2. Béla Novák Molecular Network Dynamics Research Group Hungarian Academy of Sciences and Budapest University of Technology and Economics Béla Novák Molecular Network Dynamics Research Group Hungarian Academy of Sciences and Budapest University of Technology and Economics Collaborator: John J. Tyson Department of Biology Virginia Polytechnic Institute and State University Collaborator: John J. Tyson Department of Biology Virginia Polytechnic Institute and State University The Eukaryotic Cell Cycle: molecules, mechanisms, modules and mathematical models The Eukaryotic Cell Cycle: molecules, mechanisms, modules and mathematical models

3. DNA mRNA protein The central dogma

4. DNA mRNA protein cell physiology protein network A B C D Beyond the central dogma

5. Hanahan & Weinberg, 2000

6. The cell cycle S M The cell cycle is the sequence of events whereby a growing cell replicates all its components and divides them more-or-less evenly between two daughter cells...

7. G1 G2 Cdk CycB

8. Cdk CycB G1 G2 cell mass doubling time + + Start G2/M exit

9. G1 G2 + Cdk CycB pheromone -

10. Cdk CycB G1 G2 inhibitor - Start

11. Cdk CycB G1 G2 inhibitor - Start G2/M

12. Start CKI Cdk CycB CKI P AA Exit APC M Cdk G2/M P Cdc25 Wee1 Cdk CycB APC G1 Cdk CycB AA Cdk CycB

13. Regulatory feedback loops X Y - - X Y + + Positive feedback loop X Y + - Negative feedback loop X Y + -

14. Start CKI Cdk CycB CKI P AA Exit APC M Cdk G2/M P Cdc25 Wee1 Cdk CycB APC G1 Cdk CycB AA Cdk CycB inactive Wee1 P inactive Cdc25 P inactive APC M delay inactive APC G1 inactive

15. ? fission yeast budding yeast

16. Mutants in Fission Yeast gene viability trait cdc2 - noblock in G1 and G2 cdc13 - noendoreplication rum1 - yessterile ste9 - yessterile wee1 - yessmall cells cdc25 - noblock in G2 cdc2 op yeswt cdc13 op yeswt rum1 op noendoreplication ste9 op noendoreplication wee1 op yeslarge cells cdc25 op yessmall cells wee1 - rum1  noextremely small wee1 - cdc25  yesquantized cycles wee1 - cdc25 op nomitotic catastrophe

17. period of oscillation = cycle time = doubling time (t D ) tDtD mass (m) period dm/dt =  m where  = ln2/t D rate ~ mass APC M Cdk CycB APCG1 CKI S/G2G1M time (min) M CycB

18. tDtD mass (m) period dm/dt =  m where  = ln2/t D APC G1 Cdk CycB APC M CycB CKI S/G2G1M time (min) M mass Size control over the cell cycle rate ~ mass

19. Inside view ?

20. Start CKI Cdk CycB CKI P AA Exit APC M Cdk P Cdc25 Wee1 Cdk CycB APC G1 Cdk CycB AA Cdk CycB Wee1 P Cdc25 P APC G1 APC M delay cell mass Cdk/CycB cell mass Cdk/CycB cell mass Cdk/CycB G2/M

21. stable s.s. unstable s.s. min/max  Cdk/CycB G1 S/G2 M cell mass Bifurcation diagram of the cell cycle control network

22. stable s.s. unstable s.s. min/max  Cdk/CycB G1 S/G2 M cell mass Cell cycle regulation on the bifurcation diagram dividing cell newborn cell Start G2/M Exit

23. G1 S/G2 0.4 0 0.8 1.2 1.6 02 4 3 1 5 M metaphase checkpoint cell mass Cdk/CycB G2/M Exit

24. John Tyson Attila Csikász-Nagy Béla Győrffy Ákos Sveiczer Kathy Chen Attila Tóth Laurence Calzone Andrea Ciliberto Jason Zwolak Chris Hong

25. Homepage:http://www.cellcycle.bme.hu/Homepage:http://www.cellcycle.bme.hu/ Hungarian Academy of Sciences Supporting agencies:

26. Béla Novák Molecular Network Dynamics Research Group Hungarian Academy of Sciences and Budapest University of Technology and Economics Béla Novák Molecular Network Dynamics Research Group Hungarian Academy of Sciences and Budapest University of Technology and Economics Modelling the cell division cycle Paul Nurse Frank Uhlmann