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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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Transitions between gate types. (A) transition from gate OR to gate AND, (B) transition from gate OR to AND*. Apoptotic (Bax = Baxbif = 5000) isolines are plotted in the input signals (p53killer, Aktu)-plane. Black dots in (A) denote {p53killer, Aktu} pairs of input signals analyzed in Figures 9 and 10.
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Figure 8: Transitions between gate types. (A) transition from gate OR to gate AND, (B) transition from gate OR to AND*. Apoptotic (Bax = Baxbif = 5000) isolines are plotted in the input signals (p53killer, Aktu)-plane. Black dots in (A) denote {p53killer, Aktu} pairs of input signals analyzed in Figures 9 and 10.

Mentions: In Figure 8A we determinedBax = 5000 isolines in the (p53killer,Aktu)-plane for different levels ofBadtot. For {p53killer,Aktu} “above” each isoline value the cell undergoes apoptosis, whenever itsBadtot is greater or equalBadtot value for that isoline. Gate AND arises forBadtot≲0.9 × 105, while gate OR arises for. ForBadtot∈(0.9 × 105,1.1 × 105) the full dephosphorylation of Akt (Aktu= Akttot) leads to apoptosis (for an arbitraryp53killer) but the increase ofp53killer to its highest assumed value () does not suffice for apoptosis without the additional signal from Akt.


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)

Transitions between gate types. (A) transition from gate OR to gate AND, (B) transition from gate OR to AND*. Apoptotic (Bax = Baxbif = 5000) isolines are plotted in the input signals (p53killer, Aktu)-plane. Black dots in (A) denote {p53killer, Aktu} pairs of input signals analyzed in Figures 9 and 10.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Transitions between gate types. (A) transition from gate OR to gate AND, (B) transition from gate OR to AND*. Apoptotic (Bax = Baxbif = 5000) isolines are plotted in the input signals (p53killer, Aktu)-plane. Black dots in (A) denote {p53killer, Aktu} pairs of input signals analyzed in Figures 9 and 10.
Mentions: In Figure 8A we determinedBax = 5000 isolines in the (p53killer,Aktu)-plane for different levels ofBadtot. For {p53killer,Aktu} “above” each isoline value the cell undergoes apoptosis, whenever itsBadtot is greater or equalBadtot value for that isoline. Gate AND arises forBadtot≲0.9 × 105, while gate OR arises for. ForBadtot∈(0.9 × 105,1.1 × 105) the full dephosphorylation of Akt (Aktu= Akttot) leads to apoptosis (for an arbitraryp53killer) but the increase ofp53killer to its highest assumed value () does not suffice for apoptosis without the additional signal from Akt.

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