Network Dynamics and Cell Physiology John J. Tyson Biological Sciences Virginia Tech.
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Transcript of Network Dynamics and Cell Physiology John J. Tyson Biological Sciences Virginia Tech.
![Page 1: Network Dynamics and Cell Physiology John J. Tyson Biological Sciences Virginia Tech.](https://reader035.fdocuments.in/reader035/viewer/2022070306/55173b8c55034603568b6177/html5/thumbnails/1.jpg)
Network Dynamics andNetwork Dynamics andCell PhysiologyCell Physiology
John J. Tyson John J. Tyson
Biological Sciences Biological Sciences
Virginia TechVirginia Tech
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CollaboratorCollaboratorss
Kathy ChenKathy ChenJill SibleJill SibleBela Novak Bela Novak Attila CsikaszAttila Csikasz
Funding Funding AgenciesAgencies
DARPADARPAMcDonnell FoundMcDonnell Found
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Hanahan & Weinberg (2000)
Cell signaling
Externalsignals
InformationProcessing System
Death
DivisionReproduction
GrowthDevelopment
InternalSignals
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Information Processing Systems
Laptop CellSilicon Carbon
Solid state Watery
Programmable Hard-wired
Precise Sloppy
Digital Analog
Sequential Parallel
Manufactured Self-reproducing
Designed Evolved
Silicon Carbon
BrainCarbon
Membrany
Learning
Accurate
Analog/digital
Parallel
Soma/germ
Evolved
Carbon
$$
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Hanahan & Weinberg (2000)
Signal Transduction Network
p21
Smad
MAPK
MKK
MAPK-P
PP2A
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R
S
0
0.5
0 1 2 3
res
po
ns
e (
R)
signal (S)
linear
0
5
0 0.5 1
S=1
R
rate
(d
R/d
t)
rate of degradation
rate of synthesis
S=2
S=3
Gene Expression
Signal-ResponseCurve
1 2
d,
d
Rk S k R
t 1
ss2
k SR
k
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R
Kinase
RP
ATP ADP
H2OPi
Protein Phosphorylation
0
1
2
0 0.5 1
RP
rate
(d
RP
/dt)
0.25
0.5
1
1.5
2
Phosphatase 0
0.5
1
0 1 2 3
res
po
ns
e (
RP
)
Signal (Kinase)
“Buzzer”
Goldbeter & Koshland, 1981
1 R 0
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R
S
EP E0
0.1
0.2
0.3
0.4
0.5
0.6
0 0.5R
rate
(d
R/d
t) S=0
S=8
S=16
0
0.5
0 10
res
po
ns
e (
R)
signal (S)
Protein Synthesis:Positive Feedback
“Fuse”Bistability
Closed
Open
Griffith, 1968
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Example: Fuse
0
0.5
0 10
resp
on
se (
R)
signal (S)
dying
Apoptosis(Programmed Cell Death)
living
Eissing et al. (2004) J Biol Chem 279:36892
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R
S = Rtotal
E EP0
0.5
1
0 0.5 1 1.5
R
E
Coupled Buzzers
0
0.5
1
0 1 2
res
po
ns
e (
R)
signal (S)
SN
SN
“Toggle”Bistability
RP
S=0.5 S=1.5S=1
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Frog egg
MPF
Cdc25-PCdc25
MPF-P
Wee1
0
0.5
1
0 1 2
resp
on
se (
MP
F)
signal (cyclin)
interphase
met
apha
se
(inactive)
S = Total Cyclin
CycBMPF =
M-phase Promoting Factor
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02468
101214
0 6 12 18 24 30 60
MPF activity depends on total cyclin concentration
and on the history of the extract
Cyclin concentration increasing
inactivation threshold at 90 min
MP
F a
ctiv
ity
nM cyclin B
M
IIIIII
02468
101214
0 6 12 18 24 30 60
MP
F a
ctiv
ity
nM cyclin B
M
M
MI/MIII
Cyclin concentration decreasing
I M
bistabilityWei Sha & Jill Sible (2003)
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Oscillations
0
0.5
1
0 1 2
MP
F
cyclin
MPF
Cdc25-PCdc25
MPF-P(inactive)
cyclin synthesis
cyclin degradationAPC
negative feedback loop
0.0 0.5
0
1
signal (rate of cyclin synthesis)
Hopf Hopf
res
po
ns
e (
MP
F)
sss
sssuss
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Pomerening, Kim & FerrellCell (2005)
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If knock-out positive feedback loop, then oscillations become faster and smaller amplitude…
Figure 4. Pomerening, Kim and Ferrell
With + feedback Without + feedback
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P Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
CycB
APC-PAPCTFBI
TFBA
Cdc14
Cdc14
Cdc14
Cdc25
MPF
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P Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
TFEA
TFEI
CycE
TFIA
TFII
Cdc20
Cdc14
Cdc14
Cdc14
CycA
CycB
CycD
Cdh1CycD
Cdc25
SPF
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primed RC
fired RC primed MEN
fired MEN
Cdk1
CycB
high MPF
low MPF
high SPF
low SPF
Cdk2
CycA
Cell Cycle Regulation
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Cdk2
CycA
LicensingFactor
ReplicationComplex time
Csikasz-Nagy & Novak, 2005
SPF
“Cock-and-Fire”
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Cdk1
CycB
Primer
Mitotic ExitNetwork
time
Csikasz-Nagy & Novak, 2005
MPF
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
mass/nucleus
Fission Yeast
bistable switch
bistable switch
neg fdbk osc
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
mass/ DNA
0.0 0.5 1.0 1.5
Cdc2
/Cdc1
3
10-5
10-4
10-3
10-2
10-1
100
G1
Mmass/ DNA
0 1 2
Cdc2
/Cdc1
3
10-3
10-2
10-1
100
S/G2
M
mass/nucleus
mass/ DNA
0.0 0.5 1.0 1.5 2.0
Cdc2
/Cdc1
3
0.1
1
M
Fission Yeast
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0 1 2 3 4 5
0
0.4
0.8
3.0
mass/nucleus
Cd
k1:C
ycB
G1S/G2
MWild type
SNIC
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SNICSNIC BifurcationBifurcation
Invariant Circle
Limit Cycle
x2
p1
node
saddle
Saddle-Node on anInvariant Circle
max
min
max
SNIC
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0 1 2 3 4 5
0
0.4
0.8
3.0
mass/nucleus
Cd
k1:C
ycB
G1S/G2
MWild type
cell divisionG1
S/G2
enter Mexit M
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Genetic control of cell size at cell division in yeastPaul NurseDepartment of Zoology, West Mains Road, Edinburgh EH9 3JT, UK
Nature, Vol, 256, No. 5518, pp. 547-551, August 14, 1975
wild-type wee1
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
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wee1
mass/nucleus
Cd
k1:C
ycB
0 1 2 3 4 5
0
0.4
0.8
1.2
G1
S/G2
M
wee1wee1 cells are about one-half the size of wild type cells are about one-half the size of wild type
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0 1 2 3 4 5 60.0
0.2
0.4
0.6
0.8
1.0
Two-parameter Bifurcation Diagram
cell mass (au.)
Wee
1 ac
tivity
wild-type
B
SN2
SN1
wee1-
<30 60 90
120
150
180 210
240 270 300
period(min)
300<
HB1 2 x wee1+
Gen
etic
s
Physiology
wee1+/-
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? ?
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• Tyson, Chen & Novak, “Network dynamics and cell physiology,” Nature Rev. Molec. Cell Biol. 2:908 (2001).
• Tyson, Csikasz-Nagy & Novak, “The dynamics of cell cycle regulation,” BioEssays 24:1095 (2002).
• Tyson, Chen & Novak, “Sniffers, buzzers, toggles and blinkers,” Curr. Opin. Cell Biol. 15:221 (2003).
• Csikasz-Nagy et al., “Analysis of a generic model of eukaryotic cell-cycle regulation,” Biophys. J. 90:4361 (2006).
References