Attractor Landscape Analysis Reveals Feedback Loops in the p53 Network That Control the Cellular Response to DNA Damage
Attractor Landscape Analysis Reveals Feedback Loops in the p53 Network That Control the Cellular Response to DNA Damage
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DOI：
10.1126/scisignal.2003363
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发表时间：
2012-11-20
影响因子：
7.3
通讯作者：
Cho, Kwang-Hyun
中科院分区：
文献类型：
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作者：
Choi, Minsoo;Shi, Jue;Cho, Kwang-Hyun
蛋白质p53作为一种肿瘤抑制因子发挥作用，并且能够在DNA损伤时触发细胞周期停滞或细胞凋亡。我们使用布尔网络建模和吸引子景观分析来分析一个简化的p53网络的状态转换动态，其中分子激活状态的特定组合对应于特定的细胞结果。我们的研究结果确定了网络中决定细胞对DNA损伤反应的五个关键相互作用，并且缺少任何这些相互作用的模拟产生了与持续的p53活性相关的状态，这对应于一种细胞死亡反应。对乳腺癌细胞系MCF7细胞对DNA损伤的反应以及Mdm2（鼠双微体2）抑制剂nutlin - 3的作用进行吸引子景观分析表明，nutlin - 3在触发细胞死亡方面效果有限，因为通过nutlin - 3模拟在很大程度上没有诱导出细胞死亡状态，而是产生了一种与p53动态振荡和细胞周期停滞一致的状态。吸引子景观分析还表明，将nutlin - 3与Wip1抑制相结合将协同刺激p53活性的持续增加并促进p53介导的细胞死亡。我们通过对MCF7细胞中荧光p53报告基因的单细胞成像验证了这种在刺激p53活性和触发细胞死亡方面的协同效应。因此，对p53网络动态及其调控的吸引子景观分析能够确定治疗癌症的潜在治疗策略。
The protein p53 functions as a tumor suppressor and can trigger either cell cycle arrest or apoptosis in response to DNA damage. We used Boolean network modeling and attractor landscape analysis to analyze the state transition dynamics of a simplified p53 network for which particular combinations of activation states of the molecules corresponded to specific cellular outcomes. Our results identified five critical interactions in the network that determined the cellular response to DNA damage, and simulations lacking any of these interactions produced states associated with sustained p53 activity, which corresponded to a cell death response. Attractor landscape analysis of the cellular response to DNA damage of the breast cancer cell line MCF7 and the effect of the Mdm2 (murine double minute 2) inhibitor nutlin-3 indicated that nutlin-3 would exhibit limited efficacy in triggering cell death, because the cell death state was not induced to a large extent by simulations with nutlin-3 and instead produced a state consistent with oscillatory p53 dynamics and cell cycle arrest. Attractor landscape analysis also suggested that combining nutlin-3 with inhibition of Wip1 would synergize to stimulate a sustained increase in p53 activity and promote p53-mediated cell death. We validated this synergistic effect in stimulating p53 activity and triggering cell death with single-cell imaging of a fluorescent p53 reporter in MCF7 cells. Thus, attractor landscape analysis of p53 network dynamics and its regulation can identify potential therapeutic strategies for treating cancer.