Case Study: Cell Cycle Control Mechanism - Virginia...
Transcript of Case Study: Cell Cycle Control Mechanism - Virginia...
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Case Study: Cell Cycle Control Mechanism
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Chemostat
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Chemostat
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Chemostat
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Chemostat
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Chemostat
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S
DNA synthesis
G2
G1
cell division +
Metaphase
Anaphase
Telophase
Prophase
The cell cycle is the sequence of events whereby a growing cell replicates all its components and divides them more-or-less evenly
between two daughter cells ...
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G1
G2
24/0
12
18
G1
M
G2
S
A T
dusk (Checkpoint)
Start Exit
6 dawn
(Clock)
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Diversity of Cell Cycle Organization
Slime Mold
M G2
S
A T
Fission Yeast
M G2
S
A T
Size Control
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Diversity of Cell Cycle Organization
Fission Yeast Fission Yeast wee mutant
WT wee
M G2
S
A T G1
G2
S M
A T
Size Control
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R
S
resp
onse
(R)
signal (S)
linear
Gene Expression
Signal-Response Curve
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R
S
EP E
R
rate
(dR
/dt) S=0
S=8
S=16
resp
onse
(R)
signal (S)
Protein Synthesis: Positive Feedback
Bistability
off
on
Griffith, J Theor Biol (1968)
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R
S2
Cooperative Binding
S+S→
resp
onse
(R)
Signal (S)
sigmoidal
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R
Kinase
RP
ATP ADP
H2O Pi
Protein Phosphorylation
Phosphatase
resp
onse
(RP)
Signal (Kinase)
Goldbeter & Koshland, PNAS (1981)
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Cdc14
Universal Control Mechanism for the Eukaryotic Cell Cycle
Cdk1 CycB
DNA synthesis P P
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X Y X Y X Y
Toggle Switches Homeostasis
CycB Cdc25 CycB Cdh1 CycB APC
CycB
APC
CycB CycB
Cdc25 Cdh1
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P
Cdc25
Wee1
Wee1 P
Cdc25
CycB
P
Cdc20
CK
I
CycB
CycB CK
I
CK
I
CycE
CycE
APC-P APC TFBI
TFBA
CycA E2FA
E2FI
Cyc E,A,B
CycE
TFIA
TFII
CK
I
CycA
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1 CycD
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P
Cdc25
Wee1
Wee1 P
Cdc25
CycB
P
Cdc20
CK
I
CycB
CycB CK
I
CK
I
CycE
CycE
APC-P APC TFBI
TFBA
CycA E2FA
E2FI
Cyc E,A,B
CycE
TFIA
TFII
CK
I
CycA
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1 CycD
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http://mpf.biol.vt.edu 50,000
Detailed Simulations
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P
Cdc25
Wee1
Wee1 P
CycB
P
Cdc20
CK
I
CycB CK
I
CK
I
CycA
CycA
APC-P APC TFBI
TFBA
CycE E2FA
E2FI
Cyc E,A,B
CycE
TFIA
TFII
CK
I
CycE
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1 CycD
Cdc25
Cdc14 CycB
-
-
differential equations
General Principles
X
YP
Y
mechanism
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differential equations
Cyc
B-d
ep k
inas
e
p, parameter
ON
OFF
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high CycB, low Cdh1
low CycB, high Cdh1
Cell Cycle Regulation
CycB
Cdh1
What mechanisms flip the switch up and down?
G2/M
G1
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P
Cdc25
Wee1
Wee1 P
Cdc25
CycB
P
Cdc20
CK
I
CycB
CycB CK
I
CK
I
CycE
CycE
APC-P APC TFBI
TFBA
CycA E2FA
E2FI
Cyc E,A,B
CycE
TFIA
TFII
CK
I
CycA
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1 CycD
-
- -
-
CycB
Cdh1
CycE
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CycB
CycE
Entry
DN
A Synthesis
G1
G2/M
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P
Cdc25
Wee1
Wee1 P
CycB
P
Cdc20
CK
I
CycB CK
I
CK
I
CycA
CycA
APC-P APC TFBI
TFBA
CycE E2FA
E2FI
Cyc E,A,B
CycE
TFIA
TFII
CK
I
CycE
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1 CycD
Cdc25
Cdc14 CycB
-
-
+
+
CycB
Cdh1
Cdc14
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CycB
Cdc14
Exit
Cell D
ivision
G1
G2/M
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CycB
CycE Cdc14
G1 G1
S
G2 M A
T
CycB
Cdh1
CycE Cdc14
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CycE Cdc14
G1 G1
S
G2 M A
T
G1
M
G2
S
A T
Start Exit
CycB
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CycE Cdc14
G1 G1
S
G2 M A
T
G1
M
G2
S
A T
Start Exit
CycB
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CycE Cdc14
G1 G1
S
G2 M A
T
G1
M
G2
S
A T
Start Exit
CycB
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CycE Cdc14
G1 G1
S
G2 M A
T
G1
M
G2
S
A T
Start Exit
CycB
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CycB
CycE Cdc14
G1 G1
S
G2 M A
T
Growth/ Damage
Problems
CycB
Cdh1
CycE Cdc14
Chromosome Alignment Problems