Spanish National Cancer Research Center, Madrid, Spain.
Cell Cycle. 2012 Feb 1;11(3):503-10. doi: 10.4161/cc.11.3.19002.
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 to pluripotent cells the functionality of the ribosomal stress pathway and we speculate that this could be a relevant cellular checkpoint during early embryogenesis.
核糖体生物发生是增殖细胞中最具挑战性的能量过程，它正成为细胞内稳态的关键传感器。核糖体生物发生受到干扰时，特定的游离核糖体蛋白，尤其是 L11，会结合并抑制 Mdm2，从而激活肿瘤抑制因子 p53。这条途径已在体细胞和癌细胞中得到了描述，但它在胚胎多能细胞中的功能仍未被探索。在这里，我们表明，低剂量放线菌素 D 处理或核糖体蛋白 L37 耗竭，这两种公认的核糖体应激诱导剂，以 L11 依赖性方式在小鼠胚胎干细胞（ESCs）和诱导多能干细胞（iPSCs）中激活 p53。p53 的激活导致 p53 靶基因，包括 p21、Mdm2、Pidd、Puma、Noxa 和 Bax 的转录诱导。最后，核糖体应激在 ESCs/iPSCs 中引发 L11 和 p53 依赖性细胞凋亡。这些结果将核糖体应激途径的功能扩展到多能细胞，我们推测这可能是早期胚胎发生中的一个相关细胞检查点。
