Srividhya J, Gopinathan M S
Indiana University School of Informatics, Indiana University, Bloomington, IN 47406, USA.
J Theor Biol. 2006 Aug 7;241(3):617-27. doi: 10.1016/j.jtbi.2005.12.020. Epub 2006 Feb 13.
We propose a seven variable model with time delay in one of the variables for the cell cycle in higher eukaryotes. The model consists of four important phosphorylation-dephosphorylation (P-D) cycles that govern the cell cycle, namely Pre-MPF-MPF, Cdc25P-Cdc25, Wee1P-Wee1 and APCP-APC. Other variables are cyclin, free cyclin dependent kinase (Cdk) and mass. The mass acts as a G2/M checkpoint and the checkpoint is represented by a saddle node loop bifurcation. The key feature of the model is that a time lag has been introduced in the activation of anaphase promoting complex (APC) by maturation promoting factor (MPF). This is effected by treating MPF as a time-delayed variable in the activation step of APC. The time lag acts as a spindle checkpoint. Absence of time delay induces a bistability in our model. Time delay also brings about variability in G1 phase timings. The model also reproduces the mutant phenotype experiments on wee1 cells. Stochasticity has been introduced in the model to simulate the dependence of the cycle time on cell birth length. Mutant phenotypes in the stochastic model reproduce the experimental observations better than the deterministic model.
我们提出了一个用于高等真核生物细胞周期的七变量模型，其中一个变量存在时间延迟。该模型由四个控制细胞周期的重要磷酸化 - 去磷酸化（P-D）循环组成，即前促成熟因子 - 促成熟因子（Pre-MPF-MPF）、细胞分裂周期蛋白25磷酸化形式 - 细胞分裂周期蛋白25（Cdc25P-Cdc25）、wee1磷酸化形式 - wee1（Wee1P-Wee1）和后期促进复合体磷酸化形式 - 后期促进复合体（APCP-APC）。其他变量为细胞周期蛋白、游离细胞周期蛋白依赖性激酶（Cdk）和质量。质量充当G2/M检查点，该检查点由鞍结环分岔表示。该模型的关键特征是在成熟促进因子（MPF）激活后期促进复合体（APC）的过程中引入了时间滞后。这是通过在APC的激活步骤中将MPF视为一个具有时间延迟的变量来实现的。时间滞后充当纺锤体检查点。没有时间延迟会在我们的模型中诱导双稳态。时间延迟还会导致G1期时间的变异性。该模型还重现了对wee1细胞的突变体表型实验。已在模型中引入随机性以模拟周期时间对细胞出生长度的依赖性。随机模型中的突变体表型比确定性模型更能重现实验观察结果。
