ArticlePloS one2008
Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
Article in PloS one, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Dynamical analysis of a model of BCL-2-dependent cellular decision making.NPJ systems biology and applications · 2025Article
- Computational modeling of DLBCL predicts response to BH3-mimetics.NPJ systems biology and applications · 2023Article
- Mathematical Models of Death Signaling Networks.Entropy (Basel, Switzerland) · 2022Review
- An integrative systems biology approach to overcome venetoclax resistance in acute myeloid leukemia.PLoS computational biology · 2022Article
- Modeling the neuro-protection of theaflavic acid from black tea and its synergy with nimodipine via mitochondria apoptotic pathway.Journal of Zhejiang University. Science. B · 2021Article
- Joining and decomposing reaction networks.Journal of mathematical biology · 2020Article
- Systems analysis of phosphorylation-regulated Bcl-2 interactions establishes a model to reconcile the controversy over the significance of Bcl-2 phosphorylation.British journal of pharmacology · 2019Article
- Time to Decide? Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis.PloS one · 2016Article
- Mathematical models of the transitions between endocrine therapy responsive and resistant states in breast cancer.Journal of the Royal Society, Interface · 2014Article
- Boolean network-based model of the Bcl-2 family mediated MOMP regulation.Theoretical biology & medical modelling · 2013Article
- Data-driven modeling of SRC control on the mitochondrial pathway of apoptosis: implication for anticancer therapy optimization.PLoS computational biology · 2013Article
- Article
- Programming biological models in Python using PySB.Molecular systems biology · 2013Article
- The mathematical model of the Bcl-2 family mediated MOMP regulation can perform a non-trivial pattern recognition.PloS one · 2013Article
- Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.Biophysical journal · 2012Article
- Rigor of cell fate decision by variable p53 pulses and roles of cooperative gene expression by p53.Biophysics (Nagoya-shi, Japan) · 2012Article
- Dynamical behaviors of Rb-E2F pathway including negative feedback loops involving miR449.PloS one · 2012Article
- Computational modeling of signaling pathways mediating cell cycle checkpoint control and apoptotic responses to ionizing radiation-induced DNA damage.Dose-response : a publication of International Hormesis Society · 2012Article
- Steady states and dynamics of urokinase-mediated plasmin activation in silico and in vitro.Biophysical journal · 2011Article
- Dynamic modelling of oestrogen signalling and cell fate in breast cancer cells.Nature reviews. Cancer · 2011Review
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Authors and funding
5 authors.
Funding
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Abstract
backgroundThe complex interplay between B-cell lymphoma 2 (Bcl-2) family proteins constitutes a crucial checkpoint in apoptosis. Its detailed molecular mechanism remains controversial. Our former modeling studies have selected the 'Direct Activation Model' as a better explanation for experimental observations. In this paper, we continue to extend this model by adding interactions according to updating experimental findings. METHODOLOGY/PRINCIPAL
findingsThrough mathematical simulation we found bistability, a kind of switch, can arise from a positive (double negative) feedback in the Bcl-2 interaction network established by anti-apoptotic group of Bcl-2 family proteins. Moreover, Bax/Bak auto-activation as an independent positive feedback can enforce the bistability, and make it more robust to parameter variations. By ensemble stochastic modeling, we also elucidated how intrinsic noise can change ultrasensitive switches into gradual responses. Our modeling result agrees well with recent experimental data where bimodal Bax activation distributions in cell population were found. CONCLUSIONS/SIGNIFICANCE: Along with the growing experimental evidences, our studies successfully elucidate the switch mechanism embedded in the Bcl-2 interaction network and provide insights into pharmacological manipulation of Bcl-2 apoptotic switch as further cancer therapies.
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