Systems-level feedbacks in the control of cell proliferation
Cell cycle progression in eukaryotes is controlled by a seemingly universal protein interaction network composed of protein kinases and phosphatases, transcription factors, ubiquitin-conjugating enzymes, and stoichiometric inhibitors. These molecular interactions embody a dynamical system that (when all is well) oscillates once per cell cycle. When genomic integrity is in jeopardy, however, the oscillation ceases immediately at checkpoints until the problem can be resolved. Fundamental for the cell cycle oscillation is the negative feedback loop by which Cdk1/CycB promotes CycB degradation via activation of
APC/C (Anaphase Promoting Complex/Cyclosome). I will argue that bistable (‘toggle’) switches are also important design principles of eukaryotic cell cycle control network. A bistable switch arises as a consequence of positive or double-negative feedback loops. A bistable switch is characterized by two alternative steady states which could represent active and inactive states of regulatory molecules, corresponding to different phases of the cell cycle. Bistable cell cycle switches provide conceptual framework for unidirectional progression through the cell cycle and underlie G1/S and G2/M transitions as well as Start/Restriction Point and mitotic exit. The meta/anaphase transition guarded by the spindle assembly checkpoint is also characterized by a ‘toggle’ switch. I will also discuss the prophase/metaphase-I transition of budding yeast meiosis based on our work with Wolfgang Zachariae.