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

Nat Cell Biol. 2003 Apr;5(4):346-51. doi: 10.1038/ncb954.

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 blocked. At the core of the oscillator 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 feedback, 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 mitosis, and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Clocks / drug effects
  • Biological Clocks / genetics*
  • CDC2-CDC28 Kinases*
  • Cell Cycle / drug effects
  • Cell Cycle / genetics*
  • Cell Extracts / pharmacology
  • Cyclin B / genetics*
  • Cyclin B / metabolism*
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / genetics*
  • Cyclin-Dependent Kinases / metabolism*
  • Eukaryotic Cells / drug effects
  • Eukaryotic Cells / enzymology*
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / genetics*
  • Female
  • Mitosis / drug effects
  • Mitosis / genetics
  • Models, Biological
  • Oocytes
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism*
  • Reaction Time / drug effects
  • Reaction Time / genetics
  • Xenopus Proteins
  • Xenopus laevis

Substances

  • Cell Extracts
  • Cyclin B
  • Xenopus Proteins
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cdk2 protein, Xenopus
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases