Underlying principles of cell fate determination during G1 phase of the mammalian cell cycle
Underlying principles of cell fate determination during G1 phase of the mammalian cell cycle
复制标题
DOI：
10.4161/cc.7.20.6853
复制
发表时间：
2008-10-15
期刊：
影响因子：
4.3
通讯作者：
Kaneko, Kunihiko
中科院分区：
文献类型：
--
作者：
Pfeuty, Benjamin;David-Pfeuty, Therese;Kaneko, Kunihiko
哺乳动物细胞一旦退出有丝分裂，就进入G(1)期，在此期间它们敏锐地感受到各种环境刺激。根据它们首先需要破译和整合的这些信号，它们决定是否经历分裂、分化、衰老或凋亡。我们质疑，尽管G(1)调控网络的复杂性，是否可以确定简单的组织原则，以解释特定的输入信号如何转换为适当的细胞命运。为此，我们建立了G(1)调控网络的数学模型，使用与信号转导、细胞生长、细胞分裂和细胞死亡相关的活动的简化描述。模型的分支分析表明，与G(0)-停滞、G(1)-停滞、S相进入和细胞凋亡命运相对应的几个吸引子状态之间存在多重稳定性。我们进一步解开了G(1)调控网络中的相互关联的反馈和前馈回路，它们驱动了G(0)停滞和其他细胞命运之间的信号依赖转换。最初，从G(0)退出并在G(1)早期进展需要依赖于生长因子的上游正反馈环的激活，该环激活了细胞生长机制。一旦核糖体合成在G(1)中恢复，下游的正反馈环和压力激活的通路之间就会产生竞争，正反馈环一旦激活，就会触发S阶段的进入，而应激激活的通路则会促进G(1)的停滞。如果S的细胞周期进入超过G(1)期的停滞，由于应激诱导的促凋亡通路的激活或促生存通路的抑制，细胞对凋亡敏感。因此，在G(1)期四种可能的细胞命运之间的选择依赖于灵活地相互关联的生长激活模块和分裂激活模块，其中某些成分对参与推动细胞凋亡和G(1)停滞的通路具有拮抗作用。最终结果最终取决于细胞生长和细胞分裂过程之间的上下文相关协调。
Upon their exit from mitosis, mammalian cells enter a G(1) phase during which they acutely sense all sorts of environmental stimuli. On the basis of these signals that they first need to decipher and integrate, they decide whether to undergo division, differentiation, senescence or apoptosis. We questioned whether, despite the complexity of the G(1) regulatory network, simple organizing principles might be identified that could explain how specific input signals are converted into appropriate cell fates. For this purpose, we formulated a mathematical model of the G(1) regulatory network using a simplified description of activities linked to signal transduction, cell growth, cell division and cell death. Bifurcation analysis of the model revealed the existence of multistability between several attractor states corresponding to G(0)-arrest, G(1)-arrest, S-phase entry and apoptosis cell fates. We further unravelled interlinked feedback and feedforward loops within the G(1) regulatory network that drive the signal-dependent transition between G(0) arrest and the other cell fates. Initially, exit from G(0) and progression in early G(1) entail growth factor-dependent activation of an upstream positive feedback loop that activates the cell-growth machinery. Once ribosome synthesis is restored in G(1), a competition develops between a downstream positive feedback loop, which, upon activation, triggers S phase entry, and stress-activated pathways that promote G(1) arrest. If S phase entry prevails over G(1) arrest, cells are sensitized to apoptosis due to stress-induced activation of pro-apoptotic pathways or repression of pro-survival pathways. Thus, the choice between the four possible cell fates in the G(1) phase relies on the flexibly interlinked growth-activatory and division-activatory modules, certain components of which have antagonistic effects on pathways involved in driving apoptosis and G(1) arrest. The final outcome ultimately depends on the context-dependent coordination between the cell-growth and cell-division processes.