Department of Physics, National Laboratory of Solid State Microstructures, Nanjing University, Nanjing, China.
Biophys J. 2010 Sep 22;99(6):1696-705. doi: 10.1016/j.bpj.2010.07.042.
The tumor suppressor p53 plays a key role in the cellular response to various stresses. Most previous studies have focused on either the nuclear or cytoplasmic proapoptotic functions of p53, ignoring the combination of both functions. To explore how the two functions of p53 are coordinated in the DNA damage response via computer simulation, we construct a model for the p53 network comprising coupled positive and negative feedback loops involving p53, Mdm2, and Akt, as well as PUMA and Bax. In our model p53 is stabilized and accumulates in the nucleus and cytoplasm upon DNA damage. Nuclear p53 induces expression of Mdm2, PTEN, PUMA, and Bax. Cytoplasmic p53 is then released from the p53.Bcl-xL complex by PUMA to activate Bax directly. We find that the switching between low and high protein levels underlies the decision between cell survival and death. Moreover, a balance between the nuclear and cytoplasmic p53 levels and appropriate levels of Akt and PUMA are required for reliable cell fate decision. Our results indicate that coordination of the transcription-dependent and -independent activities of p53 is important in determining cellular outcomes. These findings advance our understanding of the mechanism for p53-mediated cellular responses and provide clues to p53-based cancer therapy.
肿瘤抑制因子 p53 在细胞对各种应激的反应中起着关键作用。大多数先前的研究都集中在 p53 的核或细胞质促凋亡功能上，而忽略了这两种功能的结合。为了通过计算机模拟探索 p53 如何在 DNA 损伤反应中协调这两种功能，我们构建了一个包含 p53、Mdm2 和 Akt 以及 PUMA 和 Bax 的正反馈和负反馈回路的 p53 网络模型。在我们的模型中，p53 在 DNA 损伤后在细胞核和细胞质中稳定积累。核 p53 诱导 Mdm2、PTEN、PUMA 和 Bax 的表达。然后，细胞质 p53 通过 PUMA 从 p53.Bcl-xL 复合物中释放出来，直接激活 Bax。我们发现，低蛋白水平和高蛋白水平之间的转换是细胞存活和死亡之间决策的基础。此外，核和细胞质 p53 水平之间的平衡以及 Akt 和 PUMA 的适当水平是可靠的细胞命运决定所必需的。我们的结果表明，p53 转录依赖性和非依赖性活性的协调对于确定细胞结果至关重要。这些发现提高了我们对 p53 介导的细胞反应机制的理解，并为基于 p53 的癌症治疗提供了线索。
