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BIOMD0000000265 - Conradie2010_RPControl_CellCycle

 

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Reference Publication
Publication ID: 20015233
Conradie R, Bruggeman FJ, Ciliberto A, Csikász-Nagy A, Novák B, Westerhoff HV, Snoep JL.
Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex.
FEBS J. 2010 Jan; 277(2): 357-367
Triple J Group for Molecular Cell Physiology, Department of Biochemistry, Stellenbosch University, Matieland, South Africa.  [more]
Model
Original Model: BIOMD0000000265.xml.origin
Submitter: Kieran Smallbone
Submission ID: MODEL1008240000
Submission Date: 24 Aug 2010 14:04:12 UTC
Last Modification Date: 28 May 2014 01:17:47 UTC
Creation Date: 20 Jul 2010 10:27:30 UTC
Encoders:  Jacky L Snoep
   Vijayalakshmi Chelliah
   Kieran Smallbone
set #1
bqmodel:isDerivedFrom PubMed 15363676
set #2
bqbiol:isVersionOf Gene Ontology cell cycle
set #3
bqbiol:hasVersion Gene Ontology mitotic cell cycle G1/S transition checkpoint
set #4
bqbiol:hasTaxon Taxonomy Mammalia
Notes

This model is from the article:
Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex.
Conradie R, Bruggeman FJ, Ciliberto A, Csikász-Nagy A, Novák B, Westerhoff HV, Snoep JL FEBS J.2010 Jan; 277(2): 357-67 20015233,
Abstract:
Numerous top-down kinetic models have been constructed to describe the cell cycle. These models have typically been constructed, validated and analyzed using model species (molecular intermediates and proteins) and phenotypic observations, and therefore do not focus on the individual model processes (reaction steps). We have developed a method to: (a) quantify the importance of each of the reaction steps in a kinetic model for the positioning of a switch point [i.e. the restriction point (RP)]; (b) relate this control of reaction steps to their effects on molecular species, using sensitivity and co-control analysis; and thereby (c) go beyond a correlation towards a causal relationship between molecular species and effects. The method is generic and can be applied to responses of any type, but is most useful for the analysis of dynamic and emergent responses such as switch points in the cell cycle. The strength of the analysis is illustrated for an existing mammalian cell cycle model focusing on the RP [Novak B, Tyson J (2004) J Theor Biol230, 563-579]. The reactions in the model with the highest RP control were those involved in: (a) the interplay between retinoblastoma protein and E2F transcription factor; (b) those synthesizing the delayed response genes and cyclin D/Cdk4 in response to growth signals; (c) the E2F-dependent cyclin E/Cdk2 synthesis reaction; as well as (d) p27 formation reactions. Nine of the 23 intermediates were shown to have a good correlation between their concentration control and RP control. Sensitivity and co-control analysis indicated that the strongest control of the RP is mediated via the cyclin E/Cdk2:p27 complex concentration. Any perturbation of the RP could be related to a change in the concentration of this complex; apparent effects of other molecular species were indirect and always worked through cyclin E/Cdk2:p27, indicating a causal relationship between this complex and the positioning of the RP.

The rate constants presented in the paper have units [per tenth of an hour] and have been changed here to [per hour] (e.g. k16 = 0.25 not 0.025); for further confirmation of the correctness of this change, see the original model (Novak, J Theor Biol 2004 230:563).

Model
Publication ID: 20015233 Submission Date: 24 Aug 2010 14:04:12 UTC Last Modification Date: 28 May 2014 01:17:47 UTC Creation Date: 20 Jul 2010 10:27:30 UTC
Mathematical expressions
Reactions
v1 v2 v3 v4
v5 v6 v7 v8
v9 v10 v11 v12
v13 v14 v15 v16
v17 v18 v19 v20
v21 v22 v23 v24
v25 v26 v27 v28
v29 v30 v31 v32
v33 v34 v35 v36
v37 v38 v39 v40
v41 v42 v43 v44
v45 v46 v47 v48
v49 v50 v51 v52
Rules
Assignment Rule (variable: PP1A) Assignment Rule (variable: V2) Assignment Rule (variable: V4) Assignment Rule (variable: V6)
Assignment Rule (variable: V8) Assignment Rule (variable: CYCET) Assignment Rule (variable: CYCDT) Assignment Rule (variable: CYCAT)
Assignment Rule (variable: P27T)      
Events
r31Ifpart1 r31Ifpart2 divisionEvent checkEvent
Physical entities
Compartments Species
cell Cdc20 Cdh1 cyclin A:Cdk2
cyclin B:Cdk2 cyclin D:Cdk2 cyclin E:Cdk2
delayed-response genes E2F E2F:Rb
early-response genes general machinery for protein synthesis hypophosphorylated Rb
inactive Cdc20 mass P27
P27:cyclin A:Cdk2 P27:cyclin D:Cdk2 P27:cyclin E:Cdk2
phosphorylated E2F phosphorylated E2F:Rb phosphorylated intermediary enzyme
PPX retinoblastoma protein (Rb)  
Global parameters
Flag r31switch PP1A V2
V4 V6 V8 CYCET
CYCDT CYCAT P27T K10
K8a K8 K25 K25R
J8 YE YB K30
K2a K2 K2aa K6a
K6 HE HB HA
RBT LD LE LB
LA K20 K21 PP1T
FE FB K4 GE
GB GA K12 E2FT
K22 K23a K23 K26
K26R eps    
Reactions (52)
 
 v1 [early-response genes] ↔ ;  
 
 v2 [delayed-response genes] ↔ ;  
 
 v3 [P27:cyclin D:Cdk2] ↔ [P27];  
 
 v4 [cyclin D:Cdk2] ↔ ;  
 
 v5 [cyclin E:Cdk2] + [P27] ↔ [P27:cyclin E:Cdk2];  
 
 v6 [cyclin A:Cdk2] + [P27] ↔ [P27:cyclin A:Cdk2];  
 
 v7 [cyclin D:Cdk2] + [P27] ↔ [P27:cyclin D:Cdk2];  
 
 v8 [P27:cyclin D:Cdk2] ↔ [cyclin D:Cdk2] + [P27];  
 
 v9 [cyclin A:Cdk2] ↔ ;   {Cdc20}
 
 v10 [P27:cyclin A:Cdk2] ↔ [P27];   {Cdc20}
 
 v11 [P27:cyclin E:Cdk2] ↔ [cyclin E:Cdk2] + [P27];  
 
 v12 [P27:cyclin A:Cdk2] ↔ [cyclin A:Cdk2] + [P27];  
 
 v13 [P27:cyclin E:Cdk2] ↔ [P27];   {cyclin B:Cdk2} , {cyclin A:Cdk2} , {cyclin E:Cdk2}
 
 v14 [cyclin E:Cdk2] ↔ ;   {cyclin B:Cdk2} , {cyclin A:Cdk2} , {P27:cyclin E:Cdk2}
 
 v15 [P27] ↔ ;   {cyclin A:Cdk2} , {cyclin B:Cdk2} , {cyclin E:Cdk2}
 
 v16 [P27:cyclin E:Cdk2] ↔ [cyclin E:Cdk2];   {cyclin A:Cdk2} , {cyclin B:Cdk2}
 
 v17 [P27:cyclin D:Cdk2] ↔ [cyclin D:Cdk2];   {cyclin A:Cdk2} , {cyclin B:Cdk2} , {cyclin E:Cdk2}
 
 v18 [P27:cyclin A:Cdk2] ↔ [cyclin A:Cdk2];   {cyclin B:Cdk2} , {cyclin E:Cdk2}
 
 v19 [cyclin B:Cdk2] ↔ ;   {Cdc20} , {Cdh1}
 
 v20  ↔ [Cdh1];   {Cdc20}
 
 v21 [Cdh1] ↔ ;   {cyclin A:Cdk2} , {cyclin B:Cdk2} , {cyclin E:Cdk2}
 
 v22 [PPX] ↔ ;  
 
 v23  ↔ [phosphorylated intermediary enzyme];   {cyclin B:Cdk2}
 
 v24 [phosphorylated intermediary enzyme] ↔ ;   {PPX}
 
 v25 [inactive Cdc20] ↔ ;  
 
 v26  ↔ [Cdc20];   {inactive Cdc20} , {phosphorylated intermediary enzyme}
 
 v27 [Cdc20] ↔ ;  
 
 v28 [Cdc20] ↔ ;  
 
 v29 [E2F:Rb] ↔ [hypophosphorylated Rb] + [E2F];   {cyclin A:Cdk2} , {cyclin B:Cdk2} , {P27:cyclin D:Cdk2} , {cyclin D:Cdk2} , {cyclin E:Cdk2}
 
 v30 [phosphorylated E2F:Rb] ↔ [hypophosphorylated Rb] + [phosphorylated E2F];   {cyclin A:Cdk2} , {cyclin B:Cdk2} , {P27:cyclin D:Cdk2} , {cyclin D:Cdk2} , {cyclin E:Cdk2}
 
 v31  ↔ [general machinery for protein synthesis];   {mass}
 
 v32 [general machinery for protein synthesis] ↔ ;  
 
 v33  ↔ [mass];   {general machinery for protein synthesis}
 
 v34  ↔ [early-response genes];   {delayed-response genes}
 
 v35  ↔ [inactive Cdc20];   {cyclin B:Cdk2}
 
 v36  ↔ [cyclin A:Cdk2];   {mass} , {E2F}
 
 v37  ↔ [PPX];  
 
 v38  ↔ [cyclin E:Cdk2];   {E2F}
 
 v39  ↔ [cyclin D:Cdk2];   {delayed-response genes}
 
 v40  ↔ [P27];  
 
 v41  ↔ [delayed-response genes];   {early-response genes}
 
 v42  ↔ [cyclin B:Cdk2];  
 
 v43 [retinoblastoma protein (Rb)] ↔ [hypophosphorylated Rb];   {cyclin A:Cdk2} , {cyclin B:Cdk2} , {P27:cyclin D:Cdk2} , {cyclin D:Cdk2} , {cyclin E:Cdk2}
 
 v44 [hypophosphorylated Rb] ↔ [retinoblastoma protein (Rb)];   {cyclin B:Cdk2} , {cyclin A:Cdk2} , {cyclin E:Cdk2}
 
 v45 [E2F:Rb] ↔ [E2F] + [retinoblastoma protein (Rb)];  
 
 v46 [E2F] ↔ [phosphorylated E2F];   {cyclin A:Cdk2} , {cyclin B:Cdk2}
 
 v47 [phosphorylated E2F] ↔ [E2F];  
 
 v48 [E2F] + [retinoblastoma protein (Rb)] ↔ [E2F:Rb];  
 
 v49 [phosphorylated E2F:Rb] ↔ [phosphorylated E2F] + [retinoblastoma protein (Rb)];  
 
 v50 [phosphorylated E2F] + [retinoblastoma protein (Rb)] ↔ [phosphorylated E2F:Rb];  
 
 v51 [phosphorylated E2F:Rb] ↔ [E2F:Rb];  
 
 v52 [E2F:Rb] ↔ [phosphorylated E2F:Rb];   {cyclin A:Cdk2} , {cyclin B:Cdk2}
 
Rules (9)
 
 Assignment Rule (name: PP1A) PP1A = PP1T/(1+K21*(FB*CYCB+FE*(CYCA+CYCE)))
 
 Assignment Rule (name: V2) V2 = K2aa*CDc20+K2a*(1-CDh1)+K2*CDh1
 
 Assignment Rule (name: V4) V4 = K4*(GA*CYCA+GB*CYCB+GE*CYCE)
 
 Assignment Rule (name: V6) V6 = K6a+K6*(HA*CYCA+HB*CYCB+HE*CYCE)
 
 Assignment Rule (name: V8) V8 = K8a+K8*(YB*CYCB+YE*(CYCA+CYCE))/(CYCET+J8)
 
 Assignment Rule (name: CYCET) CYCET = CE+CYCE
 
 Assignment Rule (name: CYCDT) CYCDT = CD+CYCD
 
 Assignment Rule (name: CYCAT) CYCAT = CA+CYCA
 
 Assignment Rule (name: P27T) P27T = CA+CD+CE+P27
 
Events (4)
 
 r31Ifpart1
r31switch = 0
 
 r31Ifpart2
r31switch = 1
 
 divisionEvent
general machinery for protein synthesis = 0.5*GM
mass = 0.5*MASS
Flag = 2
 
 checkEvent
Flag = 1
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 Cdc20
Compartment: cell
Initial concentration: 0.00220177
 
 Cdh1
Compartment: cell
Initial concentration: 6.53278E-4
 
 cyclin A:Cdk2
Compartment: cell
Initial concentration: 1.4094
 
 cyclin B:Cdk2
Compartment: cell
Initial concentration: 2.72898
 
 cyclin D:Cdk2
Compartment: cell
Initial concentration: 0.43929
 
 cyclin E:Cdk2
Compartment: cell
Initial concentration: 0.0229112
 
   delayed-response genes
Compartment: cell
Initial concentration: 0.900533
 
 E2F
Compartment: cell
Initial concentration: 0.989986
 
 E2F:Rb
Compartment: cell
Initial concentration: 0.00478911
 
   early-response genes
Compartment: cell
Initial concentration: 0.0121809
 
   general machinery for protein synthesis
Compartment: cell
Initial concentration: 1.35565
 
 hypophosphorylated Rb
Compartment: cell
Initial concentration: 9.97574
 
 inactive Cdc20
Compartment: cell
Initial concentration: 2.36733
 
 mass
Compartment: cell
Initial concentration: 1.68776
 
 P27
Compartment: cell
Initial concentration: 0.00922806
 
 P27:cyclin A:Cdk2
Compartment: cell
Initial concentration: 0.0356927
 
 P27:cyclin D:Cdk2
Compartment: cell
Initial concentration: 0.010976
 
 P27:cyclin E:Cdk2
Compartment: cell
Initial concentration: 5.42587E-4
 
 phosphorylated E2F
Compartment: cell
Initial concentration: 3.98594
 
 phosphorylated E2F:Rb
Compartment: cell
Initial concentration: 0.0192822
 
 phosphorylated intermediary enzyme
Compartment: cell
Initial concentration: 0.154655
 
 PPX
Compartment: cell
Initial concentration: 1.0
 
 retinoblastoma protein (Rb)
Compartment: cell
Initial concentration: 1.90871E-4
 
Global Parameters (50)
 
   Flag
Value: 1.0   (Units: dimensionless)
 
   r31switch
Value: 1.0   (Units: dimensionless)
 
   PP1A
Value: NaN   (Units: dimensionless)
 
   V2
Value: NaN   (Units: dimensionless)
 
   V4
Value: NaN   (Units: dimensionless)
 
   V6
Value: NaN   (Units: dimensionless)
 
   V8
Value: NaN   (Units: dimensionless)
 
   CYCET
Value: NaN   (Units: dimensionless)
 
   CYCDT
Value: NaN   (Units: dimensionless)
 
   CYCAT
Value: NaN   (Units: dimensionless)
 
   P27T
Value: NaN   (Units: dimensionless)
 
   K10
Value: 5.0   (Units: per hour)
Constant
 
   K8a
Value: 0.1   (Units: per hour)
Constant
 
   K8
Value: 2.0   (Units: per hour)
Constant
 
   K25
Value: 1000.0   (Units: per hour)
Constant
 
   K25R
Value: 10.0   (Units: per hour)
Constant
 
   J8
Value: 0.1   (Units: dimensionless)
Constant
 
   YE
Value: 1.0   (Units: dimensionless)
Constant
 
   YB
Value: 0.05   (Units: dimensionless)
Constant
 
   K30
Value: 20.0   (Units: per hour)
Constant
 
   K2a
Value: 0.05   (Units: per hour)
Constant
 
   K2
Value: 20.0   (Units: per hour)
Constant
 
   K2aa
Value: 1.0   (Units: per hour)
Constant
 
   K6a
Value: 10.0   (Units: per hour)
Constant
 
   K6
Value: 100.0   (Units: per hour)
Constant
 
   HE
Value: 0.5   (Units: dimensionless)
Constant
 
   HB
Value: 1.0   (Units: dimensionless)
Constant
 
   HA
Value: 0.5   (Units: dimensionless)
Constant
 
   RBT
Value: 10.0   (Units: dimensionless)
Constant
 
   LD
Value: 3.3   (Units: dimensionless)
Constant
 
   LE
Value: 5.0   (Units: dimensionless)
Constant
 
   LB
Value: 5.0   (Units: dimensionless)
Constant
 
   LA
Value: 3.0   (Units: dimensionless)
Constant
 
   K20
Value: 10.0   (Units: per hour)
Constant
 
   K21
Value: 1.0   (Units: dimensionless)
Constant
 
   PP1T
Value: 1.0   (Units: dimensionless)
Constant
 
   FE
Value: 25.0   (Units: dimensionless)
Constant
 
   FB
Value: 2.0   (Units: dimensionless)
Constant
 
   K4
Value: 40.0   (Units: per hour)
Constant
 
   GE
Constant
 
   GB
Value: 1.0   (Units: dimensionless)
Constant
 
   GA
Value: 0.3   (Units: dimensionless)
Constant
 
   K12
Value: 1.5   (Units: per hour)
Constant
 
   E2FT
Value: 5.0   (Units: dimensionless)
Constant
 
   K22
Value: 1.0   (Units: per hour)
Constant
 
   K23a
Value: 0.0050   (Units: per hour)
Constant
 
   K23
Value: 1.0   (Units: per hour)
Constant
 
   K26
Value: 10000.0   (Units: per hour)
Constant
 
   K26R
Value: 200.0   (Units: per hour)
Constant
 
   eps
Value: 1.0   (Units: dimensionless)
Constant
 
v1 (1)
 
   k16
Value: 0.25   (Units: per hour)
Constant
 
v2 (1)
 
   k18
Value: 10.0   (Units: per hour)
Constant
 
v7 (1)
 
   k24
Value: 1000.0   (Units: per hour)
Constant
 
v8 (1)
 
   k24r
Value: 10.0   (Units: per hour)
Constant
 
v20 (3)
 
   J3
Value: 0.01   (Units: dimensionless)
Constant
 
   K3
Value: 140.0   (Units: per hour)
Constant
 
   K3a
Value: 7.5   (Units: per hour)
Constant
 
v21 (1)
 
   J4
Value: 0.01   (Units: dimensionless)
Constant
 
v22 (1)
 
   K34
Value: 0.05   (Units: per hour)
Constant
 
v23 (2)
 
   J31
Value: 0.01   (Units: dimensionless)
Constant
 
   K31
Value: 0.7   (Units: per hour)
Constant
 
v24 (2)
 
   J32
Value: 0.01   (Units: dimensionless)
Constant
 
   K32
Value: 1.8   (Units: per hour)
Constant
 
v26 (2)
 
   J13
Value: 0.0050   (Units: dimensionless)
Constant
 
   K13
Value: 5.0   (Units: per hour)
Constant
 
v27 (2)
 
   J14
Value: 0.0050   (Units: dimensionless)
Constant
 
   K14
Value: 2.5   (Units: per hour)
Constant
 
v31 (1)
 
   K27
Value: 0.2   (Units: per hour)
Constant
 
v32 (1)
 
   K28
Value: 0.2   (Units: per hour)
Constant
 
v33 (1)
 
   MU
Value: 0.061   (Units: per hour)
Constant
 
v34 (2)
 
   J15
Value: 0.1   (Units: dimensionless)
Constant
 
   k15
Value: 0.25   (Units: per hour)
Constant
 
v35 (2)
 
   K11
Value: 1.5   (Units: per hour)
Constant
 
   K11a
Constant
 
v36 (1)
 
   K29
Value: 0.05   (Units: per hour)
Constant
 
v37 (1)
 
   K33
Value: 0.05   (Units: per hour)
Constant
 
v38 (2)
 
   K7
Value: 0.6   (Units: per hour)
Constant
 
   K7a
Constant
 
v39 (1)
 
   K9
Value: 2.5   (Units: per hour)
Constant
 
v40 (1)
 
   K5
Value: 20.0   (Units: per hour)
Constant
 
v41 (3)
 
   J17
Value: 0.3   (Units: dimensionless)
Constant
 
   k17
Value: 10.0   (Units: per hour)
Constant
 
   k17a
Value: 0.35   (Units: per hour)
Constant
 
v42 (3)
 
   J1
Value: 0.1   (Units: dimensionless)
Constant
 
   K1
Value: 0.6   (Units: per hour)
Constant
 
   K1a
Value: 0.1   (Units: per hour)
Constant
 
v44 (2)
 
   K19
Value: 20.0   (Units: per hour)
Constant
 
   K19a
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000265

Curator's comment: (updated: 24 Aug 2010 16:10:49 BST)

Figure 2 of the reference publication has been reproduced. The model was integrated and simulated using Copasi v4.5.31

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