Control of mammalian cell

1
Control of mammalian cell proliferation
fibroblasts
2
fission yeast
frog egg
fibroblasts
3
Hanahan Weinberg (2000)
4
Kurt Kohn (1999) Mol Biol Cell
5
CycB
AA
Cdc20
Cdk
Finish
Wee1
Cdc20
P
Cdk
Cdk
Cdk
CycB
CycB
Cdc25
P
Cdh1
G2/M
Cdh1
Cdk
CKI
CycB
P
CKI
CKI
AA
Start
6
Getting in Touch with Your Inner Yeast
7
Cdk4
Cdk4
CycD
CycB/Cdk1 CycA/Cdk2
fast
Cdk2
Cdk2
CycE
CycE
P
Rb
Cdk2
P
P
P
PP1
Cdk2
Kip1
CycB/Cdk1 CycA/Cdk2
CycE
CycE/Cdk2
P
Kip1
Kip1
Kip1
E2F
E2F
fast
Cdk2
Kip1
E2F
P
CycA
Cdc20
Cdk2
CycB/Cdk1 CycA/Cdk2
Cdk2
CycB/Cdk1
CycA
Cdc20
Cdk1
Cdk1
CycB
Cdh1
Cdh1
8
Simulation of mammalian cell cycle
mass
Cdk2
p27
CycE
CycE
total
Rb
Cdk1
CycA/B
APC
Time (h)
9
Cell divides (mitosis)
M
G2
Cell rests
G0
G1
S
Restriction point cell decides whether to commit
itself to complete the cycle
Cell replicates its DNA
10
Cycle time
Size control
Cdh1 off
Time (h)
Rb phosphorylation
Restriction point
Constant timer
Size at Birth
11
Effects of growth factors
growth factor
growth factor receptor
GF

activated intracellular signalling proteins
ERG
-

LRG
degraded CycD


Cdk4
CycD
Cdk4
ERG
LRG
Rb
mRNA
cycD
Cell cycle engine
Protein synthesis
time
12
Zetterberg Larsson
experiment Where is the restriction point? What
is the effect of transient GF deprivation on
cycle time?
cycle time
division delay
treatment
- GF
GF
(Zetterberg, A. Larsson, O. (1985) Kinetic
analysis of regulatory events in G1 leading to
proliferation or quiescence of Swiss 3T3 cells.
Proc. Natl. Acad. Sci. U. S. A., 82 5365-5369)
13
First cell cycle
Experiment
Second cell cycle
Experiment
Simulation
14
Effect of transient (1h) serum deprivation
Age 2h
Age 10h
mass
mass
ERG
LRG
LRG
ERG
APC
APC
Time (h)
Time (h)
15
Growth Factors
CycD
16
mechanism
???
physiology
dynamical systems theory