Levels of pro-apoptotic regulator Bad and anti-apoptotic regulator Bcl-xL determine the type of the apoptotic logic gate

BMC Systems Biology

Tomasz Lipniacki¹  Marek Kochańczyk²  Beata Hat²  Marta N Bogdał³ 

[1] Department of Statistics, Rice University, Houston, TX 77025, USA;Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw 02-106, Poland;Department of Mathematics, Informatics and Mechanics, University of Warsaw, Warsaw 02-097, Poland

关键词: Ordinary differential equations;    Boolean logic;    Bistability;    Bcl-2 family;    Signaling pathway;    Cell survival;    Apoptosis;   

Others  :  1142472
DOI  :  10.1186/1752-0509-7-67

 received in 2013-03-21, accepted in 2013-07-11,  发布年份 2013

【 摘 要 】

Background

Apoptosis is a tightly regulated process: cellular survive-or-die decisions cannot be accidental and must be unambiguous. Since the suicide program may be initiated in response to numerous stress stimuli, signals transmitted through a number of checkpoints have to be eventually integrated.

Results

In order to analyze possible mechanisms of the integration of multiple pro-apoptotic signals, we constructed a simple model of the Bcl-2 family regulatory module. The module collects upstream signals and processes them into life-or-death decisions by employing interactions between proteins from three subgroups of the Bcl-2 family: pro-apoptotic multidomain effectors, pro-survival multidomain restrainers, and pro-apoptotic single domain BH3-only proteins. Although the model is based on ordinary differential equations (ODEs), it demonstrates that the Bcl-2 family module behaves akin to a Boolean logic gate of the type dependent on levels of BH3-only proteins (represented by Bad) and restrainers (represented by Bcl-xL). A low level of pro-apoptotic Bad or a high level of pro-survival Bcl-xL implies gate AND, which allows for the initiation of apoptosis only when two stress stimuli are simultaneously present: the rise of the p53 killer level and dephosphorylation of kinase Akt. In turn, a high level of Bad or a low level of Bcl-xL implies gate OR, for which any of these stimuli suffices for apoptosis.

Conclusions

Our study sheds light on possible signal integration mechanisms in cells, and spans a bridge between modeling approaches based on ODEs and on Boolean logic. In the proposed scheme, logic gates switching results from the change of relative abundances of interacting proteins in response to signals and involves system bistability. Consequently, the regulatory system may process two analogous inputs into a digital survive-or-die decision.

【 授权许可】

   
2013 Bogdał et al.; licensee BioMed Central Ltd.

【 图 表 】

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