1. Cell cycles and clocking mechanisms in systems biology ESE 680 – 003 : Systems Biology Spring 2007

2. Cell cycles Cell division is a well organized cycle. Stages in the cycle: G1 (gap) = cell grows in volume S (synthesis) = the DNA replicates G2 (gap) = the cell prepares to divide M (mitosis) = the cell divides

3. Cell cycles regulation The regulation of cell cycles is very complex. Errors can lead to diseases, such as cancer. The main regulator proteins are called cyclin. There are various checkpoints on the cell cycle to make sure that the process is proper. DNA integrity Cell/cytoplasmic volume check: based on the DNA density

4. Cell cycles regulation Different cyclins bind with CDK (cyclin dependent kinase) and activate different transcription factors during different stages. There are a number of proteins that function as “integrity check”. p53: level increases with DNA is damaged (UV radiation, chemical agents,etc), can block cell cycle and trigger apoptosis. p27: can block entry into S (synthesis) phase.

5. Cell division cycle Eukaryotes cell cycles have a generic underlying structure.

6. Cell cycle regulatory network 1 2 3 4 5 6 7 8 10 1113 12 9

7. The modules Modules 4,10,13: synthesis and degradation of cyclins. Modules 1 and 2: degradation of CycB Module 8: synthesis and degradation of CKI. CKI inhibits CDK through stoichiometric inhibition (modules 6,9,12). Modules 3,7,11: regulation of cyclins and CKI transcription factors. Module 5: inhibition of CycB by phosporylation

8. Phosporylated states of CycB Y = tyrosine T = threonine [Borisuk1998]

9. Feedback loops CycB  TFB  CycB CycB  Cdc25  CycB CKI --| CycB --| CKI Cdh1 --| CycB --| Cdh1 CycB  APC  Cdc20 --| CycB CycB  APC  Cdc20  Cdc14 --| CycB TFE  CycA --| TFE

10. Cell cycle regulatory network 1 2 3 4 5 6 7 8 10 1113 12 9

11. Role of cell growth Cell cycle has to be synch’ed with cell growth/size. Erroneous synch leads to improper cell sizes. Influences of cell growth to kinetics: Larger cell  more ribosomes  faster cyclins synthesis. Cyclins are nucleus bound. Larger cell implies higher ‘effective’ concentration. Empirical proof [Cross2002].

12. Various roles in the network

13. Synthesis rate as control variable Different cyclin synthesis rates lead to different behavior of the network. Frog egg model: modules 1,4,5 [Borisuk1998] -Low stable : interphase arrest -Hi stable: metaphase arrest -Oscillation: fertilized egg, mitosis.

14. Bifurcation diagram

15. Fission yeast cell cycle Consists of modules 1,2,4,5,6,8,11,12,13. Initiate growth at mass = 2.2. SN1 = transition from G1 to S. SN2 = transition from G2 to M. Surge in CycB triggers mitosis, cell divides. A period of G1-like transient follows.

16. Cell cycle regulatory network 1 2 4 5 6 8 1113 12

17. Mutant behavior Mutant type: reduce/increase the activity of wee1. Reduced/increased wee1 shifts SN2 relatively w.r.t. SN1. Increased wee1 leads to larger cells and vice versa.

18. Budding yeast cell cycles Include all modules, except for 9. Regulation of cell size.

19. Cell cycle regulatory network 1 2 3 4 5 6 7 8 10 1113 12 9

20. Cell size regulation

21. Mammalian cell cycles Includes all modules, except 7. There is no stable G2 phase.