Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch

The 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 ob...

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Bibliographic Details
Published in:PloS one 2008-01, Vol.3 (1), p.e1469
Main Authors: Cui, Jun, Chen, Chun, Lu, Haizhu, Sun, Tingzhe, Shen, Pingping
Format: Article
Language:English
Subjects:
Activation
Analysis
Apoptosis
B-cell lymphoma
BAX protein
Bcl-2 protein
Biochemistry/Theory and Simulation
Biophysics
Biotechnology
Bistability
Cancer
Cell activation
Cell Biology/Cell Signaling
Computational Biology/Systems Biology
Computer simulation
Feedback
Laboratories
Life sciences
Lymphocytes B
Lymphoma
Lymphomas
Mathematical models
Mitochondria
Models, Theoretical
Permeability
Pharmaceuticals
Pharmacology
Positive feedback
Proteins
Proto-Oncogene Proteins c-bcl-2 - drug effects
Proto-Oncogene Proteins c-bcl-2 - physiology
Robustness (mathematics)
Simulation
Stochasticity
Switches
Tumors
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Summary:The 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. Through 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0001469