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

Bogdał MN, Hat B, Kochańczyk M, Lipniacki T - BMC Syst Biol (2013)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw 02-106, Poland.

ABSTRACT

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.

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Bifurcation diagram for Casp vs. Bax. Saddle-node bifurcation point is (Baxbif, Caspbif) ≃ (5000, 1000). The unstable steady state is marked by dashed line. Solid lines show high and low stable steady states corresponding to apoptosis and survival, respectively. (Note the logarithmic scale on the vertical axis).
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Figure 3: Bifurcation diagram for Casp vs. Bax. Saddle-node bifurcation point is (Baxbif, Caspbif) ≃ (5000, 1000). The unstable steady state is marked by dashed line. Solid lines show high and low stable steady states corresponding to apoptosis and survival, respectively. (Note the logarithmic scale on the vertical axis).

Mentions: The last two equations exhibit bistability. In Figure 3 we show the bifurcation diagram of Casp with Bax considered as a bifurcation parameter. Casp undergoes the saddle-node bifurcation at Bax=Baxbif≃5000 (with Casp≃1000). Below the bifurcation point there exist three steady states: one unstable and two stable corresponding to low (<1000) and high (>9.9 × 104) caspase levels. Above the bifurcation point there exists the unique stable steady state characterized by high Casp. The structure of the bifurcation diagram ensures that the apoptotic switch is irreversible, i.e. once the system switches to the apoptotic state, it may not switch back even if the level of free effectors, Bax, drops to zero. The apoptotic switch occurs when Bax exceeds Baxbif for sufficiently long time; as we will show later, short excursions of Bax over Baxbif do not induce apoptosis. For the steady state analysis, however, the states with Bax>Baxbif will be interpreted as apoptotic.


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

Bogdał MN, Hat B, Kochańczyk M, Lipniacki T - BMC Syst Biol (2013)

Bifurcation diagram for Casp vs. Bax. Saddle-node bifurcation point is (Baxbif, Caspbif) ≃ (5000, 1000). The unstable steady state is marked by dashed line. Solid lines show high and low stable steady states corresponding to apoptosis and survival, respectively. (Note the logarithmic scale on the vertical axis).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750306&req=5

Figure 3: Bifurcation diagram for Casp vs. Bax. Saddle-node bifurcation point is (Baxbif, Caspbif) ≃ (5000, 1000). The unstable steady state is marked by dashed line. Solid lines show high and low stable steady states corresponding to apoptosis and survival, respectively. (Note the logarithmic scale on the vertical axis).
Mentions: The last two equations exhibit bistability. In Figure 3 we show the bifurcation diagram of Casp with Bax considered as a bifurcation parameter. Casp undergoes the saddle-node bifurcation at Bax=Baxbif≃5000 (with Casp≃1000). Below the bifurcation point there exist three steady states: one unstable and two stable corresponding to low (<1000) and high (>9.9 × 104) caspase levels. Above the bifurcation point there exists the unique stable steady state characterized by high Casp. The structure of the bifurcation diagram ensures that the apoptotic switch is irreversible, i.e. once the system switches to the apoptotic state, it may not switch back even if the level of free effectors, Bax, drops to zero. The apoptotic switch occurs when Bax exceeds Baxbif for sufficiently long time; as we will show later, short excursions of Bax over Baxbif do not induce apoptosis. For the steady state analysis, however, the states with Bax>Baxbif will be interpreted as apoptotic.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw 02-106, Poland.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus