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Modeling the Cell Cycle Engine of Eukaryotes

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Presentation on theme: "Modeling the Cell Cycle Engine of Eukaryotes"— Presentation transcript:

1 Modeling the Cell Cycle Engine of Eukaryotes
John J. Tyson & Bela Novak Virginia Polytechnic Institute & State Univ. Budapest Univ. Technology & Economics

2 The cell cycle is the sequence of events by which a growing cell replicates all its components and divides them more-or-less evenly between two daughter cells... …so that the two daughter cells contain all the information and machinery necessary to repeat the process.

3 G1 cell division S (DNA synthesis) M (mitosis) G2

4 1. Alternation of S and M phases (DNA synthesis) Unaligned
Too small? DNA damage? G1/S checkpoint cell division S 1. Alternation of S and M phases (DNA synthesis) Unaligned chromosomes? 2. Balanced growth and division Metaphase checkpoint Unreplicated DNA? Too small? M (mitosis) G2 G2/M checkpoint

5 Cyclin-dependent kinase S
G1 cell division Cyclin-dependent kinase S Cdk1 CycB DNA replication Tar Tar- P M (mitosis) G2

6 G1 G1/S cell division S DNA replication Exit M G2 (mitosis) G2/M Cdk1
CycB DNA replication Exit M (mitosis) G2 G2/M


8 cyclin B synthesis cyclin B degradation cyclin B degradation Wee1-P
less active Wee1 Cdk1 CycB P- less active cyclin B degradation Cdk1 CycB active MPF Cdc25-P Cdc25 cyclin B degradation less active

9 no degradation of cyclin
Solomon’s protocol for cyclin-induced activation of MPF Cyclin M Ca2+ centrifuge Wee1 Cyclo- heximide Cyclin Cdk1 Cdk1 Cdc25 cytoplasmic extract no synthesis of cyclin pellet no degradation of cyclin

10 Threshold MPF Cyclin (nM) Solomon et al. (1990) Cell 63:1013.

11 Novak & Tyson (1993) J. Cell Sci. 106:1153 active MPF no synthesis or
Frog egg Novak & Tyson (1993) J. Cell Sci. 106:1153 active MPF no synthesis or degradation of cyclin total cyclin

12 hysteretic non-hysteretic MPF activity MPF activity Ti Ta T cyclin level cyclin level Prediction: The threshold concentration of cyclin B required to activate MPF is higher than the threshold concentration required to inactivate MPF.

13 Norel & Agur (1991). “A model for the adjustment of the mitotic clock by cyclin and MPF levels,” Science 251: Tyson (1991). “Modeling the cell division cycle: cdc2 and cyclin interactions,” PNAS 88: Goldbeter (1991). “A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase,” PNAS 88: Novak & Tyson (1993). “Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos,” J. Cell Sci. 106: Thron (1996). “A model for a bistable biochemical trigger of mitosis,” Biophys. Chem. 57: Thron (1997). “Bistable biochemical switching and the control of the events of the cell cycle,” Oncogene 15:

14 G1 Start cell division S DNA replication Finish M (mitosis) G2 G2/M

15 G1 Start S DNA replication Finish M G2 (mitosis) G2/M CKI Cdh1 Cln2
cell division APC Cdh1 CKI Cln2 S APC Cdc20 Clb5 DNA replication Cdk Finish Clb2 M (mitosis) G2 G2/M

16 Cdk Cdk CycB Cdk CycB Cdk Cln2 CycB P
Cdc20 Cdk Cdk AA CycB Cdk CycB Cdh1 Cdh1 P Cdk Cln2 Cdc14 CKI Cdk CycB AA P CKI CKI Cdc14

17 The mathematical model
synthesis degradation binding activation inactivation

18 Simulation of the budding yeast cell cycle
mass CKI Cln2 G1 S/M Cdh1 Clb2 Cdc20 Time (min)

19 30 equations 100 parameters fitted by brute force
These are the “brutes” Kathy Chen Laurence Calzone

20 Is the model yeast-shaped?
“With four parameters I can fit an elephant…” Is the model yeast-shaped?

21 Differential equations Parameter values
k1 = , v2’ = 0.001, v2” = 0.17, k3’ = 0.02, k3” = 0.85, k4’ = 0.01, k4” = 0.9, J3 = 0.01, J4 = 0.01, k9 = 0.38, k10 = 0.2, k5’ = 0.005, k5” = 2.4, J5 = 0.5, k6 = 0.33, k7 = 2.2, J7 = 0.05, k8 = 0.2, J8 = 0.05,

22 CKI Cln Cdk CKI +APC Cdh1 +APC Cdk Cdc20 Cln Cdk CycB

23 Mutual antagonism and bistability...
Cdk CycB Cdc14 CKI Cdh1 Cln2

24 S/G2/M A/B Start Clb2/Cdk activity Finish G1 A + Cln2 B+Cdc14 time Cln2 Cdc14

25 From molecular networks to cell physiology…
Wee1 0.2 0.4 0.6 0.8 1.0 10 20 30 time (min) MPF differential equations simulation & analysis P Wee1 P Cdc2 Cdc2 CycB CycB Cdc25 P G2/M Cdc25 ??? molecules physiology

26 Our thanks to... National Science Foundation (USA)
National Science Foundation (Hungary) National Institutes of Health James S. McDonnell Foundation Defense Advanced Research Project Agency

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