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Network Dynamics and Cell Physiology

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Title: Sniffers, Buzzers, Toggles & Blinkers: Feedback Control in Biological Signaling Pathways Last modified by: John Tyson Created Date: 6/5/2005 6:21:25 PM – PowerPoint PPT presentation

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Title: Network Dynamics and Cell Physiology


1
Network Dynamics andCell Physiology
  • John J. Tyson
  • Department of Biological Sciences
  • Virginia Bioinformatics Institute

2
Signal Transduction Network
Hanahan Weinberg (2000)
3
Gene Expression
Signal-Response Curve
S
R
Lever
4
Protein Phosphorylation
Kinase
ADP
ATP
R
RP
H2O
Pi
Phosphatase
Goldbeter Koshland (1981)
5
Protein Synthesis Positive Feedback
S
Open
R
EP
E
Closed
Bistability
Fuse
Griffith (1968)
6
(No Transcript)
7
Solomons protocol for cyclin-induced
activation of MPF
Solomon et al. (1990) Cell 631013.
Ca2
centrifuge
Wee1
Cyclo- heximide
Cdk1
Cdc25
cytoplasmic extract
no synthesis of cyclin
pellet
no degradation of cyclin
8
Threshold
Solomon et al. (1990) Cell 631013.
CDK activity
Novak Tyson (1993) J. Cell Sci. 1061153
Cyclin (nM)
Sha et al., PNAS 100975-980 (2003)
Pomerening et al., Nature Cell Biology 5346-351
(2003)
9
The activation threshold for Mitosis I is between
32 and 40 nM.
16
24
32
0
D90 cyclin B (nM)
40
0 min
90 min
M
D90 cyclin B (nM)
10
negative feedback loop
MPF
cyclin
11
Pomerening, Kim Ferrell Cell (2005)
12
Dynamical Perspective onMolecular Cell Biology
MPF
Cyclin
  • Vector Field, Steady State, Bifurcation

13
Wee1
Cdc25
d MPF dt
k1 - (kwee k2) MPF k25 (cyclin - MPF)
k1 - k2 cyclin
d cyclin dt
14
dx/dtf(x,y)
Phase Plane
dy/dtg(x,y)
(xo,yo)
MPF
Cyclin
15
One-parameter bifurcation diagram
(response)
ON
OFF
(signal)
16
dx/dtf(x,y)
Phase Plane
dy/dtg(x,y)
MPF
Cyclin
17
dx/dtf(x,y)
Phase Plane
dy/dtg(x,y)
MPF
Cyclin
18
dx/dtf(x,y)
Phase Plane
dy/dtg(x,y)
MPF
Cyclin
19
Hopf Bifurcation
20
supercritical
21
subcritical
22
(No Transcript)
23
SNIC Bifurcation
Invariant Circle
Limit Cycle
24
(No Transcript)
25
Review
Molec Genetics Biochemistry
Cell Biology
Molecular Mechanism
Kinetic Equations
State Space, Vector Field
Attractors, Transients, Repellors
Bifurcation Diagrams
26
The Cell Cycle of Fission Yeast
27
G1
cell division
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 ...
S
DNA replication
M mitosis
G2
28
Wee1
P
mass/nucleus
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
Fission Yeast
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
29
The mathematical model
30
S
G2
M
G1
S
G2
M
G1
S
5
mass/nucleus
4
3
2
1
0
CKI
Cdh1
Cdc20
Wee1
Cdc25
Time (min)
31
Mutants in Fission Yeast
32
Wee1
P
mass/nucleus
Cdc20
Cdc14
TFBA
neg fdbk osc
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
bistable switch
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
bistable switch
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
Fission Yeast
CycD
CycB
CycA
TFEI
33
(No Transcript)
34
3.0
Wild type
M
Balanced Growth and Division
0.8
Cdk1CycB
0.4
S/G2
G1
0
0
1
2
3
4
5
mass/nucleus
35
3.0
Wild type
M
Alternation of S phase and M phase
0.8
Cdk1CycB
0.4
S/G2
G1
0
0
1
2
3
4
5
mass/nucleus
36
Nature, Vol, 256, No. 5518, pp. 547-551, August
14, 1975
Genetic control of cell size at cell division in
yeast Paul Nurse Department of Zoology, West
Mains Road, Edinburgh EH9 3JT, UK
wild-type wee1D
37
Wee1
P
mass/nucleus
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
38
wee1?
M
Cdk1CycB
S/G2
G1
mass/nucleus
39
Wee1
P
mass/nucleus
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
40
cki?
M
Cdk1CycB
S/G2
G1
mass/nucleus
41
Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
42
cki? wee1ts
2.0
0.8
M
Cdk1CycB
0.4
S/G2
G1
0
0 1 2 3 4 5
mass/nucleus
43
The Cell Cycle of Budding Yeast
44
Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
mass/nucleus
CycA
CycE
TFEA
Growth
CycD
CycB
CycA
TFEI
45
Wild type cells
M
MDT 90 min 120 min 150 min
S/G2
CycB-dependent kinase activity
G1
mass
SNIPER
46
CycB
G1
Period
180
150
time (min)
120
90
60
0
1
2
3
4
cell mass (au.)
47
ckiD
cdh1D
CycB-dependent kinase activity
lack of one of the G1 enemies viable
mass
mass
mass
mass
cdc20D
cdc14D
CycB-dependent kinase activity
Incomplete CycB destruction
No CycB destruction
mass
mass
48
Defects in Exit from Mitosis
APC-A cdh1D
wild-type
A
D
MDT 300 min 200 min 150 min 120 min 90 min
D
CycB-dependent kinase activity
CLB2Ddb
cdc20ts pds1D
E
F
cell mass (au.)
49
Two-parameter bifurcation diagram
SN
SL
CF
BISTABILITY
SN
50
GENETICS
activation
Cdh1
synthesis
Cki
cell mass (au.)
cell mass (au.)
PHYSIOLOGY
activation
Cdc14
Cdc20
synthesis
cell mass (au.)
cell mass (au.)
51
(No Transcript)
52
The Dynamical Perspective
Molec Genetics Biochemistry
Cell Biology
Molecular Mechanism
Kinetic Equations
State Space, Vector Field
Attractors, Transients, Repellors
Bifurcation Diagrams
Signal-Response Curves
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