通过无意义介导的 RNA 降解途径对干细胞和神经发生程序的转录后控制。
Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway.
机构信息
Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
出版信息
Cell Rep. 2014 Feb 27;6(4):748-64. doi: 10.1016/j.celrep.2014.01.028. Epub 2014 Feb 13.
The mechanisms dictating whether a cell proliferates or differentiates have undergone intense scrutiny, but they remain poorly understood. Here, we report that UPF1, a central component in the nonsense-mediated RNA decay (NMD) pathway, plays a key role in this decision by promoting the proliferative, undifferentiated cell state. UPF1 acts, in part, by destabilizing the NMD substrate encoding the TGF-β inhibitor SMAD7 and stimulating TGF-β signaling. UPF1 also promotes the decay of mRNAs encoding many other proteins that oppose the proliferative, undifferentiated cell state. Neural differentiation is triggered when NMD is downregulated by neurally expressed microRNAs (miRNAs). This UPF1-miRNA circuitry is highly conserved and harbors negative feedback loops that act as a molecular switch. Our results suggest that the NMD pathway collaborates with the TGF-β signaling pathway to lock in the stem-like state, a cellular state that is stably reversed when neural differentiation signals that induce NMD-repressive miRNAs are received.
调控细胞增殖或分化的机制已经过深入研究，但仍知之甚少。在这里，我们报告称，无义介导的 RNA 降解 (NMD) 途径中的核心组成部分 UPF1 通过促进增殖、未分化的细胞状态在这一决定中发挥关键作用。UPF1 部分通过使编码 TGF-β 抑制剂 SMAD7 的 NMD 底物不稳定并刺激 TGF-β 信号传导来发挥作用。UPF1 还促进编码许多其他蛋白的 mRNA 的衰减，这些蛋白反对增殖、未分化的细胞状态。当 NMD 被神经表达的 microRNAs (miRNAs) 下调时，神经分化就会被触发。这个 UPF1-miRNA 电路非常保守，并且具有负反馈回路，充当分子开关。我们的研究结果表明，NMD 途径与 TGF-β 信号通路合作，锁定干细胞样状态，当接收到诱导 NMD 抑制性 miRNA 的神经分化信号时，这种细胞状态会稳定逆转。
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