Decision making of the p53 network: Death by integration

作者：Li Zhiyuan; Ni Ming; Li Jikun; Zhang Yuping; Ouyang Qi^*; Tang Chao

来源：Journal of Theoretical Biology, 2011, 271(1): 205-211.

DOI：10.1016/j.jtbi.2010.11.041

• Cell death
• Cellular decision making
• DNA damage
• Modeling
• p53 network

The tumor suppressor protein p53 plays a central role in the multiple response pathways activated by DNA damage. In particular, p53 is involved in both the pro-survival response of cell cycle arrest and DNA repair, and the pro-death response of apoptosis. How does the p53 network coordinate the different pathways that lead to the opposite cell fates and what is its strategy in making the life-death decisions? To address these questions, we develop an integrated mathematical model that embraces three key modules of the p53 network: p53 core regulation, p53-induced cell cycle arrest and p53-dependent apoptosis initiation. Our analyses reveal that different aspects of the nuclear p53 dynamic profile are being used to differentially regulate the pro-survival and the pro-death modules. While the activation of the pro-survival module is dependent on the current or recent status of the DNA damage, the activation of the pro-death module relies on the accumulation or integration of the damage level over time. Thus, the cell will take the death fate if it cannot recover from the damage within a time period that is inversely proportional to the damage level. This "adaptive timer" strategy is likely to be adopted in other stress response systems.

• 出版日期2011-2-21
• 单位北京大学