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

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Presentation on theme: "Modeling the Cell Cycle Engine of Eukaryotes John J. Tyson & Bela Novak Virginia Polytechnic Institute & State Univ. Budapest Univ. Technology & Economics."— 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 S cell division G1 (DNA synthesis) G2 M (mitosis)

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

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

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

7

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

9 centrifuge Solomon’s protocol for cyclin-induced activation of MPF cytoplasmic extract pellet Ca 2+ M Cyclin Cyclo- heximide Cdk1 Wee1 Cdc25 Cyclin Cdk1 no synthesis of cyclin no degradation of cyclin

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

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

12 TiTi TaTa T cyclin level MPF activity hystereticnon-hysteretic 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 251:1076-1078. Tyson (1991). “Modeling the cell division cycle: cdc2 and cyclin interactions,” PNAS 88:7328-7332. Goldbeter (1991). “A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase,” PNAS 88:9107-9111. Novak & Tyson (1993). “Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos,” J. Cell Sci. 106:1153-1168. Thron (1996). “A model for a bistable biochemical trigger of mitosis,” Biophys. Chem. 57:239-251. Thron (1997). “Bistable biochemical switching and the control of the events of the cell cycle,” Oncogene 15:317-325.

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

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

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

17 The mathematical model synthesisdegradation synthesis degradation binding activation inactivation

18 Time (min) CKI mass Clb2 Cln2 Cdh1 Simulation of the budding yeast cell cycle G1S/M Cdc20

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…”

21 Differential equations Parameter values k1 = 0.0013, 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 Cdk CycB Cdh1 CKI Cdc20 Cln Cdk +APC Cln Cdk +APC CKI

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

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

25 P Wee1 P Cdc25 Wee1 G2/M Cdc2 CycB P Cdc2 CycB ??? molecules physiology From molecular networks to cell physiology… 0 0.2 0.4 0.6 0.8 1.0 0102030 time (min) MPF differential equations simulation & analysis

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


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