Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2

Abstract

In the early embryonic cell cycle, Cdc2–cyclin B functions like an autonomous oscillator, whose robust biochemical rhythm continues even when DNA replication or mitosis is blocked1. At the core of the oscillator is a negative feedback loop; cyclins accumulate and produce active mitotic Cdc2–cyclin B2,3; 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 (refs 5–7) and inactivating its inhibitors Wee1 and Myt1 (refs 8–11). Under the correct circumstances, these positive feedback loops could function as a bistable trigger for mitosis12,13, and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation14,15,16,17. Therefore, we examined whether Cdc2 activation is bistable. We confirm that the response of Cdc2 to non-degradable cyclin B is temporally abrupt and switch-like, as would be expected if Cdc2 activation were bistable. We also show 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.

Cite this article

Pomerening, J., Sontag, E. & Ferrell, J. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nat Cell Biol 5, 346–351 (2003). https://doi.org/10.1038/ncb954

View full text

>> Full Text:   Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2