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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
1
2
3
4
7
5
6
8
12
9
10
11
13
The modules

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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
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CycB  TFB  CycB
CycB  Cdc25  CycB
CKI --| CycB --| CKI
Cdh1 --| CycB --| Cdh1
CycB  APC Cdc20 --| CycB
CycB  APC Cdc20Cdc14 --| CycB
TFE  CycA --| TFE
Cell cycle regulatory network
1
2
3
4
7
5
6
8
12
9
10
11
13
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

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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
1
2
4
5
6
8
12
11
13
Mutant behavior


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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
1
2
3
4
7
5
6
8
12
9
10
11
13
Cell size regulation
Mammalian cell cycles

Includes all
modules, except 7.
 There is no stable
G2 phase.