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Publications of Eduardo D. Sontag jointly with J. R. Pomerening
Articles in journal or book chapters
J. R. Pomerening,
and J. E. Ferrell.
Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2.
Nature Cell Biology,
Note: Supplementary materials 2-4 are here: http://sontaglab.org/FTPDIR/pomerening-sontag-ferrell-additional.pdf.
Keyword(s): systems biology,
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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