Zhou Chun-Hong, Zhang Xiao-Peng, Liu Feng, Wang Wei
National Laboratory of Solid State Microstructures, and Department of Physics, Nanjing University, Nanjing, China; School of Physics and Electronic Engineering, Jiangsu Normal University, Xuzhou, China.
National Laboratory of Solid State Microstructures, and Department of Physics, Nanjing University, Nanjing, China.
Biophys J. 2014 Apr 15;106(8):1792-800. doi: 10.1016/j.bpj.2014.02.032.
MicroRNAs are key regulators of gene expression at the posttranscriptional level. In this study, we focus on miR-605 and miR-34a, which are direct transcriptional targets of p53 and in turn enhance its tumor suppressor function by acting upstream and downstream of it, respectively. miR-605 promotes p53 activation by repressing the expression of mdm2, whereas miR-34a promotes p53-dependent apoptosis by suppressing the expression of antiapoptotic genes such as bcl-2. What roles they play in the p53-mediated DNA damage response is less well understood. Here, we develop a four-module model of the p53 network to investigate the effect of miR-605 and miR-34a on the cell-fate decision after ionizing radiation. Results of numerical simulation indicate that the cell fate is closely associated with network dynamics. The concentration of p53 undergoes few pulses in response to repairable DNA damage, or it first oscillates and then switches to high plateau levels after irreparable damage. The amplitude of p53 pulses rises to various extents depending on miR-605 expression, and miR-605 accelerates the switching behavior of p53 levels to induce apoptosis. In parallel, miR-34a promotes apoptosis by enhancing the accumulation of free p53AIP1, a key proapoptotic protein. Thus, both miR-605 and miR-34a can mediate cellular outcomes and the timing of apoptosis. Moreover, miR-605 and PTEN complement each other in elevating p53 levels to trigger apoptosis. Taken together, miR-605 and miR-34a cooperate to endow the network with a fail-safe mechanism for apoptosis induction. This computational study also enriches our understanding of the action modes of p53-targeted microRNAs.
微小RNA是转录后水平基因表达的关键调节因子。在本研究中，我们聚焦于miR - 605和miR - 34a，它们是p53的直接转录靶点，分别通过在p53的上游和下游发挥作用，进而增强其肿瘤抑制功能。miR - 605通过抑制mdm2的表达促进p53激活，而miR - 34a通过抑制抗凋亡基因如bcl - 2的表达促进p53依赖的细胞凋亡。它们在p53介导的DNA损伤反应中发挥何种作用尚不太清楚。在此，我们构建了一个p53网络的四模块模型，以研究miR - 605和miR - 34a对电离辐射后细胞命运决定的影响。数值模拟结果表明，细胞命运与网络动态密切相关。p53的浓度在应对可修复的DNA损伤时仅有少量脉冲，或者在不可修复的损伤后先振荡然后切换到高平台水平。p53脉冲的幅度根据miR - 605的表达程度不同程度地升高，并且miR - 605加速p53水平的切换行为以诱导细胞凋亡。同时，miR - 34a通过增强关键促凋亡蛋白游离p53AIP1的积累促进细胞凋亡。因此，miR - 605和miR - 34a都可以介导细胞结果和细胞凋亡的时机。此外，miR - 605和PTEN在提高p53水平以触发细胞凋亡方面相互补充。综上所述，miR - 605和miR - 34a协同作用，赋予网络一种诱导细胞凋亡的故障安全机制。这项计算研究也丰富了我们对p53靶向微小RNA作用模式的理解。
