Debashis Barik

1
Debashis Barik Sandip Kar
Mark Paul
Bill Baumann
Jean Peccoud
Yang Cao
Andrea Ciliberto Mohsen
Sabouri
2
Wee1
P
Cdc20
Central Motif
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
S
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
E2FA
CycB
CycA
E2FI
3
Cdc20 ?
ON
Growth ?
OFF
4
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
E2FA
negative feedback loop
CycB
CycA
E2FI
5
CycB/Cdk1
P-Cdh1/APC
Cdh1/APC
(Cdc14)
Cdc20
6

• Deterministic Model

Tyson Novak, J Theor Biol (2001)
Size
7
CycB/Cdk1
P-Cdh1/APC
Cdh1/APC
Cdc14
Cdc20
8
S
X
YP
Y
A
9
S
X
YP
Y
A
CRNT says No Multiple Steady States
10
XYX
X
YX
XY
Y
YP
AYP
A
CRNT says Yes
11
YPX
X
YX
XY
Y
YP
AYP
A
CRNT says Yes
12
YPX
X
bistable switch
YX
XY
Y
YP
ZYP
Z
negative feedback loop
mRNAs for X, Y, F (18 variables, 36 params)
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Half-life 12 s
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Statistics
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General Conclusions

• We need accurate stochastic models of single-cell
  dynamics.
• Stochastic models are more complex than
  deterministic models and require better data.
• Stochastic models should be built from verified
  deterministic models, based on mass-action
  kinetics.

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Specific Conclusions

• Intrinsic and extrinsic sources of noise are
  mostly independent in their effects on cell cycle
  variability.
• Intrinsic molecular fluctuations in the control
  system are noisier than extrinsic inequities in
  the division process.
• Low number of mRNA molecules are sources of
  extreme variability in protein regulatory
  networks.

20
References

• Ciliberto et al., Modeling networks of coupled
  enzymatic reactions using the total quasi-steady
  state approximation, PLoS Comput Biol 3463-472
  (2007).
• Sabouri et al., Antagonism and bistability in
  protein interaction networks, J Theor Biol
  250209-218 (2008)
• Barik et al., Stochastic simulation of
  enzyme-catalyzed reactions with disparate time
  scales, Biophys J 953563-3574 (2008)
• Kar et al., Exploring the roles of noise in the
  eukaryotic cell cycle, PNAS (in press)