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Two Independent Positive Feedbacks and Bistability in the Bcl-2 Apoptotic Switch

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  • Jun Cui
  • Chun Chen
  • Haizhu Lu
  • Tingzhe Sun
  • Pingping Shen

Abstract

Background: 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. Methodology/Principal 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. 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.

Suggested Citation

  • Jun Cui & Chun Chen & Haizhu Lu & Tingzhe Sun & Pingping Shen, 2008. "Two Independent Positive Feedbacks and Bistability in the Bcl-2 Apoptotic Switch," PLOS ONE, Public Library of Science, vol. 3(1), pages 1-9, January.
  • Handle: RePEc:plo:pone00:0001469
    DOI: 10.1371/journal.pone.0001469
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    References listed on IDEAS

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    1. Michael O. Hengartner, 2000. "The biochemistry of apoptosis," Nature, Nature, vol. 407(6805), pages 770-776, October.
    2. Tilman Oltersdorf & Steven W. Elmore & Alexander R. Shoemaker & Robert C. Armstrong & David J. Augeri & Barbara A. Belli & Milan Bruncko & Thomas L. Deckwerth & Jurgen Dinges & Philip J. Hajduk & Mary, 2005. "An inhibitor of Bcl-2 family proteins induces regression of solid tumours," Nature, Nature, vol. 435(7042), pages 677-681, June.
    3. Stefan Legewie & Nils Blüthgen & Hanspeter Herzel, 2006. "Mathematical Modeling Identifies Inhibitors of Apoptosis as Mediators of Positive Feedback and Bistability," PLOS Computational Biology, Public Library of Science, vol. 2(9), pages 1-13, September.
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