Decision making of the p53 network: death by integration.
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.
Center for Theoretical Biology, Peking University, Beijing 100871, China.
Zhiyuan
Z
Li
Center for Theoretical Biology, Peking University, Beijing 100871, China.
Ming
M
Ni
Center for Theoretical Biology, Peking University, Beijing 100871, China.
Jikun
J
Li
Center for Theoretical Biology, Peking University, Beijing 100871, China.
Yuping
Y
Zhang
Center for Theoretical Biology, Peking University, Beijing 100871, China; School of Physics, Peking University, Beijing 100871, China.
Qi
Q
Ouyang
Center for Theoretical Biology, Peking University, Beijing 100871, China; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA.
Chao
C
Tang
D017209:Apoptosis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D053263:Gene Regulatory Networks; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008957:Models, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D016159:Tumor Suppressor Protein p53