Albeck2008_extrinsic_apoptosis

  public model
Model Identifier
BIOMD0000000220
Short description

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 .


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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.

Format
SBML (L2V1)
Related Publication
  • Quantitative analysis of pathways controlling extrinsic apoptosis in single cells.
  • Albeck JG, Burke JM, Aldridge BB, Zhang M, Lauffenburger DA, Sorger PK
  • Molecular cell , 4/ 2008 , Volume 30 , pages: 11-25 , PubMed ID: 18406323
  • Department of Systems Biology, Harvard Medical School, WAB Room 438, 200 Longwood Avenue, Boston, MA 02115, USA.
  • 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.
Contributors
Laurence Calzone

Metadata information

is
BioModels Database MODEL6964793701
BioModels Database BIOMD0000000220
isDescribedBy
PubMed 18406323
hasTaxon
Taxonomy Homo sapiens
isVersionOf

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000220_url.xml SBML L2V1 representation of Albeck2008_extrinsic_apoptosis 310.49 KB Preview | Download

Additional files

BIOMD0000000220.png Auto-generated Reaction graph (PNG) 341.82 KB Preview | Download
BIOMD0000000220_urn.xml Auto-generated SBML file with URNs 309.09 KB Preview | Download
BIOMD0000000220-biopax2.owl Auto-generated BioPAX (Level 2) 71.62 KB Preview | Download
BIOMD0000000220.pdf Auto-generated PDF file 356.51 KB Preview | Download
BIOMD0000000220.xpp Auto-generated XPP file 16.34 KB Preview | Download
BIOMD0000000220.sci Auto-generated Scilab file 18.06 KB Preview | Download
BIOMD0000000220-biopax3.owl Auto-generated BioPAX (Level 3) 121.11 KB Preview | Download
BIOMD0000000220.m Auto-generated Octave file 21.08 KB Preview | Download
BIOMD0000000220.svg Auto-generated Reaction graph (SVG) 112.00 KB Preview | Download
BIOMD0000000220.vcml Auto-generated VCML file 130.38 KB Preview | Download

  • Model originally submitted by : Laurence Calzone
  • Submitted: 13-Mar-2009 17:19:53
  • Last Modified: 25-Feb-2015 12:42:31
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 25-Feb-2015 12:42:31
    • Submitted by: Laurence Calzone
    • With comment: Current version of Albeck2008_extrinsic_apoptosis
  • Version: 1 public model Download this version
    • Submitted on: 13-Mar-2009 17:19:53
    • Submitted by: Laurence Calzone
    • With comment: Original import of BIOMD0000000220.xml.origin
Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
(L + R) => (L:R)

([Tumor necrosis factor ligand superfamily member 10; TNFSF10 [extracellular region]] + [Tumor necrosis factor receptor superfamily member 10B; TNFRSF10B [plasma membrane]]) => ([REACT_5556; Tumor necrosis factor ligand superfamily member 10; Tumor necrosis factor receptor superfamily member 10B])
cell*(L*R*k1-L_R*k_1)

cell*([Tumor necrosis factor ligand superfamily member 10; TNFSF10 [extracellular region]]*[Tumor necrosis factor receptor superfamily member 10B; TNFRSF10B [plasma membrane]]*k1-[REACT_5556; Tumor necrosis factor ligand superfamily member 10; Tumor necrosis factor receptor superfamily member 10B]*k_1)
k_1 = 0.001; k1 = 4.0E-7
(R# + flip) => (flip:R#)

([Tumor necrosis factor receptor superfamily member 10B] + [CASP8 and FADD-like apoptosis regulator; CFLAR(1-376) [cytosol]; 603599]) => ([flip:R#])
cell*(R_hash*flip*k2-flip_R_hash*k_2)

cell*([Tumor necrosis factor receptor superfamily member 10B]*[CASP8 and FADD-like apoptosis regulator; CFLAR(1-376) [cytosol]; 603599]*k2-[[CASP8 and FADD-like apoptosis regulator; CFLAR(1-376) [cytosol]; 603599]:[Tumor necrosis factor receptor superfamily member 10B; TNFRSF10B [plasma membrane]]#]*k_2)
k_2 = 0.001; k2 = 1.0E-6
(R# + proC8) => (R#:pC8)

([Tumor necrosis factor receptor superfamily member 10B] + [Caspase-8; CASP8(1-479) [cytosol]]) => ([R#:pC8])
cell*(R_hash*pC8*k3-R_hash_pC8*k_3)

cell*([Tumor necrosis factor receptor superfamily member 10B]*[Caspase-8; CASP8(1-479) [cytosol]]*k3-[[Tumor necrosis factor receptor superfamily member 10B; TNFRSF10B [plasma membrane]]#:[Caspase-8; CASP8(1-479) [cytosol]]]*k_3)
k3 = 1.0E-6; k_3 = 0.001
(casp6 + proC8) => (C6:pC8)

([casp6] + [Caspase-8; CASP8(1-479) [cytosol]]) => ([C6:pC8])
cell*(C6*pC8*k7-C6_pC8*k_7)

cell*([casp6]*[Caspase-8; CASP8(1-479) [cytosol]]*k7-[[casp6]:[Caspase-8; CASP8(1-479) [cytosol]]]*k_7)
k_7 = 0.001; k7 = 3.0E-8
(R#:pC8) => (casp8 + R#)

([R#:pC8]) => ([Caspase-8 dimer [cytosol]] + [Tumor necrosis factor receptor superfamily member 10B])
cell*R_hash_pC8*kc3

cell*[[Tumor necrosis factor receptor superfamily member 10B; TNFRSF10B [plasma membrane]]#:[Caspase-8; CASP8(1-479) [cytosol]]]*kc3
kc3 = 1.0
(C6:pC8) => (casp8 + casp6)

([C6:pC8]) => ([Caspase-8 dimer [cytosol]] + [casp6])
cell*C6_pC8*kc7

cell*[[casp6]:[Caspase-8; CASP8(1-479) [cytosol]]]*kc7
kc7 = 1.0
(C8:pC3) => (casp8 + casp3)

([C8:pC3]) => ([Caspase-8 dimer [cytosol]] + [casp3])
cell*C8_pC3*kc5

cell*[[Caspase-8 dimer [cytosol]]:[Caspase-3]]*kc5
kc5 = 1.0
(casp8 + Bid) => (C8:Bid)

([Caspase-8 dimer [cytosol]] + [BH3-interacting domain death agonist; BID(1-195) [cytosol]; 601997]) => ([C8:Bid])
cell*(C8*Bid*k10-C8_Bid*k_10)

cell*([Caspase-8 dimer [cytosol]]*[BH3-interacting domain death agonist; BID(1-195) [cytosol]; 601997]*k10-[C8:Bid]*k_10)
k10 = 1.0E-7; k_10 = 0.001
(C3:pC6) => (casp3 + casp6)

([C3:pC6]) => ([casp3] + [casp6])
cell*C3_pC6*kc6

cell*[[casp3]:[Caspase-6]]*kc6
kc6 = 1.0
(proC3 + casp8) => (C8:pC3)

([Caspase-3] + [Caspase-8 dimer [cytosol]]) => ([C8:pC3])
cell*(pC3*C8*k5-C8_pC3*k_5)

cell*([Caspase-3]*[Caspase-8 dimer [cytosol]]*k5-[[Caspase-8 dimer [cytosol]]:[Caspase-3]]*k_5)
k5 = 1.0E-7; k_5 = 0.001
(proC3 + Apop) => (pC3:Apop)

([Caspase-3] + [Cytochrome c; Apoptotic protease-activating factor 1; Caspase-9; Cytochrome C:Apaf-1:ATP:Procaspase-9 [cytosol]; apoptosome]) => ([pC3:Apop])
cell*(pC3*Apop*k25-pC3_Apop*k_25)

cell*([Caspase-3]*[Cytochrome c; Apoptotic protease-activating factor 1; Caspase-9; Cytochrome C:Apaf-1:ATP:Procaspase-9 [cytosol]; apoptosome]*k25-[[Caspase-3]:[Cytochrome c; Apoptotic protease-activating factor 1; Caspase-9; Cytochrome C:Apaf-1:ATP:Procaspase-9 [cytosol]; apoptosome]]*k_25)
k25 = 5.0E-9; k_25 = 0.001
(pC3:Apop) => (casp3 + Apop)

([pC3:Apop]) => ([casp3] + [Cytochrome c; Apoptotic protease-activating factor 1; Caspase-9; Cytochrome C:Apaf-1:ATP:Procaspase-9 [cytosol]; apoptosome])
cell*pC3_Apop*kc25

cell*[[Caspase-3]:[Cytochrome c; Apoptotic protease-activating factor 1; Caspase-9; Cytochrome C:Apaf-1:ATP:Procaspase-9 [cytosol]; apoptosome]]*kc25
kc25 = 1.0
Curator's comment:
(added: 07 Jul 2009, 15:11:24, updated: 07 Jul 2009, 15:11:24)
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.