1. D. Angeli, J. E. Ferrell, and E.D. Sontag. Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems.. Proc Natl Acad Sci USA, 101(7):1822-1827, 2004. Note: A revision of Suppl. Fig. 7(b) is here: http://sontaglab.org/FTPDIR/nullclines-f-g-REV.jpg; and typos can be found here: http://sontaglab.org/FTPDIR/angeli-ferrell-sontag-pnas04-errata.txt. [WWW] [PDF] [doi:10.1073/pnas.0308265100] Keyword(s): MAPK cascades, multistability, systems biology, reaction networks, nonlinear stability, dynamical systems, monotone systems. Abstract:

   Multistability is an important recurring theme in cell signaling, of particular relevance to biological systems that switch between discrete states, generate oscillatory responses, or "remember" transitory stimuli. Standard mathematical methods allow the detection of bistability in some very simple feedback systems (systems with one or two proteins or genes that either activate each other or inhibit each other), but realistic depictions of signal transduction networks are invariably much more complex than this. Here we show that for a class of feedback systems of arbitrary order, the stability properties of the system can be deduced mathematically from how the system behaves when feedback is blocked. Provided that this "open loop," feedback-blocked system is monotone and possesses a sigmoidal characteristic, the system is guaranteed to be bistable for some range of feedback strengths. We present a simple graphical method for deducing the stability behavior and bifurcation diagrams for such systems, and illustrate the method with two examples taken from recent experimental studies of bistable systems: a two-variable Cdc2/Wee1 system and a more complicated five-variable MAPK cascade.




2. J. R. Pomerening, E.D. Sontag, and J. E. Ferrell. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nature Cell Biology, 5(4):346-351, 2003. Note: Supplementary materials 2-4 are here: http://sontaglab.org/FTPDIR/pomerening-sontag-ferrell-additional.pdf. [WWW] [PDF] [doi:10.1038/ncb954] Keyword(s): systems biology, reaction networks, oscillations, nonlinear stability, dynamical systems, monotone systems. Abstract:

   In the early embryonic cell cycle, Cdc2-cyclin B functions like an autonomous oscillator, at whose core is a negative feedback loop: cyclins accumulate and produce active mitotic Cdc2-cyclin B Cdc2 activates the anaphase-promoting complex (APC); the APC then promotes cyclin degradation and resets Cdc2 to its inactive, interphase state. Cdc2 regulation also involves positive feedback4, with active Cdc2-cyclin B stimulating its activator Cdc25 and inactivating its inhibitors Wee1 and Myt1. Under the correct circumstances, these positive feedback loops could function as a bistable trigger for mitosis, and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation. This paper examined whether Cdc2 activation is bistable, confirming that the response of Cdc2 to non-degradable cyclin B is temporally abrupt and switchlike, as would be expected if Cdc2 activation were bistable. It is also shown that Cdc2 activation exhibits hysteresis, a property of bistable systems with particular relevance to biochemical oscillators. These findings help establish the basic systems-level logic of the mitotic oscillator.

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