Cell cycles and clocking mechanisms in systems biology

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 7 5 6 8 12 9 10 11 13

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 7 5 6 8 12 9 10 11 13

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 12 11 13

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 7 5 6 8 12 9 10 11 13

20. Cell size regulation

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