System Biology of Cellular Rhythms: Modeling the Dynamics of the Mammalian Cell Cycle

摘要: Cellular rhythms originate from the regulatory feedback loops that control the dynamics of biochemical processes and represent a phenomenon of temporal self-organization. They illustrate how an emergent property, autonomous oscillatory behavior, arises from molecular interactions in regulatory networks. This explains why oscillatory phenomena abound at the cellular level. After providing an overview of biological rhythms and of their underlying mechanisms, I will focus on the cell cycle, which provides a major example of rhythmic behavior at the cellular level. The mammalian cell cycle, driven by an enzymatic network of cyclindependent kinases, behaves as a self-sustained oscillator. A detailed computational model shows that the regulatory structure of this network results in its temporal self-organization in the form of sustained oscillations that bring about the orderly progression along cell cycle phases. The coupling of the cell cycle to the circadian clock results in the synchronization of these two major cellular rhythms. To understand the dynamics of the cell cycle we need to characterize the balance between cell cycle arrest and cell proliferation, which is often deregulated in cancers. We address this issue by means of the detailed computational model for the network of cyclin-dependent kinases (Cdks) driving the mammalian cell cycle. Previous analysis of the model focused on how this balance is controlled by growth factors or by the levels of activators (oncogenes) and inhibitors (tumor suppressors) of cell cycle progression. Suprathreshold changes in the level of any of these factors can trigger a switch in the dynamical behavior of the Cdk …