotent cells has remained unexplored. Here, we show that treatment with low doses of actinomycin D or depletion of ribosomal protein L37, two well-established inducers of ribosomal stress, activate p53 in an L11-dependent manner in mouse embryonic stem cells (ESCs) and in induced pluripotent stem cells (iPSCs). Activation of p53 results in transcriptional induction of p53 targets, including p21, Mdm2, Pidd, Puma, Noxa and Bax. Finally, ribosomal stress elicits L11- and p53-dependent apoptosis in ESCs/iPSCs. These results extend the functionality of the ribosomal stress pathway to pluripotent cells, and therefore it could be a relevant cellular checkpoint during early embryogenesis.
机译:核糖体生物发生是增殖细胞中最苛刻的能量过程,它正在成为细胞稳态的关键传感器。核糖体生物发生受到干扰后,特定的游离核糖体蛋白(最明显的是L11)会结合并抑制Mdm2,从而激活肿瘤抑制因子p53。该途径已在体细胞和癌细胞中表征,但其在胚胎多能细胞中的功能仍未探索。在这里,我们显示低剂量的放线菌素D或核糖体蛋白L37的耗尽(两种成熟的核糖体应激诱导剂)的治疗以L11依赖性方式在小鼠胚胎干细胞(ESC)和诱导的多能干细胞中激活p53。 (iPSC)。 p53的激活导致p53靶标的转录诱导,包括p21,Mdm2,Pidd,Puma,Noxa和Bax。最后,核糖体应激在ESC / iPSC中引起L11和p53依赖性凋亡。这些结果将核糖体应激途径的功能扩展至多能细胞,因此它可能是早期胚胎发生过程中的一个相关细胞检查点。

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