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Cell cycles and clocking mechanisms in systems biology

This article discusses the regulation and control of cell cycles in systems biology, including the stages of the cell cycle, the role of cyclin proteins, and the importance of DNA integrity. It also explores different cell cycle regulatory networks and their modules, the role of cell growth in cell cycle kinetics, and the behavior of mutant cells. Additionally, it examines cell size regulation in budding yeast and mammalian cell cycles.

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Cell cycles and clocking mechanisms in systems biology

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  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.

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