No abstract

Cellular rhythms are generated by complex interactions among genes, proteins and metabolites. They are used to control every aspect of cell physiology from signaling, motility and development to growth, division and death. By considering specific examples of oscillatory processes, we pick out three general requirements for biochemical oscillations: delayed negative feedback, sufficient ‘nonlinearity’ of the reaction kinetics, and proper balancing of the time-scales of opposing chemical reactions. Positive feedback is one mechanism to delay the negative feedback signal. Biological oscillators can be classified according to the topology of the positive and negative feedback loops in the underlying regulatory mechanism.

The adaptive responses of a living cell to internal and external signals are controlled by networks of proteins whose interactions are so complex that the functional integration of the network cannot be comprehended by intuitive reasoning alone. Mathematical modeling, based on biochemical rate equations, provides a rigorous and reliable tool for unraveling the complexities of molecular regulatory networks. The budding yeast cell cycle is a challenging test case for this approach, because the control system is known in exquisite detail and its function is constrained by the phenotypic properties of >100 genetically engineered strains. We show that a mathematical model built on a consensus picture of this control system is largely successful in explaining the phenotypes of mutants described so far. A few inconsistencies between the model and experiments indicate aspects of the mechanism that require revision. In addition, the model allows one to frame and critique hypotheses about how the division cycle is regulated in wild-type and mutant cells, to predict the phenotypes of new mutant combinations, and to estimate the effective values of biochemical rate constants that are difficult to measure directly in vivo.