Kohn K W
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Oncogene. 1998 Feb 26;16(8):1065-75. doi: 10.1038/sj.onc.1201608.
The molecular interactions implicated in the mammalian G1/S cell cycle phase transition comprise a highly nonlinear network which can produce seemingly paradoxical results and make intuitive interpretations unreliable. A new approach to this problem is presented, consisting of (1) a convention of unambiguous reaction diagrams, (2) a convenient computer simulation method, and (3) a quasi-evolutionary method of probing the functional capabilities of simplified components of the network. Simulations were carried out for a sequence of hypothetical primordial systems, beginning with the simplest plausibly functional system. The complexity of the system was then increased in small steps, such that functionality was added at each step. The results suggested new functional concepts: (1) Rb-family proteins could store E2F in a manner analogous to the way a condenser stores electric charge, and, upon phosphorylation, release a large wave of active E2F; (2) excessive or premature cyclin-dependent kinase activities could paradoxically impair E2F activity during the G1/S transition period. The results show how network simulations, carried out by means of the methods described, can assist in the design and interpretation of experiments probing the control of the G1/S phase transition.
哺乳动物G1/S细胞周期相变中涉及的分子相互作用构成了一个高度非线性的网络，该网络可能产生看似矛盾的结果，并使直观的解释变得不可靠。本文提出了一种解决该问题的新方法，包括：（1）明确反应图的约定；（2）便捷的计算机模拟方法；（3）一种探索网络简化组件功能能力的准进化方法。针对一系列假设的原始系统进行了模拟，从最简单的可能具有功能的系统开始。然后系统的复杂性以小步骤增加，使得在每个步骤都增加功能。结果提出了新的功能概念：（1）Rb家族蛋白可以以类似于电容器存储电荷的方式存储E2F，并且在磷酸化后释放大量活性E2F；（2）在G1/S过渡期，过量或过早的细胞周期蛋白依赖性激酶活性可能反常地损害E2F活性。结果表明，通过所述方法进行的网络模拟如何能够辅助设计和解释探索G1/S相变控制的实验。
