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BIOMD0000000407 - Schliemann2011_TNF_ProAntiApoptosis

 

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Reference Publication
Publication ID: 22204418
Schliemann M, Bullinger E, Borchers S, Allgöwer F, Findeisen R, Scheurich P.
Heterogeneity reduces sensitivity of cell death for TNF-stimuli.
BMC Syst Biol 2011; 5: 204
Institute for Automation Engineering, Laboratory for Systems Theory and Automatic Control, Otto-von-Guericke University Magdeburg, Germany.  [more]
Model
Original Model: BIOMD0000000407.xml.origin
Submitter: Monica Schliemann
Submission ID: MODEL1112210000
Submission Date: 21 Dec 2011 21:08:27 UTC
Last Modification Date: 08 Mar 2012 11:11:11 UTC
Creation Date: 16 Jan 2012 14:48:14 UTC
Encoders:  Vijayalakshmi Chelliah
   Monica Schliemann
set #1
bqbiol:isPartOf KEGG Pathway map04210
set #2
bqbiol:occursIn Taxonomy Homo sapiens
Brenda Tissue Ontology BTO:0002267
set #3
bqbiol:isVersionOf Gene Ontology apoptotic process
Notes

This model is from the article:
Heterogeneity Reduces Sensitivity of Cell Death for TNF-Stimuli
Schliemann M, Bullinger E, Borchers S, Allgower F, Findeisen R, Scheurich P. BMC Syst Biol. 2011 Dec 28;5(1):204. 22204418 ,
Abstract:
BACKGROUND: Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor kappaB (NF-kappaB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner. RESULTS: This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-kappaB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability. CONCLUSIONS: Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-kappaB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity.

Note: SBML model generated from Matlab system description on 12-July-2011 21:08:15 by exportSBML Copyright Eric Bullinger 2007-2011

Model
Publication ID: 22204418 Submission Date: 21 Dec 2011 21:08:27 UTC Last Modification Date: 08 Mar 2012 11:11:11 UTC Creation Date: 16 Jan 2012 14:48:14 UTC
Mathematical expressions
Reactions
TNFR transport into membrane TNFR production TNFR degradation RIP turnover
TRADD turnover TRAF2 turnover FADD turnover TNF~TNFR degradation
TNF:TNFR:TRADD degradation TNFR Complex1 degradation TNFR Complex2 degradation TNFR Complex2~FLIP degradation
TNFR Complex2~FLIP~FLIP degradation TNFR Complex2~Procaspase-8 degradation TNFR Complex2~Procaspase-8~Procaspase-8 degradation TNFR Complex2~FLIP~Procaspase-8 degradation
TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 degradation TNF~TNFR binding and release TNF~TNFR~TRADD building TNFR Complex1 building
Receptor internalisation step1 Receptor internalisation step2 Receptor internalisation step3 Receptor internalisation step4
FLIP recruitment to TNFR Complex2 FLIP recruitment to TNFR Complex2~FLIP Procaspase-8 recruitment to TNFR Complex2 Procaspase-8 recruitment to TNFR Complex2~Procaspase-8
Caspase-8 activation by TNFR Complex2 FLIP recruitment to TNFR Complex2~Procaspase-8 Procaspase-8 recruitment to TNFR Complex2~FLIP Caspase-8 activation by TNFR Complex2~FLIP~Procaspase-8
RIP~TRAF2 recruitment at TNFR Complex2~FLIP~Procaspase-8 IKK activation by TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 IKK turnover NF-kappaB turnover
FLIP turnover XIAP turnover A20 turnover IKK* degradation
IkappaBalpha~NF-kappaB complex degradation nuclear NF-kappaB degradation IkappaBalpha-mRNA degradation IkappaBalpha degradation
free nuclear IkappaBalpha degradation nuclear IkappaBalpha~NF-kappaB complex degradation P-IkappaBa degradation A20-mRNA degradation
XIAP-mRNA degradation FLIP-mRNA degradation IKK activation by TNFR Complex1 IKK* inactivation
TNFR Complex1 inactivation by A20 IkappaBalpha NF-kappaB association release and degradation of bound IkappaBalpha NF-kappaB nuclear translocation
IkappaBalpha-mRNA transcription IkappaBalpha translation IkappaBalpha nuclear translocation IkappaBalpha binding NF-kappaB in nucleus
IkappaBalpha_NF-kappaB N-C export A20-mRNA transcription A20 translation XIAP-mRNA transcription
XIAP translation FLIP-mRNA transcription FLIP translation Procaspase-8 turnover
Procaspase-3 turnover Procaspase-6 turnover Caspase-8 degradation Caspase-3 degradation
Caspase-6 degradation XIAP~Caspase-3 complex degradation BAR turnover BAR~Caspase-8 complex degradation
PARP turnover CPARP degradation Caspase-3 activation Caspase-6 activation
Caspase-8 activation XIAP~Caspase-3 complex formation XIAP degradation due to Caspase-3 XIAP~Caspase-3 complex breakup
negative feedback loop Caspase-3 on TNFR Complex1 FLIP degradation by Caspase-3 PARP cleavage as Casp3 substrate BAR~Caspase-8 complex formation
Physical entities
Compartments Species
cytoplasm TNFR RIP TRADD
TRAF2 FADD TNF:TNFR:TRADD
TNFRC1 TNFRCint1 TNFRCint2
TNFRCint3 TNFRC2 FLIP
TNFRC2:FLIP TNFRC2:pCasp8 TNFRC2:FLIP:FLIP
TNFRC2:pCasp8:pCasp8 TNFRC2:FLIP:pCasp8 TNFRC2:FLIP:pCasp8:RIP:TRAF2
IKK IKKa A20
NFkB IkBa IkBa:NFkB
PIkBa BAR XIAP
pCasp8 pCasp3 pCasp6
Casp8 Casp3 Casp6
BAR:Casp8 XIAP:Casp3 PARP
cPARP    
extracellular TNFR_E TNF_E TNF:TNFR_E
     
nucleus NFkB_N IkBa_N IkBa:NFkB_N
A20_mRNA IkBa_mRNA XIAP_mRNA
FLIP_mRNA    
Reactions (88)
 
 TNFR transport into membrane [TNFR] → [TNFR_E];  
 
 TNFR production  → [TNFR];  
 
 TNFR degradation [TNFR_E] → ;  
 
 RIP turnover  ↔ [RIP];  
 
 TRADD turnover  ↔ [TRADD];  
 
 TRAF2 turnover  ↔ [TRAF2];  
 
 FADD turnover  ↔ [FADD];  
 
 TNF~TNFR degradation [TNF:TNFR_E] → ;  
 
 TNF:TNFR:TRADD degradation [TNF:TNFR:TRADD] → ;  
 
 TNFR Complex1 degradation [TNFRC1] → ;  
 
 TNFR Complex2 degradation [TNFRC2] → ;  
 
 TNFR Complex2~FLIP degradation [TNFRC2:FLIP] → ;  
 
 TNFR Complex2~FLIP~FLIP degradation [TNFRC2:FLIP:FLIP] → ;  
 
 TNFR Complex2~Procaspase-8 degradation [TNFRC2:pCasp8] → ;  
 
 TNFR Complex2~Procaspase-8~Procaspase-8 degradation [TNFRC2:pCasp8:pCasp8] → ;  
 
 TNFR Complex2~FLIP~Procaspase-8 degradation [TNFRC2:FLIP:pCasp8] → ;  
 
 TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 degradation [TNFRC2:FLIP:pCasp8:RIP:TRAF2] → ;  
 
 TNF~TNFR binding and release [TNFR_E] + [TNF_E] ↔ [TNF:TNFR_E];  
 
 TNF~TNFR~TRADD building [TNF:TNFR_E] + [TRADD] → [TNF:TNFR:TRADD];  
 
 TNFR Complex1 building [RIP] + [TRAF2] + [TNF:TNFR:TRADD] → [TNFRC1];  
 
 Receptor internalisation step1 [TNFRC1] → [TNFRCint1];  
 
 Receptor internalisation step2 [TNFRCint1] → [RIP] + [TRAF2] + [TNFRCint2];  
 
 Receptor internalisation step3 2.0 × [FADD] + [TNFRCint2] → [TNFRCint3];  
 
 Receptor internalisation step4 [TNFRCint3] → [TNFRC2];  
 
 FLIP recruitment to TNFR Complex2 [TNFRC2] + [FLIP] → [TNFRC2:FLIP];  
 
 FLIP recruitment to TNFR Complex2~FLIP [FLIP] + [TNFRC2:FLIP] → [TNFRC2:FLIP:FLIP];  
 
 Procaspase-8 recruitment to TNFR Complex2 [TNFRC2] + [pCasp8] → [TNFRC2:pCasp8];  
 
 Procaspase-8 recruitment to TNFR Complex2~Procaspase-8 [TNFRC2:pCasp8] + [pCasp8] → [TNFRC2:pCasp8:pCasp8];  
 
 Caspase-8 activation by TNFR Complex2 [TNFRC2:pCasp8:pCasp8] → [TNFRC2] + [Casp8];  
 
 FLIP recruitment to TNFR Complex2~Procaspase-8 [FLIP] + [TNFRC2:pCasp8] → [TNFRC2:FLIP:pCasp8];  
 
 Procaspase-8 recruitment to TNFR Complex2~FLIP [TNFRC2:FLIP] + [pCasp8] → [TNFRC2:FLIP:pCasp8];  
 
 Caspase-8 activation by TNFR Complex2~FLIP~Procaspase-8 [TNFRC2:FLIP:pCasp8] → [TNFRC2] + [Casp8];  
 
 RIP~TRAF2 recruitment at TNFR Complex2~FLIP~Procaspase-8 [RIP] + [TRAF2] + [TNFRC2:FLIP:pCasp8] → [TNFRC2:FLIP:pCasp8:RIP:TRAF2];  
 
 IKK activation by TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 [IKK] → [IKKa];   {TNFRC2:FLIP:pCasp8:RIP:TRAF2}
 
 IKK turnover  ↔ [IKK];  
 
 NF-kappaB turnover  ↔ [NFkB];  
 
 FLIP turnover  ↔ [FLIP];  
 
 XIAP turnover  ↔ [XIAP];  
 
 A20 turnover  ↔ [A20];  
 
 IKK* degradation [IKKa] → ;  
 
 IkappaBalpha~NF-kappaB complex degradation [IkBa:NFkB] → ;  
 
 nuclear NF-kappaB degradation [NFkB_N] → ;  
 
 IkappaBalpha-mRNA degradation [IkBa_mRNA] → ;  
 
 IkappaBalpha degradation [IkBa] → ;  
 
 free nuclear IkappaBalpha degradation [IkBa_N] → ;  
 
 nuclear IkappaBalpha~NF-kappaB complex degradation [IkBa:NFkB_N] → ;  
 
 P-IkappaBa degradation [PIkBa] → ;  
 
 A20-mRNA degradation [A20_mRNA] → ;  
 
 XIAP-mRNA degradation [XIAP_mRNA] → ;  
 
 FLIP-mRNA degradation [FLIP_mRNA] → ;  
 
 IKK activation by TNFR Complex1 [IKK] → [IKKa];   {TNFRC1}
 
 IKK* inactivation [IKKa] → [IKK];  
 
 TNFR Complex1 inactivation by A20 [TNFRC1] → [TRAF2] + [TNF:TNFR:TRADD];   {A20}
 
 IkappaBalpha NF-kappaB association [NFkB] + [IkBa] → [IkBa:NFkB];  
 
 release and degradation of bound IkappaBalpha [IkBa:NFkB] → [NFkB] + [PIkBa];   {IKKa}
 
 NF-kappaB nuclear translocation [NFkB] → [NFkB_N];  
 
 IkappaBalpha-mRNA transcription  → [IkBa_mRNA];   {NFkB_N}
 
 IkappaBalpha translation  → [IkBa];   {IkBa_mRNA}
 
 IkappaBalpha nuclear translocation [IkBa] ↔ [IkBa_N];  
 
 IkappaBalpha binding NF-kappaB in nucleus [NFkB_N] + [IkBa_N] → [IkBa:NFkB_N];  
 
 IkappaBalpha_NF-kappaB N-C export [IkBa:NFkB_N] → [IkBa:NFkB];  
 
 A20-mRNA transcription  → [A20_mRNA];   {NFkB_N}
 
 A20 translation  → [A20];   {A20_mRNA}
 
 XIAP-mRNA transcription  → [XIAP_mRNA];   {NFkB_N}
 
 XIAP translation  → [XIAP];   {XIAP_mRNA}
 
 FLIP-mRNA transcription  → [FLIP_mRNA];   {NFkB_N}
 
 FLIP translation  → [FLIP];   {FLIP_mRNA}
 
 Procaspase-8 turnover  ↔ [pCasp8];  
 
 Procaspase-3 turnover  ↔ [pCasp3];  
 
 Procaspase-6 turnover  ↔ [pCasp6];  
 
 Caspase-8 degradation [Casp8] → ;  
 
 Caspase-3 degradation [Casp3] → ;  
 
 Caspase-6 degradation [Casp6] → ;  
 
 XIAP~Caspase-3 complex degradation [XIAP:Casp3] → ;  
 
 BAR turnover  ↔ [BAR];  
 
 BAR~Caspase-8 complex degradation [BAR:Casp8] → ;  
 
 PARP turnover [PARP] ↔ ;  
 
 CPARP degradation [cPARP] → ;  
 
 Caspase-3 activation [pCasp3] → [Casp3];   {Casp8}
 
 Caspase-6 activation [pCasp6] → [Casp6];   {Casp3}
 
 Caspase-8 activation [pCasp8] → [Casp8];   {Casp6}
 
 XIAP~Caspase-3 complex formation [XIAP] + [Casp3] ↔ [XIAP:Casp3];  
 
 XIAP degradation due to Caspase-3 [XIAP] → ;   {Casp3}
 
 XIAP~Caspase-3 complex breakup [XIAP:Casp3] → [XIAP];  
 
 negative feedback loop Caspase-3 on TNFR Complex1 [RIP] → ;   {Casp3}
 
 FLIP degradation by Caspase-3 [FLIP] → ;   {Casp3}
 
 PARP cleavage as Casp3 substrate [PARP] → [cPARP];   {Casp3}
 
 BAR~Caspase-8 complex formation [BAR] + [Casp8] ↔ [BAR:Casp8];  
 
  Spatial dimensions: 3.0  Compartment size: 3.2  (Units: pl)
 
 TNFR
Compartment: cytoplasm
Initial amount: 2.8E-4  (Units: a_mole)
 
 RIP
Compartment: cytoplasm
Initial amount: 0.20256  (Units: a_mole)
 
 TRADD
Compartment: cytoplasm
Initial amount: 0.29344  (Units: a_mole)
 
 TRAF2
Compartment: cytoplasm
Initial amount: 0.33056  (Units: a_mole)
 
 FADD
Compartment: cytoplasm
Initial amount: 0.30944  (Units: a_mole)
 
 TNF:TNFR:TRADD
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRC1
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRCint1
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRCint2
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRCint3
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRC2
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 FLIP
Compartment: cytoplasm
Initial amount: 0.0320472  (Units: a_mole)
 
 TNFRC2:FLIP
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRC2:pCasp8
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRC2:FLIP:FLIP
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRC2:pCasp8:pCasp8
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRC2:FLIP:pCasp8
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 TNFRC2:FLIP:pCasp8:RIP:TRAF2
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 IKK
Compartment: cytoplasm
Initial amount: 0.64  (Units: a_mole)
 
 IKKa
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 A20
Compartment: cytoplasm
Initial amount: 0.104434  (Units: a_mole)
 
 NFkB
Compartment: cytoplasm
Initial amount: 1.15365E-4  (Units: a_mole)
 
 IkBa
Compartment: cytoplasm
Initial amount: 0.00101518  (Units: a_mole)
 
 IkBa:NFkB
Compartment: cytoplasm
Initial amount: 0.0151032  (Units: a_mole)
 
 PIkBa
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 BAR
Compartment: cytoplasm
Initial amount: 0.28789  (Units: a_mole)
 
 XIAP
Compartment: cytoplasm
Initial amount: 7.83371  (Units: a_mole)
 
 pCasp8
Compartment: cytoplasm
Initial amount: 3.2  (Units: a_mole)
 
 pCasp3
Compartment: cytoplasm
Initial amount: 0.8  (Units: a_mole)
 
 pCasp6
Compartment: cytoplasm
Initial amount: 0.064  (Units: a_mole)
 
 Casp8
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 Casp3
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 Casp6
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 BAR:Casp8
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 XIAP:Casp3
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
 PARP
Compartment: cytoplasm
Initial amount: 1.66667  (Units: a_mole)
 
 cPARP
Compartment: cytoplasm
Initial amount: 0.0  (Units: a_mole)
 
  Spatial dimensions: 3.0  Compartment size: 1344.0  (Units: pl)
 
 TNFR_E
Compartment: extracellular
Initial amount: 0.0050  (Units: a_mole)
 
 TNF_E
Compartment: extracellular
Initial amount: 0.2688  (Units: a_mole)
 
 TNF:TNFR_E
Compartment: extracellular
Initial amount: 0.0  (Units: a_mole)
 
  Spatial dimensions: 3.0  Compartment size: 1.056  (Units: pl)
 
 NFkB_N
Compartment: nucleus
Initial amount: 6.91431E-4  (Units: a_mole)
 
 IkBa_N
Compartment: nucleus
Initial amount: 0.0013839  (Units: a_mole)
 
 IkBa:NFkB_N
Compartment: nucleus
Initial amount: 9.00189E-5  (Units: a_mole)
 
 A20_mRNA
Compartment: nucleus
Initial amount: 5.56657E-5  (Units: a_mole)
 
 IkBa_mRNA
Compartment: nucleus
Initial amount: 5.31517E-5  (Units: a_mole)
 
 XIAP_mRNA
Compartment: nucleus
Initial amount: 2.19646E-4  (Units: a_mole)
 
 FLIP_mRNA
Compartment: nucleus
Initial amount: 1.39056E-4  (Units: a_mole)
 
TNFR transport into membrane (1)
 
 TNFR transport into membrane ka
Value: 0.0010   (Units: per_second)
Constant
 
TNFR production (1)
 
 TNFR production ka
Value: 2.8E-7   (Units: a_mole_per_second)
Constant
 
TNFR degradation (1)
 
 TNFR degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
RIP turnover (2)
 
 RIP turnover ka
Value: 2.0256E-5   (Units: a_mole_per_second)
Constant
 
 RIP turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
TRADD turnover (2)
 
 TRADD turnover ka
Value: 2.9344E-5   (Units: a_mole_per_second)
Constant
 
 TRADD turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
TRAF2 turnover (2)
 
 TRAF2 turnover ka
Value: 3.3056E-5   (Units: a_mole_per_second)
Constant
 
 TRAF2 turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
FADD turnover (2)
 
 FADD turnover ka
Value: 3.0944E-5   (Units: a_mole_per_second)
Constant
 
 FADD turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
TNF~TNFR degradation (1)
 
 TNF~TNFR degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNF:TNFR:TRADD degradation (1)
 
 TNF:TNFR:TRADD degradation ka
Value: 0.02352   (Units: per_second)
Constant
 
TNFR Complex1 degradation (1)
 
 TNFR Complex1 degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNFR Complex2 degradation (1)
 
 TNFR Complex2 degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNFR Complex2~FLIP degradation (1)
 
 TNFR Complex2~FLIP degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNFR Complex2~FLIP~FLIP degradation (1)
 
 TNFR Complex2~FLIP~FLIP degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNFR Complex2~Procaspase-8 degradation (1)
 
 TNFR Complex2~Procaspase-8 degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNFR Complex2~Procaspase-8~Procaspase-8 degradation (1)
 
 TNFR Complex2~Procaspase-8~Procaspase-8 degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNFR Complex2~FLIP~Procaspase-8 degradation (1)
 
 TNFR Complex2~FLIP~Procaspase-8 degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 degradation (1)
 
 TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 degradation ka
Value: 5.6E-5   (Units: per_second)
Constant
 
TNF~TNFR binding and release (2)
 
 TNF~TNFR binding and release ka
Value: 0.00953471   (Units: per_a_mole_per_second)
Constant
 
 TNF~TNFR binding and release kd
Value: 6.60377E-5   (Units: per_second)
Constant
 
TNF~TNFR~TRADD building (1)
 
 TNF~TNFR~TRADD building ka
Value: 0.00427827   (Units: per_a_mole_per_second)
Constant
 
TNFR Complex1 building (1)
 
 TNFR Complex1 building ka
Value: 0.0976562   (Units: per_a_mole_squared_per_second)
Constant
 
Receptor internalisation step1 (1)
 
 Receptor internalisation step1 ka
Value: 0.001135   (Units: per_second)
Constant
 
Receptor internalisation step2 (1)
 
 Receptor internalisation step2 ka
Value: 0.001135   (Units: per_second)
Constant
 
Receptor internalisation step3 (1)
 
 Receptor internalisation step3 ka
Value: 0.0118534   (Units: per_a_mole_squared_per_second)
Constant
 
Receptor internalisation step4 (1)
 
 Receptor internalisation step4 ka
Value: 0.1135   (Units: per_second)
Constant
 
FLIP recruitment to TNFR Complex2 (1)
 
 FLIP recruitment to TNFR Complex2 ka
Value: 0.3125   (Units: per_a_mole_per_second)
Constant
 
FLIP recruitment to TNFR Complex2~FLIP (1)
 
 FLIP recruitment to TNFR Complex2~FLIP ka
Value: 0.3125   (Units: per_a_mole_per_second)
Constant
 
Procaspase-8 recruitment to TNFR Complex2 (1)
 
 Procaspase-8 recruitment to TNFR Complex2 ka
Value: 0.03125   (Units: per_a_mole_per_second)
Constant
 
Procaspase-8 recruitment to TNFR Complex2~Procaspase-8 (1)
 
 Procaspase-8 recruitment to TNFR Complex2~Procaspase-8 ka
Value: 0.03125   (Units: per_a_mole_per_second)
Constant
 
Caspase-8 activation by TNFR Complex2 (1)
 
 Caspase-8 activation by TNFR Complex2 ka
Value: 0.45   (Units: per_second)
Constant
 
FLIP recruitment to TNFR Complex2~Procaspase-8 (1)
 
 FLIP recruitment to TNFR Complex2~Procaspase-8 ka
Value: 0.3125   (Units: per_a_mole_per_second)
Constant
 
Procaspase-8 recruitment to TNFR Complex2~FLIP (1)
 
 Procaspase-8 recruitment to TNFR Complex2~FLIP ka
Value: 0.3125   (Units: per_a_mole_per_second)
Constant
 
Caspase-8 activation by TNFR Complex2~FLIP~Procaspase-8 (1)
 
 Caspase-8 activation by TNFR Complex2~FLIP~Procaspase-8 ka
Value: 0.3   (Units: per_second)
Constant
 
RIP~TRAF2 recruitment at TNFR Complex2~FLIP~Procaspase-8 (1)
 
 RIP~TRAF2 recruitment at TNFR Complex2~FLIP~Procaspase-8 ka
Value: 0.00976562   (Units: per_a_mole_squared_per_second)
Constant
 
IKK activation by TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 (1)
 
 IKK activation by TNFR Complex2~FLIP~Procaspase-8~RIP~TRAF2 ka
Value: 0.03125   (Units: per_a_mole_per_second)
Constant
 
IKK turnover (2)
 
 IKK turnover ka
Value: 6.4E-5   (Units: a_mole_per_second)
Constant
 
 IKK turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
NF-kappaB turnover (2)
 
 NF-kappaB turnover ka
Value: 1.6E-6   (Units: a_mole_per_second)
Constant
 
 NF-kappaB turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
FLIP turnover (2)
 
 FLIP turnover ka
Value: 2.24902E-6   (Units: a_mole_per_second)
Constant
 
 FLIP turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
XIAP turnover (2)
 
 XIAP turnover ka
Value: 7.72256E-4   (Units: a_mole_per_second)
Constant
 
 XIAP turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
A20 turnover (2)
 
 A20 turnover ka
Value: 9.6E-6   (Units: a_mole_per_second)
Constant
 
 A20 turnover kd
Value: 1.0E-4   (Units: per_second)
Constant
 
IKK* degradation (1)
 
 IKK* degradation ka
Value: 1.0E-4   (Units: per_second)
Constant
 
IkappaBalpha~NF-kappaB complex degradation (1)
 
 IkappaBalpha~NF-kappaB complex degradation ka
Value: 1.0E-4   (Units: per_second)
Constant
 
nuclear NF-kappaB degradation (1)
 
 nuclear NF-kappaB degradation ka
Value: 1.0E-4   (Units: per_second)
Constant
 
IkappaBalpha-mRNA degradation (1)
 
 IkappaBalpha-mRNA degradation ka
Value: 3.94201E-4   (Units: per_second)
Constant
 
IkappaBalpha degradation (1)
 
 IkappaBalpha degradation ka
Value: 0.00154022   (Units: per_second)
Constant
 
free nuclear IkappaBalpha degradation (1)
 
 free nuclear IkappaBalpha degradation ka
Value: 1.0E-4   (Units: per_second)
Constant
 
nuclear IkappaBalpha~NF-kappaB complex degradation (1)
 
 nuclear IkappaBalpha~NF-kappaB complex degradation ka
Value: 1.0E-4   (Units: per_second)
Constant
 
P-IkappaBa degradation (1)
 
 P-IkappaBa degradation ka
Value: 0.0115517   (Units: per_second)
Constant
 
A20-mRNA degradation (1)
 
 A20-mRNA degradation ka
Value: 4.70498E-4   (Units: per_second)
Constant
 
XIAP-mRNA degradation (1)
 
 XIAP-mRNA degradation ka
Value: 1.04931E-4   (Units: per_second)
Constant
 
FLIP-mRNA degradation (1)
 
 FLIP-mRNA degradation ka
Value: 1.65744E-4   (Units: per_second)
Constant
 
IKK activation by TNFR Complex1 (1)
 
 IKK activation by TNFR Complex1 ka
Value: 93.75   (Units: per_a_mole_per_second)
Constant
 
IKK* inactivation (1)
 
 IKK* inactivation ka
Value: 0.1   (Units: per_second)
Constant
 
TNFR Complex1 inactivation by A20 (1)
 
 TNFR Complex1 inactivation by A20 ka
Value: 0.00625   (Units: per_a_mole_per_second)
Constant
 
IkappaBalpha NF-kappaB association (1)
 
 IkappaBalpha NF-kappaB association ka
Value: 1.25   (Units: per_a_mole_per_second)
Constant
 
release and degradation of bound IkappaBalpha (1)
 
 release and degradation of bound IkappaBalpha ka
Value: 0.104167   (Units: per_a_mole_per_second)
Constant
 
NF-kappaB nuclear translocation (1)
 
 NF-kappaB nuclear translocation ka
Value: 0.0125   (Units: per_second)
Constant
 
IkappaBalpha-mRNA transcription (1)
 
 IkappaBalpha-mRNA transcription ka
Value: 3.0303E-5   (Units: per_second)
Constant
 
IkappaBalpha translation (1)
 
 IkappaBalpha translation ka
Value: 0.0606061   (Units: per_second)
Constant
 
IkappaBalpha nuclear translocation (2)
 
 IkappaBalpha nuclear translocation ka
Value: 0.0050   (Units: per_second)
Constant
 
 IkappaBalpha nuclear translocation kd
Value: 0.00257576   (Units: per_second)
Constant
 
IkappaBalpha binding NF-kappaB in nucleus (1)
 
 IkappaBalpha binding NF-kappaB in nucleus ka
Value: 1.4348   (Units: per_a_mole_per_second)
Constant
 
IkappaBalpha_NF-kappaB N-C export (1)
 
 IkappaBalpha_NF-kappaB N-C export ka
Value: 0.0151515   (Units: per_second)
Constant
 
A20-mRNA transcription (1)
 
 A20-mRNA transcription ka
Value: 3.78788E-5   (Units: per_second)
Constant
 
A20 translation (1)
 
 A20 translation ka
Value: 0.0151515   (Units: per_second)
Constant
 
XIAP-mRNA transcription (1)
 
 XIAP-mRNA transcription ka
Value: 3.33333E-5   (Units: per_second)
Constant
 
XIAP translation (1)
 
 XIAP translation ka
Value: 0.0506061   (Units: per_second)
Constant
 
FLIP-mRNA transcription (1)
 
 FLIP-mRNA transcription ka
Value: 3.33333E-5   (Units: per_second)
Constant
 
FLIP translation (1)
 
 FLIP translation ka
Value: 0.00687273   (Units: per_second)
Constant
 
Procaspase-8 turnover (2)
 
 Procaspase-8 turnover ka
Value: 1.97531E-4   (Units: a_mole_per_second)
Constant
 
 Procaspase-8 turnover kd
Value: 6.17284E-5   (Units: per_second)
Constant
 
Procaspase-3 turnover (2)
 
 Procaspase-3 turnover ka
Value: 4.93827E-5   (Units: a_mole_per_second)
Constant
 
 Procaspase-3 turnover kd
Value: 6.17284E-5   (Units: per_second)
Constant
 
Procaspase-6 turnover (2)
 
 Procaspase-6 turnover ka
Value: 3.95062E-6   (Units: a_mole_per_second)
Constant
 
 Procaspase-6 turnover kd
Value: 6.17284E-5   (Units: per_second)
Constant
 
Caspase-8 degradation (1)
 
 Caspase-8 degradation ka
Value: 5.78704E-5   (Units: per_second)
Constant
 
Caspase-3 degradation (1)
 
 Caspase-3 degradation ka
Value: 5.78704E-5   (Units: per_second)
Constant
 
Caspase-6 degradation (1)
 
 Caspase-6 degradation ka
Value: 5.78704E-5   (Units: per_second)
Constant
 
XIAP~Caspase-3 complex degradation (1)
 
 XIAP~Caspase-3 complex degradation ka
Value: 5.78704E-5   (Units: per_second)
Constant
 
BAR turnover (2)
 
 BAR turnover ka
Value: 1.66603E-6   (Units: a_mole_per_second)
Constant
 
 BAR turnover kd
Value: 5.78704E-6   (Units: per_second)
Constant
 
BAR~Caspase-8 complex degradation (1)
 
 BAR~Caspase-8 complex degradation ka
Value: 5.78704E-5   (Units: per_second)
Constant
 
PARP turnover (2)
 
 PARP turnover ka
Value: 5.78704E-6   (Units: per_second)
Constant
 
 PARP turnover kd
Value: 9.64506E-6   (Units: a_mole_per_second)
Constant
 
CPARP degradation (1)
 
 CPARP degradation ka
Value: 5.78704E-6   (Units: per_second)
Constant
 
Caspase-3 activation (1)
 
 Caspase-3 activation ka
Value: 0.015625   (Units: per_a_mole_per_second)
Constant
 
Caspase-6 activation (1)
 
 Caspase-6 activation ka
Value: 0.009375   (Units: per_a_mole_per_second)
Constant
 
Caspase-8 activation (1)
 
 Caspase-8 activation ka
Value: 0.0015625   (Units: per_a_mole_per_second)
Constant
 
XIAP~Caspase-3 complex formation (2)
 
 XIAP~Caspase-3 complex formation ka
Value: 0.625   (Units: per_a_mole_per_second)
Constant
 
 XIAP~Caspase-3 complex formation kd
Value: 0.0010   (Units: per_second)
Constant
 
XIAP degradation due to Caspase-3 (1)
 
 XIAP degradation due to Caspase-3 ka
Value: 1.875   (Units: per_a_mole_per_second)
Constant
 
XIAP~Caspase-3 complex breakup (1)
 
 XIAP~Caspase-3 complex breakup ka
Value: 5.0E-5   (Units: per_second)
Constant
 
negative feedback loop Caspase-3 on TNFR Complex1 (1)
 
 negative feedback loop Caspase-3 on TNFR Complex1 ka
Value: 0.15625   (Units: per_a_mole_per_second)
Constant
 
FLIP degradation by Caspase-3 (1)
 
 FLIP degradation by Caspase-3 ka
Value: 0.15625   (Units: per_a_mole_per_second)
Constant
 
PARP cleavage as Casp3 substrate (1)
 
 PARP cleavage as Casp3 substrate ka
Value: 0.1875   (Units: per_a_mole_per_second)
Constant
 
BAR~Caspase-8 complex formation (2)
 
 BAR~Caspase-8 complex formation ka
Value: 0.520833   (Units: per_a_mole_per_second)
Constant
 
 BAR~Caspase-8 complex formation kd
Value: 0.0010   (Units: per_second)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000407

Curator's comment: (updated: 16 Jan 2012 14:47:34 GMT)

The parameter scan for Caspase-3 and NF-kB with TNF ranging from 0.01ng/ml to 100ng/ml is shown in figure 3A of the reference published, and this has been reproduced here. The units in the model are in microMolar. So, the parameter scan was done with TNF ranging from 3.90625e-07microMolar (=0.01ng/ml) to 0.00390625microMolar (=100ng/ml). The plot shows the parameter scan done for 4 different values of TNF (0.0002, 0.00130234, 0.0026043 and 00390625).The model was integrated and simulated using Copasi v4.7 (Build 34).

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