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Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations
Published on: September 17, 2012
Theoretical dynamics of the cyclin B-MPF system: a possible role for p13suc1
1Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755-3835.
Abstract:
In dividing cells, entry into mitosis is caused by maturation promoting factor (MPF), which is formed autocatalytically by activation of a complex of p34cdc2 and cyclin B. This biochemical system may oscillate, causing repeated mitosis. It is shown mathematically that the oscillatory tendency would be enhanced by a cofactor which binds to MPF and inhibits its autocatalytic action. A candidate for such a cofactor is the suc1 gene product p13, which binds to p34cdc2/cyclin B complex and inhibits MPF-induced MPF activation. At a steady rate of cyclin biosynthesis, with small amounts converted to MPF, p13suc1 would have to be titrated by MPF before autocatalysis could begin. This would have three possibly important effects: (1) it would determine the 'threshold' cyclin accumulation (and hence the corresponding time-delay) for MPF activation; (2) it would cause the accumulation of a backlog of MPF precursor (tyrosine-phosphorylated p34cdc2/cyclin B) sufficient to produce a substantial MPF pulse when MPF autocatalysis begins; (3) it would give the autocatalysis a high reaction order, which tends to destabilize the steady state, promote autonomous oscillations, and enhance the triggering property (excitability) of the system. The MPF pulse generated by this system may be essential for the proper triggering of the events of M phase, including the cyclin degradation which inactivates MPF at the end of M phase. This model offers explanations for several puzzling effects of p13suc1, including the fact that p13suc1, though an inhibitor of MPF activation, is nevertheless necessary for mitosis.
Insights
The suc1 gene product p13 enhances cell division oscillations by inhibiting maturation promoting factor (MPF) activation. This inhibition is crucial for regulating MPF pulses, ensuring proper mitosis progression and cyclin degradation.
Area of Science:
- Cell Biology
- Biochemistry
- Mathematical Modeling
Background:
- Cell division is regulated by maturation promoting factor (MPF), a complex of p34cdc2 and cyclin B.
- MPF activation is autocatalytic and can lead to oscillations, potentially causing repeated mitosis.
Purpose of the Study:
- To investigate the role of cofactors in regulating MPF-mediated cell cycle oscillations.
- To mathematically model the effect of p13suc1 on MPF activation and its impact on mitosis.
Main Methods:
- Mathematical analysis of a biochemical system involving MPF, p34cdc2, cyclin B, and p13suc1.
- Modeling the autocatalytic activation of MPF and the influence of inhibitory cofactors.
Main Results:
- p13suc1 acts as a cofactor that enhances oscillatory tendencies by inhibiting MPF autocatalytic action.
- p13suc1 titration by MPF determines the threshold for MPF activation, creating a precursor backlog and a high reaction order for MPF autocatalysis.
- This mechanism promotes autonomous oscillations and enhances system excitability, contributing to proper M phase progression.
Conclusions:
- The p13suc1 cofactor plays a critical role in regulating MPF pulses, essential for triggering M phase events and subsequent cyclin degradation.
- The model explains the seemingly paradoxical necessity of p13suc1 for mitosis, despite its inhibitory effect on MPF activation.
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