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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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Crosstalk of pro-apoptotic and pro-survival pathways. The intracellular pro-apoptotic signal is mediated through p53killer. Elevated p53killer activates expression of PTEN, which leads to the inactivation of pro-survival Akt. Activity of Akt is also regulated by extracellular growth factors. For the apoptotic module analysis, both input signals, p53killer and Aktu, are considered independently. Arrow-headed lines indicate protein transformation, circle-headed lines denote activation or transcriptional regulation, hammer-headed lines denote repression.
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Figure 1: Crosstalk of pro-apoptotic and pro-survival pathways. The intracellular pro-apoptotic signal is mediated through p53killer. Elevated p53killer activates expression of PTEN, which leads to the inactivation of pro-survival Akt. Activity of Akt is also regulated by extracellular growth factors. For the apoptotic module analysis, both input signals, p53killer and Aktu, are considered independently. Arrow-headed lines indicate protein transformation, circle-headed lines denote activation or transcriptional regulation, hammer-headed lines denote repression.

Mentions: In this study we aim to address the question, whether the interaction network of Bcl-2 family proteins allows for the integration of apoptotic signals, and if yes, whether this signal integration is analogous to Boolean logic gates. Boolean networks are used to model various regulatory pathways, including apoptotic ones [86], however, the analysis of correspondence between biochemical reaction kinetics (which can be approximated by systems of ODEs) and the Boolean approach is missing. Here, following Wee et al. [78] we focus on two key pathways leading to apoptosis: one mediated by p53 and the other by Akt. As already discussed, p53 activates expression of PTEN, thus the elevated level of p53 results in the decreased level of phosphorylated Akt. However, since Akt activity is also regulated by growth factors (Figure 1), in our model the p53 and Akt pathways will be considered independently. We will analyze how the apoptotic signals are collected and processed before the apoptosis-or-survival decision is attained. In accordance with previous studies, we will assume that the apoptotic switch is based on bistability arising due to positive feedback mediated by caspase-3, and nonlinearity. We will demonstrate that the topology of the mitochondrial apoptotic module allows for the integration of signals in the manner analogous to the logic gates AND or OR, depending on the levels of pro-apoptotic Bad and pro-survival Bcl-xL.


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)

Crosstalk of pro-apoptotic and pro-survival pathways. The intracellular pro-apoptotic signal is mediated through p53killer. Elevated p53killer activates expression of PTEN, which leads to the inactivation of pro-survival Akt. Activity of Akt is also regulated by extracellular growth factors. For the apoptotic module analysis, both input signals, p53killer and Aktu, are considered independently. Arrow-headed lines indicate protein transformation, circle-headed lines denote activation or transcriptional regulation, hammer-headed lines denote repression.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Crosstalk of pro-apoptotic and pro-survival pathways. The intracellular pro-apoptotic signal is mediated through p53killer. Elevated p53killer activates expression of PTEN, which leads to the inactivation of pro-survival Akt. Activity of Akt is also regulated by extracellular growth factors. For the apoptotic module analysis, both input signals, p53killer and Aktu, are considered independently. Arrow-headed lines indicate protein transformation, circle-headed lines denote activation or transcriptional regulation, hammer-headed lines denote repression.
Mentions: In this study we aim to address the question, whether the interaction network of Bcl-2 family proteins allows for the integration of apoptotic signals, and if yes, whether this signal integration is analogous to Boolean logic gates. Boolean networks are used to model various regulatory pathways, including apoptotic ones [86], however, the analysis of correspondence between biochemical reaction kinetics (which can be approximated by systems of ODEs) and the Boolean approach is missing. Here, following Wee et al. [78] we focus on two key pathways leading to apoptosis: one mediated by p53 and the other by Akt. As already discussed, p53 activates expression of PTEN, thus the elevated level of p53 results in the decreased level of phosphorylated Akt. However, since Akt activity is also regulated by growth factors (Figure 1), in our model the p53 and Akt pathways will be considered independently. We will analyze how the apoptotic signals are collected and processed before the apoptosis-or-survival decision is attained. In accordance with previous studies, we will assume that the apoptotic switch is based on bistability arising due to positive feedback mediated by caspase-3, and nonlinearity. We will demonstrate that the topology of the mitochondrial apoptotic module allows for the integration of signals in the manner analogous to the logic gates AND or OR, depending on the levels of pro-apoptotic Bad and pro-survival Bcl-xL.

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