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BIOMD0000000220 - Albeck2008_extrinsic_apoptosis

 

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Reference Publication
Publication ID: 18406323
Albeck JG, Burke JM, Aldridge BB, Zhang M, Lauffenburger DA, Sorger PK.
Quantitative analysis of pathways controlling extrinsic apoptosis in single cells.
Mol. Cell 2008 Apr; 30(1): 11-25
Department of Systems Biology, Harvard Medical School, WAB Room 438, 200 Longwood Avenue, Boston, MA 02115, USA.  [more]
Model
Original Model: BIOMD0000000220.origin
Submitter: Laurence Calzone
Submission ID: MODEL6964793701
Submission Date: 13 Mar 2009 17:19:53 UTC
Last Modification Date: 05 Jul 2012 14:42:40 UTC
Creation Date: 01 Jul 2009 17:12:55 UTC
Encoders:  Lukas Endler
   Simon Fourquet
set #1
bqbiol:occursIn Taxonomy Homo sapiens
bqbiol:isVersionOf KEGG Pathway hsa04210
Reactome REACT_1059
Gene Ontology induction of apoptosis by extracellular signals
Gene Ontology apoptotic process
Notes

This the model used in the article:
Quantitative analysis of pathways controlling extrinsic apoptosis in single cells.
Albeck JG, Burke JM, Aldridge BB, Zhang M, Lauffenburger DA, Sorger PK. Mol Cell. 2008 Apr 11;30(1):11-25. PMID: 18406323 , doi: 10.1016/j.molcel.2008.02.012
Abstract:
Apoptosis in response to TRAIL or TNF requires the activation of initiator caspases, which then activate the effector caspases that dismantle cells and cause death. However, little is known about the dynamics and regulatory logic linking initiators and effectors. Using a combination of live-cell reporters, flow cytometry, and immunoblotting, we find that initiator caspases are active during the long and variable delay that precedes mitochondrial outer membrane permeabilization (MOMP) and effector caspase activation. When combined with a mathematical model of core apoptosis pathways, experimental perturbation of regulatory links between initiator and effector caspases reveals that XIAP and proteasome-dependent degradation of effector caspases are important in restraining activity during the pre-MOMP delay. We identify conditions in which restraint is impaired, creating a physiologically indeterminate state of partial cell death with the potential to generate genomic instability. Together, these findings provide a quantitative picture of caspase regulatory networks and their failure modes.
The mitochondrial compartment is just added as a logical partition and its volume is not used in the mathematical formulas, to stick closer to the expressions used in the matlab files distributed with the original publication. There only the rate constants for bimolecular reactions are adapted by division by v , the ration of the volumes of the mitochondrial compartment and the total cell.
For BCL2 overexpression in figure 5, the initial BCL2 amount was increased by a factor 12 to 2.4*10 5 . For siRNA downregulation of XIAP its amount was multiplied by 0.13 to 1.3*10 4 .


To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.


To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 18406323 Submission Date: 13 Mar 2009 17:19:53 UTC Last Modification Date: 05 Jul 2012 14:42:40 UTC Creation Date: 01 Jul 2009 17:12:55 UTC
Mathematical expressions
Reactions
re1 re2 re3 re4
re5 re6 re7 re8
re9 re10 re11 re12
re13 re14 re15 re16
re17 re18 re19 re20
re21 re22 re23 re24
re25 re26 re27 re29
re30 re31 re32 re33
re34 re35 re36 re37
re38 re39 re40 re41
re42 re43    
Rules
Assignment Rule (variable: total Caspase 3) Assignment Rule (variable: C3 fraction) Assignment Rule (variable: degraded C3 fraction) Assignment Rule (variable: pC3 fraction)
Assignment Rule (variable: free C3 fraction) Assignment Rule (variable: cPARP fraction)    
Physical entities
Compartments Species
cell L R flip
proC8 casp8 casp6
BAR proC3 casp3
Bid tBid proC6
XIAP Ub C3 PARP
cPARP Smac cytosolic Bcl-2
Bax Bax# L:R
R# flip:R# R#:pC8
C6:pC8 BAR:C8 C8:pC3
pC3:Apop Apop C8:Bid
C3:pC6 XIAP:C3 PARP:C3
Apop:XIAP Smac:XIAP Bcl2c:tBid
Bax:tBid CytoC Apaf
CytoC:Apaf Apaf# proC9
     
mitochondrion Bcl-2 Baxm:Bcl2 Bax4
Bax2:Bcl2 Bax4:Bcl2 M
Bax4:M M# Smac_m
M#:Smac_m Smac released CytoC_m
M#:CytoC_m CytoC released Baxm
Bax2    
Global parameters
k1 k_1 kc1 k2
k_2 k3 k_3 kc3
k4 k_4 k5 k_5
kc5 k6 k_6 kc6
k7 k_7 k8 k_8
kc8 k9 k_9 kc9
k10 k_10 kc10 k11
k_11 k12 k_12 kc12
k13 k_13 k14 k_14
k15 k_15 k16 k_16
k17 k_17 k18 k_18
k19 k_19 kc19 k20
k_20 kc20 k21 k_21
kc21 k22 k_22 k23
k_23 kc23 k24 k_24
k25 k_25 kc25 k26
k_26 k27 k_27 k28
k_28 kc7 v pC3 fraction
C3 fraction degraded C3 fraction cPARP fraction total Caspase 3
free C3 fraction      
Reactions (42)
 
 re1 [L] + [R] ↔ [L:R];  
 
 re2 [L:R] → [R#];  
 
 re3 [R#] + [flip] ↔ [flip:R#];  
 
 re4 [R#] + [proC8] ↔ [R#:pC8];  
 
 re5 [R#:pC8] → [casp8] + [R#];  
 
 re6 [casp6] + [proC8] ↔ [C6:pC8];  
 
 re7 [C6:pC8] → [casp8] + [casp6];  
 
 re8 [casp8] + [BAR] ↔ [BAR:C8];  
 
 re9 [proC3] + [casp8] ↔ [C8:pC3];  
 
 re10 [C8:pC3] → [casp8] + [casp3];  
 
 re11 [casp8] + [Bid] ↔ [C8:Bid];  
 
 re12 [C8:Bid] → [tBid] + [casp8];  
 
 re13 [proC3] + [Apop] ↔ [pC3:Apop];  
 
 re14 [pC3:Apop] → [casp3] + [Apop];  
 
 re15 [casp3] + [proC6] ↔ [C3:pC6];  
 
 re16 [C3:pC6] → [casp3] + [casp6];  
 
 re17 [casp3] + [XIAP] ↔ [XIAP:C3];  
 
 re18 [XIAP:C3] → [Ub C3] + [XIAP];  
 
 re19 [PARP] + [casp3] ↔ [PARP:C3];  
 
 re20 [PARP:C3] → [cPARP] + [casp3];  
 
 re21 [XIAP] + [Apop] ↔ [Apop:XIAP];  
 
 re22 [XIAP] + [Smac] ↔ [Smac:XIAP];  
 
 re23 [tBid] + [cytosolic Bcl-2] ↔ [Bcl2c:tBid];  
 
 re24 [tBid] + [Bax] ↔ [Bax:tBid];  
 
 re25 [Bax:tBid] → [tBid] + [Bax#];  
 
 re26 [Bax#] ↔ [Baxm];  
 
 re27 [Baxm] + [Bcl-2] ↔ [Baxm:Bcl2];  
 
 re29 [Baxm] + [Baxm] ↔ [Bax2];  
 
 re30 [Bax2] + [Bax2] ↔ [Bax4];  
 
 re31 [Bcl-2] + [Bax2] ↔ [Bax2:Bcl2];  
 
 re32 [Bcl-2] + [Bax4] ↔ [Bax4:Bcl2];  
 
 re33 [Bax4] + [M] ↔ [Bax4:M];  
 
 re34 [Bax4:M] → [M#];  
 
 re35 [M#] + [Smac_m] ↔ [M#:Smac_m];  
 
 re36 [M#:Smac_m] → [M#] + [Smac released];  
 
 re37 [Smac released] ↔ [Smac];  
 
 re38 [M#] + [CytoC_m] ↔ [M#:CytoC_m];  
 
 re39 [M#:CytoC_m] → [CytoC released] + [M#];  
 
 re40 [CytoC released] ↔ [CytoC];  
 
 re41 [CytoC] + [Apaf] ↔ [CytoC:Apaf];  
 
 re42 [CytoC:Apaf] → [CytoC] + [Apaf#];  
 
 re43 [Apaf#] + [proC9] ↔ [Apop];  
 
Rules (6)
 
 Assignment Rule (name: C3_tot) total Caspase 3 = pC3+C8_pC3+pC3_Apop+C3+C3_pC6+XIAP_C3+PARP_C3+C3_Ub
 
 Assignment Rule (name: C3_frac) C3 fraction = (C3+C3_pC6+XIAP_C3+PARP_C3)/C3_tot
 
 Assignment Rule (name: C3_UB_frac) degraded C3 fraction = C3_Ub/C3_tot
 
 Assignment Rule (name: pC3_frac) pC3 fraction = (pC3+C8_pC3+pC3_Apop)/C3_tot
 
 Assignment Rule (name: fC3_fract) free C3 fraction = C3/C3_tot
 
 Assignment Rule (name: cPARP_frac) cPARP fraction = CPARP/(CPARP+PARP+PARP_C3)
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 L
Compartment: cell
Initial amount: 3000.0
 
 R
Compartment: cell
Initial amount: 200.0
 
 flip
Compartment: cell
Initial amount: 100.0
 
 proC8
Compartment: cell
Initial amount: 20000.0
 
 casp8
Compartment: cell
Initial amount: 0.0
 
 casp6
Compartment: cell
Initial amount: 0.0
 
 BAR
Compartment: cell
Initial amount: 1000.0
 
 proC3
Compartment: cell
Initial amount: 10000.0
 
 casp3
Compartment: cell
Initial amount: 0.0
 
 Bid
Compartment: cell
Initial amount: 40000.0
 
 tBid
Compartment: cell
Initial amount: 0.0
 
 proC6
Compartment: cell
Initial amount: 10000.0
 
 XIAP
Compartment: cell
Initial amount: 100000.0
 
 Ub C3
Compartment: cell
Initial amount: 0.0
 
 PARP
Compartment: cell
Initial amount: 1000000.0
 
 cPARP
Compartment: cell
Initial amount: 0.0
 
 Smac
Compartment: cell
Initial amount: 0.0
 
 cytosolic Bcl-2
Compartment: cell
Initial amount: 20000.0
 
 Bax
Compartment: cell
Initial amount: 100000.0
 
 Bax#
Compartment: cell
Initial amount: 0.0
 
 L:R
Compartment: cell
Initial amount: 0.0
 
 R#
Compartment: cell
Initial amount: 0.0
 
 flip:R#
Compartment: cell
Initial amount: 0.0
 
 R#:pC8
Compartment: cell
Initial amount: 0.0
 
 C6:pC8
Compartment: cell
Initial amount: 0.0
 
 BAR:C8
Compartment: cell
Initial amount: 0.0
 
 C8:pC3
Compartment: cell
Initial amount: 0.0
 
 pC3:Apop
Compartment: cell
Initial amount: 0.0
 
 Apop
Compartment: cell
Initial amount: 0.0
 
 C8:Bid
Compartment: cell
Initial amount: 0.0
 
 C3:pC6
Compartment: cell
Initial amount: 0.0
 
 XIAP:C3
Compartment: cell
Initial amount: 0.0
 
 PARP:C3
Compartment: cell
Initial amount: 0.0
 
 Apop:XIAP
Compartment: cell
Initial amount: 0.0
 
 Smac:XIAP
Compartment: cell
Initial amount: 0.0
 
 Bcl2c:tBid
Compartment: cell
Initial amount: 0.0
 
 Bax:tBid
Compartment: cell
Initial amount: 0.0
 
 CytoC
Compartment: cell
Initial amount: 0.0
 
 Apaf
Compartment: cell
Initial amount: 100000.0
 
 CytoC:Apaf
Compartment: cell
Initial amount: 0.0
 
 Apaf#
Compartment: cell
Initial amount: 0.0
 
 proC9
Compartment: cell
Initial amount: 100000.0
 
 mitochondrion Spatial dimensions: 3.0  Compartment size: 1.0
 
 Bcl-2
Compartment: mitochondrion
Initial amount: 20000.0
 
 Baxm:Bcl2
Compartment: mitochondrion
Initial amount: 0.0
 
 Bax4
Compartment: mitochondrion
Initial amount: 0.0
 
 Bax2:Bcl2
Compartment: mitochondrion
Initial amount: 0.0
 
 Bax4:Bcl2
Compartment: mitochondrion
Initial amount: 0.0
 
 M
Compartment: mitochondrion
Initial amount: 500000.0
 
 Bax4:M
Compartment: mitochondrion
Initial amount: 0.0
 
 M#
Compartment: mitochondrion
Initial amount: 0.0
 
 Smac_m
Compartment: mitochondrion
Initial amount: 100000.0
 
 M#:Smac_m
Compartment: mitochondrion
Initial amount: 0.0
 
 Smac released
Compartment: mitochondrion
Initial amount: 0.0
 
 CytoC_m
Compartment: mitochondrion
Initial amount: 500000.0
 
 M#:CytoC_m
Compartment: mitochondrion
Initial amount: 0.0
 
 CytoC released
Compartment: mitochondrion
Initial amount: 0.0
 
 Baxm
Compartment: mitochondrion
Initial amount: 0.0
 
 Bax2
Compartment: mitochondrion
Initial amount: 0.0
 
Global Parameters (77)
 
   k1
Value: 4.0E-7
Constant
 
   k_1
Value: 0.0010
Constant
 
   kc1
Value: 1.0E-5
Constant
 
   k2
Value: 1.0E-6
Constant
 
   k_2
Value: 0.0010
Constant
 
   k3
Value: 1.0E-6
Constant
 
   k_3
Value: 0.0010
Constant
 
   kc3
Value: 1.0
Constant
 
   k4
Value: 1.0E-6
Constant
 
   k_4
Value: 0.0010
Constant
 
   k5
Value: 1.0E-7
Constant
 
   k_5
Value: 0.0010
Constant
 
   kc5
Value: 1.0
Constant
 
   k6
Value: 1.0E-6
Constant
 
   k_6
Value: 0.0010
Constant
 
   kc6
Value: 1.0
Constant
 
   k7
Value: 3.0E-8
Constant
 
   k_7
Value: 0.0010
Constant
 
   k8
Value: 2.0E-6
Constant
 
   k_8
Value: 0.0010
Constant
 
   kc8
Value: 0.1
Constant
 
   k9
Value: 1.0E-6
Constant
 
   k_9
Value: 0.01
Constant
 
   kc9
Value: 1.0
Constant
 
   k10
Value: 1.0E-7
Constant
 
   k_10
Value: 0.0010
Constant
 
   kc10
Value: 1.0
Constant
 
   k11
Value: 1.0E-6
Constant
 
   k_11
Value: 0.0010
Constant
 
   k12
Value: 1.0E-7
Constant
 
   k_12
Value: 0.0010
Constant
 
   kc12
Value: 1.0
Constant
 
   k13
Value: 0.01
Constant
 
   k_13
Value: 0.01
Constant
 
   k14
Value: 1.0E-6
Constant
 
   k_14
Value: 0.0010
Constant
 
   k15
Value: 1.0E-6
Constant
 
   k_15
Value: 0.0010
Constant
 
   k16
Value: 1.0E-6
Constant
 
   k_16
Value: 0.0010
Constant
 
   k17
Value: 1.0E-6
Constant
 
   k_17
Value: 0.0010
Constant
 
   k18
Value: 1.0E-6
Constant
 
   k_18
Value: 0.0010
Constant
 
   k19
Value: 1.0E-6
Constant
 
   k_19
Value: 0.0010
Constant
 
   kc19
Value: 1.0
Constant
 
   k20
Value: 2.0E-6
Constant
 
   k_20
Value: 0.0010
Constant
 
   kc20
Value: 10.0
Constant
 
   k21
Value: 2.0E-6
Constant
 
   k_21
Value: 0.0010
Constant
 
   kc21
Value: 10.0
Constant
 
   k22
Value: 0.01
Constant
 
   k_22
Value: 0.01
Constant
 
   k23
Value: 5.0E-7
Constant
 
   k_23
Value: 0.0010
Constant
 
   kc23
Value: 1.0
Constant
 
   k24
Value: 5.0E-8
Constant
 
   k_24
Value: 0.0010
Constant
 
   k25
Value: 5.0E-9
Constant
 
   k_25
Value: 0.0010
Constant
 
   kc25
Value: 1.0
Constant
 
   k26
Value: 0.01
Constant
 
   k_26
Value: 0.01
Constant
 
   k27
Value: 2.0E-6
Constant
 
   k_27
Value: 0.0010
Constant
 
   k28
Value: 7.0E-6
Constant
 
   k_28
Value: 0.0010
Constant
 
   kc7
Value: 1.0
Constant
 
   v
Value: 0.07
Constant
 
   pC3 fraction
Value: NaN
 
   C3 fraction
Value: NaN
 
   degraded C3 fraction
Value: NaN
 
   cPARP fraction
Value: NaN
 
   total Caspase 3
Value: NaN
 
   free C3 fraction
Value: NaN
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000220

Curator's comment: (updated: 07 Jul 2009 15:11:24 BST)

Reproduction of the first column of figure 5A of the original publication.

Simulations were performed using Copasi 4.5 (build 30). The different initial conditions were taken from the matlab files included in the supplementary materials of the article. For the upregulated Bcl-2 the initial number of mitochondrial Bcl-2 proteins was multiplied by 12 resulting in 240000. To model addition of XIAP siRNA its initial amount was multiplied by a factor 0.13 giving 13000.

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