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

PloS One
Jun CuiPingping Shen

Abstract

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 manipul...Continue Reading

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Citations

Dec 5, 2008·PLoS Biology·John G AlbeckPeter K Sorger
Dec 17, 2008·Theoretical Biology & Medical Modelling·Heather A HarringtonK C Tung
Jun 24, 2009·BMC Bioinformatics·Tingzhe SunPingping Shen
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Jan 26, 2010·FEBS Letters·Tingzhe SunPingping Shen
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Mar 4, 2020·Journal of Mathematical Biology·Elizabeth GrossAnne Shiu
Dec 12, 2012·Molecular BioSystems·Orsolya KapuyGábor Bánhegyi
Oct 19, 2011·Biophysical Journal·Lakshmi VenkatramanLisa Tucker-Kellogg

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Methods Mentioned

BETA
flow-cytometry

Software Mentioned

Matlab

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