Anderson Matthew W, Moss Joanna J, Szalai Robert, Lane Jon D
Centre for Biomedical Modelling and Analysis, Living Systems Institute, University of Exeter, Stocker Road, Exeter EX4 4QD, UK.
Cell Biology Laboratories, School of Biochemistry, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
iScience. 2019 Feb 22;12:182-193. doi: 10.1016/j.isci.2019.01.015. Epub 2019 Jan 14.
Protein kinase B/AKT is a highly connected protein involved in a range of signaling pathways. Although it is known to regulate several proteins in the apoptotic pathway, its system-level effects remain poorly understood. We investigated the dynamic interactions between AKT and key apoptotic proteins and constructed a deterministic ordinary differential equation protein interaction model of extrinsic apoptosis. Incorporating AKT and its indirect inhibitor, phosphatase and tensin homolog (PTEN), this was used to generate predictions of system dynamics. Using eigen analysis, we identified AKT and cytochrome c as the protein species most sensitive to perturbations. Cell death assays in Type II HCT116 colorectal carcinoma cells revealed a tendency toward Type I cell death behavior in the XIAP background, with cells displaying accelerated TRAIL-induced apoptosis. Finally, AKT inhibition experiments implicated AKT and not PTEN in influencing apoptotic proteins during early phases of TRAIL-induced apoptosis.
蛋白激酶B/AKT是一种高度关联的蛋白质，参与一系列信号通路。尽管已知它可调节凋亡通路中的多种蛋白质，但其系统水平的作用仍了解甚少。我们研究了AKT与关键凋亡蛋白之间的动态相互作用，并构建了一个确定性的外在凋亡常微分方程蛋白质相互作用模型。该模型纳入了AKT及其间接抑制剂——磷酸酶和张力蛋白同源物（PTEN），用于生成系统动力学预测。通过特征值分析，我们确定AKT和细胞色素c是对扰动最敏感的蛋白质种类。对II型HCT116结肠癌细胞进行的细胞死亡检测显示，在XIAP背景下细胞呈现I型细胞死亡行为的趋势，细胞表现出TRAIL诱导的凋亡加速。最后，AKT抑制实验表明，在TRAIL诱导凋亡的早期阶段，影响凋亡蛋白的是AKT而非PTEN。
