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Rigor of cell fate decision by variable p53 pulses and roles of cooperative gene expression by p53

机译:可变p53脉冲决定细胞命运的严格性以及p53协同基因表达的作用

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摘要

Upon DNA damage, the cell fate decision between survival and apoptosis is largely regulated by p53-related networks. Recent experiments found a series of discrete p53 pulses in individual cells, which led to the hypothesis that the cell fate decision upon DNA damage is controlled by counting the number of p53 pulses. Under this hypothesis, Sun et al. (2009) modeled the Bax activation switch in the apoptosis signal transduction pathway that can rigorously “count” the number of uniform p53 pulses. Based on experimental evidence, here we use variable p53 pulses with Sun et al.’s model to investigate how the variability in p53 pulses affects the rigor of the cell fate decision by the pulse number. Our calculations showed that the experimentally anticipated variability in the pulse sizes reduces the rigor of the cell fate decision. In addition, we tested the roles of the cooperativity in PUMA expression by p53, finding that lower cooperativity is plausible for more rigorous cell fate decision. This is because the variability in the p53 pulse height is more amplified in PUMA expressions with more cooperative cases.
机译:DNA受损后,存活和凋亡之间的细胞命运决定主要受p53相关网络调控。最近的实验在单个细胞中发现了一系列离散的p53脉冲,这导致了一个假设,即通过计算p53脉冲的数量来控制细胞对DNA损伤的命运决定。在这种假设下,Sun等人。 (2009)在细胞凋亡信号转导通路中模拟了Bax激活开关,可以严格“计数”统一的p53脉冲数。根据实验证据,我们在Sun等人的模型中使用可变的p53脉冲,以研究p53脉冲的可变性如何通过脉冲数影响细胞命运决定的严格性。我们的计算表明,脉冲大小的实验预期变化降低了细胞命运决定的严格性。此外,我们通过p53测试了合作性在PUMA表达中的作用,发现更低的合作性对于更严格的细胞命运决定是合理的。这是因为在更多协作情况下,PUMA表达式中p53脉冲高度的可变性会更大。

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