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BIOMD0000000243 - Neumann2010_CD95Stimulation_NFkB_Apoptosis

 

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Reference Publication
Publication ID: 20212524
Neumann L, Pforr C, Beaudouin J, Pappa A, Fricker N, Krammer PH, Lavrik IN, Eils R.
Dynamics within the CD95 death-inducing signaling complex decide life and death of cells.
Mol. Syst. Biol. 2010; 6: 352
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.  [more]
Model
Original Model: http://www.nature.com/msb/...
Submitter: Lukas Endler
Submission ID: MODEL1003100001
Submission Date: 10 Mar 2010 01:56:36 UTC
Last Modification Date: 03 Jun 2010 10:14:03 UTC
Creation Date: 12 Mar 2010 12:09:20 UTC
Encoders:  Vijayalakshmi Chelliah
   Leo Neumann
set #1
bqbiol:isPartOf Reactome REACT_1619
Reactome REACT_21281
bqbiol:occursIn Taxonomy Homo sapiens
set #2
bqbiol:isPartOf Gene Ontology positive regulation of NF-kappaB transcription factor activity
Gene Ontology induction of apoptosis by extracellular signals
Notes

This is the reduced model (model 8) described in: Dynamics within the CD95 death-inducing signaling complex decide life and death of cells.
Leo Neumann, Carina Pforr, Joel Beaudouin, Alexander Golks, Peter H. Krammer, Inna N. Lavrik and Roland Eils (German Cancer Research Center (DKFZ), http://www.dkfz.de ); Mol Sys Biol 2010; 6 :352. doi: 10.1038/msb.2010.6 ;

Abstract:
This study explores the dilemma in cellular signaling that triggering of CD95 (Fas/APO-1) in some situations results in cell death and in others leads to the activation of NF-κB. We established an integrated kinetic mathematical model for CD95-mediated apoptotic and NF-κB signaling. Systematic model reduction resulted in a surprisingly simple model well approximating experimentally observed dynamics. The model postulates a new link between c-FLIP L cleavage in the death-inducing signaling complex (DISC) and the NF-κB pathway. We validated experimentally that CD95 stimulation resulted in an interaction of p43-FLIP with the IKK complex followed by its activation. Furthermore, we showed that the apoptotic and NF-κB pathways diverge already at the DISC. Model and experimental analysis of DISC formation showed that a subtle balance of c-FLIP L and procaspase-8 determines life/death decisions in a nonlinear manner. We present an integrated model describing the complex dynamics of CD95-mediated apoptosis and NF-κB signaling.

The original was taken from the MSB article supplementary material site msb20106-s2.xml . All the species ids were changed since the model was not a valid SBML with its original ids - Lukas.

Notes added to the species [L] (the initial concentration of Anti-CD95), regarding changes to be made in the initial concentration of [L], to obtain figure 5D.

This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team.
For more information see the terms of use .
To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

Model
Publication ID: 20212524 Submission Date: 10 Mar 2010 01:56:36 UTC Last Modification Date: 03 Jun 2010 10:14:03 UTC Creation Date: 12 Mar 2010 12:09:20 UTC
Mathematical expressions
Reactions
reaction_1 reaction_2 reaction_3 reaction_4
reaction_5 reaction_6 reaction_7 reaction_8
reaction_9 reaction_10 reaction_11 reaction_12
reaction_13 reaction_14 reaction_15 reaction_16
reaction_17 reaction_18 reaction_19 reaction_20
reaction_21 reaction_22 reaction_23  
Physical entities
Compartments Species
default L L:RF L:RF:C8
L:RF:FL L:RF:FS p43/p41
C3 C8 C8*
C3* p43-FLIP NF-kB:IkB
NF-kB:IkB:P p43-FLIP:IKK* NF-kB*
RF FL FS
IKK L:RF:C8:FS L:RF:FL:FL
L:RF:FL:FS L:RF:FS:FS  
Global parameters
k1 k2 k3 k4
k5 k6 k7 k8
k9 k10 k11 k12
k13 k14 k15 k16
k17      
Reactions (23)
 
 reaction_1 [L] + [RF] → [L:RF];  
 
 reaction_2 [L:RF] + [C8] → [L:RF:C8];  
 
 reaction_3 [L:RF] + [FL] → [L:RF:FL];  
 
 reaction_4 [L:RF] + [FS] → [L:RF:FS];  
 
 reaction_5 [L:RF:C8] + [C8] → [p43/p41] + [p43/p41];  
 
 reaction_6 [L:RF:C8] + [FL] → [p43-FLIP];  
 
 reaction_7 [L:RF:C8] + [FS] → [L:RF:C8:FS];  
 
 reaction_8 [L:RF:FL] + [C8] → [p43-FLIP];  
 
 reaction_9 [L:RF:FL] + [FL] → [L:RF:FL:FL];  
 
 reaction_10 [L:RF:FL] + [FS] → [L:RF:FL:FS];  
 
 reaction_11 [L:RF:FS] + [C8] → [L:RF:C8:FS];  
 
 reaction_12 [L:RF:FS] + [FL] → [L:RF:FL:FS];  
 
 reaction_13 [L:RF:FS] + [FS] → [L:RF:FS:FS];  
 
 reaction_14 [p43/p41] + [p43/p41] → [C8*];  
 
 reaction_15 [C3] + [C8*] → [C3*] + [C8*];  
 
 reaction_16 [C8] + [C3*] → [p43/p41] + [C3*];  
 
 reaction_17 [C8*] → ;  
 
 reaction_18 [C3*] → ;  
 
 reaction_19 [p43-FLIP] + [IKK] → [p43-FLIP:IKK*];  
 
 reaction_20 [NF-kB:IkB] + [p43-FLIP:IKK*] → [NF-kB:IkB:P] + [p43-FLIP:IKK*];  
 
 reaction_21 [NF-kB:IkB:P] → [NF-kB*];  
 
 reaction_22 [p43-FLIP:IKK*] → ;  
 
 reaction_23 [NF-kB*] → ;  
 
 default Spatial dimensions: 3.0  Compartment size: 1.0
 
 L
Compartment: default
Initial concentration: 113.22
 
 L:RF
Compartment: default
Initial concentration: 0.0
 
 L:RF:C8
Compartment: default
Initial concentration: 0.0
 
 L:RF:FL
Compartment: default
Initial concentration: 0.0
 
 L:RF:FS
Compartment: default
Initial concentration: 0.0
 
 p43/p41
Compartment: default
Initial concentration: 0.0
 
 C3
Compartment: default
Initial concentration: 1.443404
 
 C8
Compartment: default
Initial concentration: 64.47652
 
 C8*
Compartment: default
Initial concentration: 0.0
 
 C3*
Compartment: default
Initial concentration: 0.0
 
 p43-FLIP
Compartment: default
Initial concentration: 0.0
 
 NF-kB:IkB
Compartment: default
Initial concentration: 4.739546
 
 NF-kB:IkB:P
Compartment: default
Initial concentration: 0.0
 
 p43-FLIP:IKK*
Compartment: default
Initial concentration: 0.0
 
 NF-kB*
Compartment: default
Initial concentration: 0.0
 
 RF
Compartment: default
Initial concentration: 91.26592
 
 FL
Compartment: default
Initial concentration: 7.398562
 
 FS
Compartment: default
Initial concentration: 5.083923
 
 IKK
Compartment: default
Initial concentration: 5.772825
 
 L:RF:C8:FS
Compartment: default
Initial concentration: 0.0
 
 L:RF:FL:FL
Compartment: default
Initial concentration: 0.0
 
 L:RF:FL:FS
Compartment: default
Initial concentration: 0.0
 
 L:RF:FS:FS
Compartment: default
Initial concentration: 0.0
 
Global Parameters (17)
 
   k1
Value: 1.0
Constant
 
   k2
Value: 1.277248E-4
Constant
 
   k3
Value: 0.6693316
Constant
 
   k4
Value: 1.0E-5
Constant
 
   k5
Value: 5.946569E-4
Constant
 
   k6
Value: 0.9999999
Constant
 
   k7
Value: 0.8875063
Constant
 
   k8
Value: 8.044378E-4
Constant
 
   k9
Value: 0.002249759
Constant
 
   k10
Value: 0.1205258
Constant
 
   k11
Value: 0.02891451
Constant
 
   k12
Value: 0.1502914
Constant
 
   k13
Value: 7.204261E-4
Constant
 
   k14
Value: 0.3588224
Constant
 
   k15
Value: 3.684162
Constant
 
   k16
Value: 0.02229912
Constant
 
   k17
Value: 0.0064182
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000243

Curator's comment: (updated: 12 Mar 2010 13:08:02 GMT)

The model reproduces figure 5D of the reference publication. The model as such reproduces the plot corresponding to Anti-CD95 conc. 1500ng/ml (black). To obtain plots corresponding to Anti-CD95 conc. 500ng/ml (blue) and Anti-CD95 conc. 250ng/ml (red), the initial concentration of L should be set as 37.74nM and 18.87nM, respectively. The model was integrated and simulated using Copasi v4.5 (Build 30).

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