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Cell cycles and clocking mechanisms in systems biology
ESE 680 – 003 : Systems Biology
Spring 2007
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
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
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.
Cell division cycle
Eukaryotes cell cycles have a generic underlying structure.
Cell cycle regulatory network
12
3
4
5 67
8
10 11 13
129
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
Phosporylated states of CycB
Y = tyrosine
T = threonine
[Borisuk1998]
Feedback loops
CycB TFB CycB CycB Cdc25 CycB CKI --| CycB --| CKI Cdh1 --| CycB --| Cdh1 CycB APC Cdc20 --| CycB CycB APC Cdc20Cdc14 --| CycB TFE CycA --| TFE
Cell cycle regulatory network
12
3
4
5 67
8
10 11 13
129
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].
Various roles in the network
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.
Bifurcation diagram
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.
Cell cycle regulatory network
12
4
5 6
8
11 13
12
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.
Budding yeast cell cycles
Include all modules, except for 9. Regulation of cell size.
Cell cycle regulatory network
12
3
4
5 67
8
10 11 13
129
Cell size regulation
Mammalian cell cycles
Includes all modules, except 7.
There is no stable G2 phase.