Zhou Pei-Yuan Center for Applied Mathematics, Tsinghua University, Beijing, China.
Biophys J. 2011 Dec 7;101(11):2582-91. doi: 10.1016/j.bpj.2011.10.044.
Programmed cell death 5 (PDCD5) is a human apoptosis-related molecule that is involved in both the cytoplasmic caspase-3 activity pathway (by regulating Bax translocation from cytoplasm to mitochondria) and the nuclear pathway (by interacting with Tip60). In this study, we developed a mathematical model of the PDCD5-regulated switching of the cell response from DNA repair to apoptosis after ultraviolet irradiation-induced DNA damage. We established the model by combining several hypotheses with experimental observations. Our simulations indicate that the ultimate cell response to DNA damage is dependent on a signal threshold mechanism, and the PDCD5 promotion of Bax translocation plays an essential role in PDCD5-regulated cell apoptosis. Furthermore, the model simulations revealed that PDCD5 nuclear translocation can attenuate cell apoptosis, and PDCD5 interactions with Tip60 can accelerate DNA damage-induced apoptosis, but the final cell fate decision is insensitive to the PDCD5-Tip60 interaction. These results are consistent with experimental observations. The effect of recombinant human PDCD5 was also investigated and shown to sensitize cells to DNA damage by promoting caspase-3 activity.
程序性细胞死亡蛋白 5（PDCD5）是一种与人类细胞凋亡相关的分子，参与细胞质 caspase-3 活性途径（通过调节 Bax 从细胞质向线粒体的易位）和核途径（通过与 Tip60 相互作用）。在这项研究中，我们建立了一个数学模型，用于研究 PDCD5 调控紫外线照射诱导 DNA 损伤后细胞从 DNA 修复到凋亡反应的转换。我们通过将几个假设与实验观察结果相结合来建立该模型。我们的模拟结果表明，细胞对 DNA 损伤的最终反应取决于信号阈值机制，并且 PDCD5 促进 Bax 易位在 PDCD5 调控细胞凋亡中起着至关重要的作用。此外，模型模拟结果揭示，PDCD5 核转位可以减轻细胞凋亡，而 PDCD5 与 Tip60 的相互作用可以加速 DNA 损伤诱导的凋亡，但最终的细胞命运决定对 PDCD5-Tip60 相互作用不敏感。这些结果与实验观察结果一致。还研究了重组人 PDCD5 的作用，结果表明通过促进 caspase-3 活性使细胞对 DNA 损伤敏感。
