Origin of irreversibility of cell cycle start in budding yeast.
Origin of irreversibility of cell cycle start in budding yeast.
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DOI：
10.1371/journal.pbio.1000284
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发表时间：
2010-01-19
期刊：
影响因子：
9.8
通讯作者：
Cross FR
中科院分区：
文献类型：
--
作者：
Charvin G;Oikonomou C;Siggia ED;Cross FR
在芽殖酵母中，通过G1细胞周期蛋白Cln 1，2的正反馈驱动表达，进入新的细胞分裂周期的承诺是不可逆的。芽殖酵母细胞在称为启动的调节过渡中不可逆转地进入新的分裂周期。这个重要的决策步骤涉及SBF/MBF转录因子的激活。SBF/MBF促进CLN 1和CLN 2编码的G1期细胞周期蛋白的表达。Cln 1，2可以通过使SBF/MBF的Whi 5阻遏物失活来激活其自身的表达。由此产生的转录正反馈提供了一个有吸引力的，但尚未证实，候选人产生不可逆的开始。在这里，我们调查的逻辑开始监管模块的定量单细胞延时显微镜，使用菌株中的关键调控因子的表达是有效地控制诱导剂在微流控室的变化。我们发现，启动激活是超敏感的G1周期蛋白。在CLN 1，2依赖性正反馈的情况下，我们观察到，开始运输是可逆的，由于重新激活的Whi 5转录抑制。正反馈环的引入使得Whi 5失活和Start激活不可逆，从而保证单向进入S期。一个简单的数学模型来描述G1细胞周期蛋白在开始时打开，完全由经验测量的参数约束，表明实验测量的超灵敏度和转录正反馈是必要的和足够的动力学特性，使开始过渡一个不可逆的和不可逆的开关。因此，我们的研究表明，启动不可逆性是由系统的结构（Whi 5/SBF/Cln 2环）引起的性质，而不是单一组分（例如，不可逆的蛋白质降解）。
In budding yeast, the commitment to entry into a new cell division cycle is made irreversible by positive feedback-driven expression of the G1 cyclins Cln1,2. Budding yeast cells irreversibly commit to a new division cycle at a regulatory transition called Start. This essential decision-making step involves the activation of the SBF/MBF transcription factors. SBF/MBF promote expression of the G1 cyclins encoded by CLN1 and CLN2. Cln1,2 can activate their own expression by inactivating the Whi5 repressor of SBF/MBF. The resulting transcriptional positive feedback provides an appealing, but as yet unproven, candidate for generating irreversibility of Start. Here, we investigate the logic of the Start regulatory module by quantitative single-cell time-lapse microscopy, using strains in which expression of key regulators is efficiently controlled by changes of inducers in a microfluidic chamber. We show that Start activation is ultrasensitive to G1 cyclin. In the absence of CLN1,2-dependent positive feedback, we observe that Start transit is reversible, due to reactivation of the Whi5 transcriptional repressor. Introduction of the positive feedback loop makes Whi5 inactivation and Start activation irreversible, which therefore guarantees unidirectional entry into S phase. A simple mathematical model to describe G1 cyclin turn on at Start, entirely constrained by empirically measured parameters, shows that the experimentally measured ultrasensitivity and transcriptional positive feedback are necessary and sufficient dynamical characteristics to make the Start transition a bistable and irreversible switch. Our study thus demonstrates that Start irreversibility is a property that arises from the architecture of the system (Whi5/SBF/Cln2 loop), rather than the consequence of the regulation of a single component (e.g., irreversible protein degradation).
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影响因子：
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作者：
Di Talia S;Wang H;Skotheim JM;Rosebrock AP;Futcher B;Cross FR
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