Bistability in the G1-to-S phase transition of the Cell cycle of C.elegans – Tim van Mourik

It is commonly thought that every transition in the cell cycle must be bistable since it is dangerous to turn back after you entered the next phase of the cell cycle. In the G1 phase it is thought that the bistability is dependent on the retinoblastoma protein (RB). RB is known to sequester a transcription factor that induces CYE expression. Once a cell is ready for the transition the G1 cell cycle dependent kinase (CYD/CDK4) phosphorylates RB which results in the release of the transcription factor that induces CYE expression. CYE in turn activates the G1/S cell cycle dependent kinase (CDK2) which also phosphorylates RB, creating a positive feedback loop. I used Boolean network analysis and ODE analysis in XPP to show that shows a bistable behavior with hysteresis. Low CYD results in low CYE, once CYD is turned on CYE is high but turning CYD off doesn’t lead to a significant decrease of CYE.

However from experiments we know that there is another pathway wherein CDH1 targets CYE for degradation. Phosphorylation of CDH1 by CYD/CDK4 and CYE/CDK2 leads to inactivation of CDH1.

If the transition of G1 to S-Phase is bistable, the CDH1 branch is supposedly also bistable otherwise there will be degradation of CYE once the CYD signal is turned off. I tested this hypothesis with ODEs in XPP and found that the CDH1 branch indeed has an bistability domain dependent on the levels of CYD.

Next I translated the whole system into a Boolean network. And analysis of this systems shows that the G1-to-S phase transition is indeed bistable and depends on both the RB branch and the FzR branch.

Next I transferred the whole ODE system to COPASY and tried to use time courses from the single branches made in XPP to estimate the parameters of the full system. This system showed with this parameter setting that the bistability is mainly dependent on the pRB branch. This suggests that if you ectopically boost CYE mRNA production, you should be able to artificially induce the G1-to-S phase transition.

I planned to do a parameter sensitivity analysis to see how robust the system is but unfortunately I didn’t have enough time for doing this.


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