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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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Bax in the input signals (p53killer, Aktu)-plane for three considered logic gates. (A) gate OR, (B) gate AND, (C) gate AND*. For all gates the black curve is the apoptotic isoline Bax = Baxbif = 5000. For values of Aktu and p53killer above the Bax = Baxbif isoline cell undergoes apoptosis, for values of Aktu and p53killer below this curve cell survives.
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Figure 7: Bax in the input signals (p53killer, Aktu)-plane for three considered logic gates. (A) gate OR, (B) gate AND, (C) gate AND*. For all gates the black curve is the apoptotic isoline Bax = Baxbif = 5000. For values of Aktu and p53killer above the Bax = Baxbif isoline cell undergoes apoptosis, for values of Aktu and p53killer below this curve cell survives.

Mentions: In Figure 7 we investigate system responses top53killer andAktu both in the range (0, 2 × 105), assuming levels ofBadtot andBcl-xL tot adequate to the gate type (Table 2). TheBax = Baxbif=5000 isoline (white line) separates inputs {p53killer,Aktu} leading either to apoptosis or to survival. In gate OR (Figure 7A), apoptosis is activated for a relatively weak stimulation. It is triggered when steady state inputs satisfyp53killer>0.66 × 105 orAktu>0.65 × 105, but even weaker signals, when in cooperation, may result in apoptosis. In contrast, in gate AND (Figure 7B) apoptosis requires cooperation of two stronger signals; for eitherp53killer<0.84 × 105 orAktu<1.37 × 105 apoptosis cannot be initiated. In gate AND*, a higherAktu than in gate AND is required to trigger apoptosis (Figure 7C).


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)

Bax in the input signals (p53killer, Aktu)-plane for three considered logic gates. (A) gate OR, (B) gate AND, (C) gate AND*. For all gates the black curve is the apoptotic isoline Bax = Baxbif = 5000. For values of Aktu and p53killer above the Bax = Baxbif isoline cell undergoes apoptosis, for values of Aktu and p53killer below this curve cell survives.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Bax in the input signals (p53killer, Aktu)-plane for three considered logic gates. (A) gate OR, (B) gate AND, (C) gate AND*. For all gates the black curve is the apoptotic isoline Bax = Baxbif = 5000. For values of Aktu and p53killer above the Bax = Baxbif isoline cell undergoes apoptosis, for values of Aktu and p53killer below this curve cell survives.
Mentions: In Figure 7 we investigate system responses top53killer andAktu both in the range (0, 2 × 105), assuming levels ofBadtot andBcl-xL tot adequate to the gate type (Table 2). TheBax = Baxbif=5000 isoline (white line) separates inputs {p53killer,Aktu} leading either to apoptosis or to survival. In gate OR (Figure 7A), apoptosis is activated for a relatively weak stimulation. It is triggered when steady state inputs satisfyp53killer>0.66 × 105 orAktu>0.65 × 105, but even weaker signals, when in cooperation, may result in apoptosis. In contrast, in gate AND (Figure 7B) apoptosis requires cooperation of two stronger signals; for eitherp53killer<0.84 × 105 orAktu<1.37 × 105 apoptosis cannot be initiated. In gate AND*, a higherAktu than in gate AND is required to trigger apoptosis (Figure 7C).

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