Network Dynamics and Cell Physiology
description
Transcript of Network Dynamics and Cell Physiology
Network Dynamics andNetwork Dynamics andCell PhysiologyCell Physiology
John J. Tyson John J. Tyson
Biological Sciences Biological Sciences
Virginia TechVirginia Tech
CollaboratorCollaboratorss
Kathy ChenKathy ChenJill SibleJill SibleBela Novak Bela Novak Attila CsikaszAttila Csikasz
Funding Funding AgenciesAgencies
DARPADARPAMcDonnell FoundMcDonnell Found
Hanahan & Weinberg (2000)
Cell signaling
Externalsignals
InformationProcessing System
Death
DivisionReproduction
GrowthDevelopment
InternalSignals
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
$$
Hanahan & Weinberg (2000)
Signal Transduction Network
p21
Smad
MAPK
MKK
MAPK-P
PP2A
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
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
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
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
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
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
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)
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
Pomerening, Kim & FerrellCell (2005)
If knock-out positive feedback loop, then oscillations become faster and smaller amplitude…
Figure 4. Pomerening, Kim and Ferrell
With + feedback Without + feedback
P Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
CycB
APC-PAPCTFBI
TFBA
Cdc14
Cdc14
Cdc14
Cdc25
MPF
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
primed RC
fired RC primed MEN
fired MEN
Cdk1
CycB
high MPF
low MPF
high SPF
low SPF
Cdk2
CycA
Cell Cycle Regulation
Cdk2
CycA
LicensingFactor
ReplicationComplex time
Csikasz-Nagy & Novak, 2005
SPF
“Cock-and-Fire”
Cdk1
CycB
Primer
Mitotic ExitNetwork
time
Csikasz-Nagy & Novak, 2005
MPF
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
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
0 1 2 3 4 5
0
0.4
0.8
3.0
mass/nucleus
Cd
k1:C
ycB
G1S/G2
MWild type
SNIC
SNICSNIC BifurcationBifurcation
Invariant Circle
Limit Cycle
x2
p1
node
saddle
Saddle-Node on anInvariant Circle
max
min
max
SNIC
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
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
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
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
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+/-
? ?
• 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