A kinetic model of the cyclin E/Cdk2 developmental timer in Xenopus

A kinetic model of the cyclin E/Cdk2 developmental timer in Xenopus

Model Status

This CellML version of the model has been checked in PCEnv and the model runs to replicate the results in the original published paper. This models uses the initial conditions that recreate the results in figure 6. The model runs in COR but the duration of the model is too long for the results to be properly displayed in COR.

ValidateCellML verifies this model as valid CellML with consistent units.

Model Structure

The cell cycle in Xenopus embryos has been the subject of several experimental and theoretical studies. Following fertilisation, the egg and sperm nuclei undergo DNA replication, nuclear fusion and the first mitotic cellular division. The next 11 embryonic cell cycles are rapid, synchronous oscillations between DNA replication and mitosis, lacking the usual intervening gap phases, cell growth and cell cycle checkpoints. After the 12th division, the Xenopus embryo undergoes the midblastula transition (MBT), when cells become motile, embryonic transcription begins and the cell cycle acquires the gap phases and checkpoints of a typical somatic cell.

The mechanisms underlying this cell cycle remodelling are not well understood, but it is thought that they may depend in part on a maternal developmental timer driven by oscillations in the activity of cyclin E/Cdk2. Cdk2 activity oscillates twice per cell cycle, despite a constant level of its partner cyclin E. Cyclin E breaks down at a fixed time after fertilisation, usually around MBT. In an effort to better understand the mechanisms underlying these phenomena, Ciliberto et al. have developed a mathematical model of the cyclin E/Cdk2 developmental timer that describes both the oscillations in Cdk2 activity and the sudden degradation of Cyclin E when the MBT begins (see the figure below). In this mathematical model,

  • oscillations in Cdk2 activity depend on changes in phosphorylation;

  • Cdk2 participates in a negative feedback loop with inhibitory kinase Wee1;

  • cyclin E is cooperatively removed from the oscillatory system; and

  • removed cyclin E is degraded by a pathway activated by cyclin E/Cdk2 itself.

The complete original paper reference is cited below:

A kinetic model of the cyclin E/Cdk2 developmental timer in Xenopus laevis embryos Andrea Ciliberto, Matthew J. Petrus, John J. Tyson, and Jill C. Sible, 2003, Biophysical Chemistry , 104, 573-589. PubMed ID: 12914904

A theoretical molecular mechanism of the cyclin E/Cdk2 developmental timer was used to construct the mathematical model. The dashed box represents a mechanism for removing cyclin E/Cdk2 from the oscillatory subsystem, which is activated by the "removed" form of cyclin E/Cdk2. The removal step is cooperative in that the more cyclin E/Cdk2 there is bound to the dashed box, the faster is the association reaction. A kinase (Kin) is introduced between cyclin E/Cdk2 and Wee1 to create a time lag in the negative feedback loop.