Model Identifier
Short description

The model reproduces active Caspase-3 time profile corresponding to the total Apaf-1 value of 20 nM as depicted in Fig 2-A . The model was successfully tested on MathSBML.

Related Publication
  • Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability.
  • Legewie S, Blüthgen N, Herzel H
  • PLoS computational biology , 9/ 2006 , Volume 2 , pages: e120 , PubMed ID: 16978046
  • Institute for Theoretical Biology, Humboldt University, Berlin, Germany.
  • The intrinsic, or mitochondrial, pathway of caspase activation is essential for apoptosis induction by various stimuli including cytotoxic stress. It depends on the cellular context, whether cytochrome c released from mitochondria induces caspase activation gradually or in an all-or-none fashion, and whether caspase activation irreversibly commits cells to apoptosis. By analyzing a quantitative kinetic model, we show that inhibition of caspase-3 (Casp3) and Casp9 by inhibitors of apoptosis (IAPs) results in an implicit positive feedback, since cleaved Casp3 augments its own activation by sequestering IAPs away from Casp9. We demonstrate that this positive feedback brings about bistability (i.e., all-or-none behaviour), and that it cooperates with Casp3-mediated feedback cleavage of Casp9 to generate irreversibility in caspase activation. Our calculations also unravel how cell-specific protein expression brings about the observed qualitative differences in caspase activation (gradual versus all-or-none and reversible versus irreversible). Finally, known regulators of the pathway are shown to efficiently shift the apoptotic threshold stimulus, suggesting that the bistable caspase cascade computes multiple inputs into an all-or-none caspase output. As cellular inhibitory proteins (e.g., IAPs) frequently inhibit consecutive intermediates in cellular signaling cascades (e.g., Casp3 and Casp9), the feedback mechanism described in this paper is likely to be a widespread principle on how cells achieve ultrasensitivity, bistability, and irreversibility.
Nicolas Le Novère

Metadata information

BioModels Database MODEL8567576821
BioModels Database BIOMD0000000102
PubMed 16978046
Gene Ontology apoptotic process

Curation status

Name Description Size Actions

Model files

BIOMD0000000102_url.xml SBML L2V1 representation of Legewie2006_apoptosis_WT 56.63 KB Preview | Download

Additional files

BIOMD0000000102.pdf Auto-generated PDF file 231.37 KB Preview | Download
BIOMD0000000102.xpp Auto-generated XPP file 8.04 KB Preview | Download
BIOMD0000000102.m Auto-generated Octave file 11.22 KB Preview | Download
BIOMD0000000102.svg Auto-generated Reaction graph (SVG) 60.54 KB Preview | Download
BIOMD0000000102.sci Auto-generated Scilab file 191.00 Bytes Preview | Download
BIOMD0000000102.png Auto-generated Reaction graph (PNG) 234.27 KB Preview | Download
BIOMD0000000102_urn.xml Auto-generated SBML file with URNs 60.97 KB Preview | Download
BIOMD0000000102.vcml Auto-generated VCML file 76.32 KB Preview | Download
BIOMD0000000102-biopax2.owl Auto-generated BioPAX (Level 2) 39.65 KB Preview | Download
BIOMD0000000102-biopax3.owl Auto-generated BioPAX (Level 3) 66.20 KB Preview | Download

  • Model originally submitted by : Nicolas Le Novère
  • Submitted: 23-Mar-2007 10:57:49
  • Last Modified: 05-Mar-2014 16:59:25
  • Version: 2 public model Download this version
    • Submitted on: 05-Mar-2014 16:59:25
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Legewie2006_apoptosis_WT
  • Version: 1 public model Download this version
    • Submitted on: 23-Mar-2007 10:57:49
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Legewie2006_apoptosis_WT

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

: Variable used inside SBML models

Reactions Rate Parameters
AC9_star => cytosol*k27*AC9_star k27 = 0.001 sec_inverse
AC9_star + X => AC9_starX cytosol*(k12*AC9_star*X-k12b*AC9_starX) k12 = 0.001 per_nM_per_sec; k12b = 0.001 sec_inverse
AC9_starX => cytosol*k28*AC9_starX k28 = 0.001 sec_inverse
C9_star + X => C9_starX cytosol*(k11*C9_star*X-k11b*C9_starX) k11b = 0.001 sec_inverse; k11 = 0.001 per_nM_per_sec
C9_star => cytosol*k26*C9_star k26 = 0.001 sec_inverse
AC9 + C3_star => AC9_star + C3_star cytosol*k5*AC9*C3_star k5 = 2.0E-4 per_nM_per_sec
C9_starX + A => AC9_starX cytosol*(k14*C9_starX*A-k14b*AC9_starX) k14 = 0.002 per_nM_per_sec; k14b = 0.1 sec_inverse
A + C9 => AC9 cytosol*(k1*A*C9-kb1*AC9) k1 = 0.002 per_nM_per_sec; kb1 = 0.1 sec_inverse
C3 + C9 => C3_star + C9 cytosol*k2*C3*C9 k2 = 5.0E-6 per_nM_per_sec
C9X + A => AC9X cytosol*(k13*C9X*A-k13b*AC9X) k13 = 0.002 per_nM_per_sec; k13b = 0.1 sec_inverse
C9X => cytosol*k19*C9X k19 = 0.001 sec_inverse
C9 + X => C9X cytosol*(k9*C9*X-k9b*C9X) k9b = 0.001 sec_inverse; k9 = 0.001 per_nM_per_sec
=> X cytosol*(k18prod-k18*X) k18prod = 0.04 nM_per_sec; k18 = 0.001 sec_inverse
Curator's comment:
(added: 22 Mar 2007, 23:30:25, updated: 22 Mar 2007, 23:30:25)
The simulation image shown corresponds to active caspase-3 temporal evolution for Apaf-1 concentration of 20nM as depicted in Fig-2A of the paper. Result obtained from MathSBML.