Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, China.
J Chem Phys. 2021 Jan 14;154(2):025101. doi: 10.1063/5.0030558.
The p53 transcription factor is a key mediator in cellular responses to various stress signals including DNA repair, cell cycle arrest, and apoptosis. In this work, we employ landscape and flux theory to investigate underlying mechanisms of p53-regulated cell fate decisions. Based on a p53 regulatory network, we quantified the potential landscape and probabilistic flux for the p53 system. The landscape topography unifies and quantifies three cell fate states, including the limit cycle oscillations (representing cell cycle arrest), high p53 state (characterizing apoptosis), and low p53 state (characterizing the normal proliferative state). Landscape and flux results provide a quantitative explanation for the biphasic dynamics of the p53 system. In the oscillatory phase (first phase), the landscape attracts the system into the ring valley and flux drives the system cyclically moving, leading to cell cycle arrest. In the fate decision-making phase (second phase), the ring valley shape of the landscape provides an efficient way for cells to return to the normal proliferative state once DNA damage is repaired. If the damage is unrepairable with larger flux, the system may cross the barrier between two states and switch to the apoptotic state with a high p53 level. By landscape-flux decomposition, we revealed a trade-off between stability (guaranteed by landscape) and function (driven by flux) in cellular systems. Cells need to keep a balance between appropriate speed to repair DNA damage and appropriate stability to survive. This is further supported by flux landscape analysis showing that flux may provide the dynamical origin of phase transition in a non-equilibrium system by changing landscape topography.
p53 转录因子是细胞对各种应激信号（包括 DNA 修复、细胞周期停滞和细胞凋亡）做出反应的关键介质。在这项工作中，我们采用景观和通量理论来研究 p53 调节的细胞命运决定的潜在机制。基于 p53 调控网络，我们量化了 p53 系统的潜在景观和概率通量。景观地形将三种细胞命运状态统一并量化，包括极限环振荡（代表细胞周期停滞）、高 p53 状态（代表细胞凋亡）和低 p53 状态（代表正常增殖状态）。景观和通量结果为 p53 系统的双相动力学提供了定量解释。在振荡相（第一相）中，景观吸引系统进入环谷，通量驱动系统周期性移动，导致细胞周期停滞。在命运决策相（第二相）中，景观的环谷形状为细胞提供了一种有效的方式，一旦 DNA 损伤得到修复，就可以返回正常增殖状态。如果损伤无法修复且通量较大，则系统可能越过两个状态之间的障碍，并切换到具有高 p53 水平的凋亡状态。通过景观通量分解，我们揭示了细胞系统中稳定性（由景观保证）和功能（由通量驱动）之间的权衡。细胞需要在适当的速度修复 DNA 损伤和适当的稳定性之间保持平衡以存活。通量景观分析进一步支持了这一观点，表明通量通过改变景观地形可能为非平衡系统中的相变提供动力学起源。
