IDEAS home Printed from
MyIDEAS: Log in (now much improved!) to save this article

Computational study of the mechanism of Bcl-2 apoptotic switch

Listed author(s):
  • Tokár, Tomáš
  • Uličný, Jozef
Registered author(s):

    In spite of attention devoted to molecular mechanisms of apoptosis, the details of functioning of one crucial component–the Bcl-2 apoptotic switch–are not completely understood. There are two competing mechanisms of its internal working—the indirect activation and the direct activation. In the absence of conclusive experimental data, we have used computational modeling to assess the properties of both mechanisms and their suitability to act as a biological switch. Since the two mechanisms form opposite poles of continuum of Bcl-2 molecular interaction models, we have constructed more general models including these two models as extreme cases. By studying the relationship between model parameters and the steady-state response we have found optimal interaction patterns which reproduce the behavior of the Bcl-2 apoptotic switch. Our results show, that stimulus–response ultrasensitivity is negatively affected by spontaneous activation of Bcl-2 effectors. We found that ultrasensitivity requires effectors activation, mediated by another subgroup of Bcl-2 proteins—activators. We have shown that the auto-activation of monomeric effector forms provides an ultrasensitivity enhancing feedback loop. Thorough robustness analysis revealed that the interaction pattern postulated in the direct activation hypothesis is able to conserve stimulus–response switching characteristics for wide range changes of its internal parameters. The robustness of the switch against the variation of the reaction parameter is strongly reduced for the intermediate hybrid model and even more for the indirect part of the models. Computer simulations of the more general model presented here suggest, that stimulus–response ultrasensitivity is an emergent property of the direct activation model that is unlikely to occur in the model of indirect activation. Introduction of indirect-model-specific interactions does not provide a better explanation of the Bcl-2 switch functionality compared to the direct model.

    If you experience problems downloading a file, check if you have the proper application to view it first. In case of further problems read the IDEAS help page. Note that these files are not on the IDEAS site. Please be patient as the files may be large.

    File URL:
    Download Restriction: Full text for ScienceDirect subscribers only. Journal offers the option of making the article available online on Science direct for a fee of $3,000

    As the access to this document is restricted, you may want to look for a different version under "Related research" (further below) or search for a different version of it.

    Article provided by Elsevier in its journal Physica A: Statistical Mechanics and its Applications.

    Volume (Year): 391 (2012)
    Issue (Month): 23 ()
    Pages: 6212-6225

    in new window

    Handle: RePEc:eee:phsmap:v:391:y:2012:i:23:p:6212-6225
    DOI: 10.1016/j.physa.2012.07.006
    Contact details of provider: Web page:

    No references listed on IDEAS
    You can help add them by filling out this form.

    This item is not listed on Wikipedia, on a reading list or among the top items on IDEAS.

    When requesting a correction, please mention this item's handle: RePEc:eee:phsmap:v:391:y:2012:i:23:p:6212-6225. See general information about how to correct material in RePEc.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: (Dana Niculescu)

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If references are entirely missing, you can add them using this form.

    If the full references list an item that is present in RePEc, but the system did not link to it, you can help with this form.

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your profile, as there may be some citations waiting for confirmation.

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    This information is provided to you by IDEAS at the Research Division of the Federal Reserve Bank of St. Louis using RePEc data.