Uncovering mechanisms of bistability in biological systems.

As the systems biology era progresses, theoreticians and experimentalists continue uncovering the molecular mechanisms that underlie the regulation of complex cellular phenomena, including those governing proliferation, differentiation, and death. The discovery of bistability in cellular responses and their signaling pathways has become a recurring theme, and prompted strong interest in understanding both the design and function of these networks. Modeling these systems has been crucial in assisting experimentalists to better understand how this and other types of behavior can emerge from a subset of regulators, and also to analyze and identify systems-level characteristics that would otherwise be difficult to intuit. In this review, recent advances in both theoretical and experimental work investigating the mechanistic as well as biological basis for bistability will be presented. These will include the role of positive feedback loops, the potential function of dual phosphorylation cycles, and substrate competition as a means of generating ultrasensitivity.