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Two Interlinked Bistable Switches Govern Mitotic Control in Mammalian Cells
Scott Rata1, Maria F Suarez Peredo Rodriguez2, Stephy Joseph2
1Department of Biochemistry, University of Oxford, South Park Road, Oxford OX1 3QU, UK.
Current Biology : CB
|November 20, 2018
Summary
Cell cycle regulation involves a bistable switch controlling Cdk1 activity and PP2A:B55 phosphatase activity. Mutual inhibition between these systems creates hysteresis, crucial for cell cycle memory and potentially exploitable for cancer therapy.
Area of Science:
- Cell Biology
- Molecular Biology
- Systems Biology
Background:
- Cell cycle progression relies on precise regulation of protein phosphorylation.
- Cyclin-dependent kinase 1 (Cdk1) activity is tightly controlled.
- Bistability in Cdk1 activation and PP2A:B55 phosphatase activity has been observed.
Purpose of the Study:
- To investigate the interplay between Cdk1 and PP2A:B55 regulation in human cells.
- To explore the mechanisms underlying cell cycle bistability and hysteresis.
- To assess the therapeutic potential of targeting cell cycle regulatory kinases.
Main Methods:
- Quantitative cell biology assays using ATP-analog-sensitive Cdk1 mutants.
- Mathematical modeling of feedback loops controlling Cdk1 and PP2A:B55.
- Measurement of mitotic entry and exit thresholds.
Main Results:
- The mitotic switch exhibits hysteresis and bistability, responding differently to Cdk1 inhibition in interphase and M phase.
- Cdk1 activation (Wee1/Cdc25) and PP2A:B55 inactivation (Greatwall) independently contribute to hysteresis.
- Eliminating both Cdk1 and PP2A:B55 inactivation abolishes bistability, indicating mutual inhibition is key.
- A model predicts a hidden intermediate steady state between interphase and M phase.
Conclusions:
- Hysteresis in cell cycle control is an emergent property of mutual inhibition between Cdk1 and PP2A:B55 feedback loops.
- Dual inhibition of Wee1 and Greatwall kinases leads to loss of cell cycle memory and synthetic lethality.
- Targeting these kinases offers a potential therapeutic strategy for cancer treatment.
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