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.

Format
SBML (L2V1)
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
  • Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.legewie@biologie.hu-berlin.de
  • 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.
Contributors
Nicolas Le Novère

Metadata information

is
BioModels Database MODEL8567576821
BioModels Database BIOMD0000000102
isDescribedBy
PubMed 16978046
hasTaxon
Taxonomy Homo sapiens
isVersionOf
Gene Ontology apoptotic process
isPartOf
Curation status
Curated
  • Model originally submitted by : Nicolas Le Novère
  • Submitted: 23-Mar-2007 10:57:49
  • Last Modified: 05-Mar-2014 16:59:25
Revisions
  • 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
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.