Limits...
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.

Show MeSH

Related in: MedlinePlus

Steady-state concentrations for gate AND. Transition from OR to AND results from the decrease of Badtot. The simultaneous presence of both input signals, p53killer and Aktu, is necessary to induce apoptosis. Heights of bars correspond to the steady-state levels of proteins. Bars sharing adjacent sides (marked with colons and color gradient) denote complexes. To keep the convention, some bars do not start from 0. (A) The steady state levels of proteins and complexes corresponding to p53killer = 0 and Aktu = 0 (surviving cell, in the presence of growth factors). (B, C) a single maximal pro-apoptotic signal neither from p53killer nor from Aktu suffices to trigger apoptosis. (D) Simultaneous presence of both signals triggers apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3750306&req=5

Figure 5: Steady-state concentrations for gate AND. Transition from OR to AND results from the decrease of Badtot. The simultaneous presence of both input signals, p53killer and Aktu, is necessary to induce apoptosis. Heights of bars correspond to the steady-state levels of proteins. Bars sharing adjacent sides (marked with colons and color gradient) denote complexes. To keep the convention, some bars do not start from 0. (A) The steady state levels of proteins and complexes corresponding to p53killer = 0 and Aktu = 0 (surviving cell, in the presence of growth factors). (B, C) a single maximal pro-apoptotic signal neither from p53killer nor from Aktu suffices to trigger apoptosis. (D) Simultaneous presence of both signals triggers apoptosis.

Mentions: We will analyze the steady states of the system for two levels of Bad in order to demonstrate that the gate OR is achieved for Badtot=2 × 105, while gate AND is achieved for Badtot=0.6 × 105; here, for both gates we assume the same Bcl-xL tot=1 × 105. Surviving cell steady state is associated with conditions in which both apoptotic signals are equal zero. In these cells (Figures 4A and 5A) most of Bad is in the phosphorylated form bound to Scaffold14-3-3. The remaining (unphosphorylated) Bad is bound to Bcl-xL. Rest of Bcl-xL sequesters Bax or remains free. Free Bcl-xL may be considered as the anti-apoptotic buffer, which may potentially capture the excess of Bax. This buffer of free Bcl-xL is small (about 104 molecules) for gate OR (Figure 4A) and much larger (about 6 × 104 molecules) for gate AND (Figure 5A). Size of the Bcl-xL buffer determines cell susceptibility to apoptosis: small buffer renders cells more prone to apoptosis.


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)

Steady-state concentrations for gate AND. Transition from OR to AND results from the decrease of Badtot. The simultaneous presence of both input signals, p53killer and Aktu, is necessary to induce apoptosis. Heights of bars correspond to the steady-state levels of proteins. Bars sharing adjacent sides (marked with colons and color gradient) denote complexes. To keep the convention, some bars do not start from 0. (A) The steady state levels of proteins and complexes corresponding to p53killer = 0 and Aktu = 0 (surviving cell, in the presence of growth factors). (B, C) a single maximal pro-apoptotic signal neither from p53killer nor from Aktu suffices to trigger apoptosis. (D) Simultaneous presence of both signals triggers apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Steady-state concentrations for gate AND. Transition from OR to AND results from the decrease of Badtot. The simultaneous presence of both input signals, p53killer and Aktu, is necessary to induce apoptosis. Heights of bars correspond to the steady-state levels of proteins. Bars sharing adjacent sides (marked with colons and color gradient) denote complexes. To keep the convention, some bars do not start from 0. (A) The steady state levels of proteins and complexes corresponding to p53killer = 0 and Aktu = 0 (surviving cell, in the presence of growth factors). (B, C) a single maximal pro-apoptotic signal neither from p53killer nor from Aktu suffices to trigger apoptosis. (D) Simultaneous presence of both signals triggers apoptosis.
Mentions: We will analyze the steady states of the system for two levels of Bad in order to demonstrate that the gate OR is achieved for Badtot=2 × 105, while gate AND is achieved for Badtot=0.6 × 105; here, for both gates we assume the same Bcl-xL tot=1 × 105. Surviving cell steady state is associated with conditions in which both apoptotic signals are equal zero. In these cells (Figures 4A and 5A) most of Bad is in the phosphorylated form bound to Scaffold14-3-3. The remaining (unphosphorylated) Bad is bound to Bcl-xL. Rest of Bcl-xL sequesters Bax or remains free. Free Bcl-xL may be considered as the anti-apoptotic buffer, which may potentially capture the excess of Bax. This buffer of free Bcl-xL is small (about 104 molecules) for gate OR (Figure 4A) and much larger (about 6 × 104 molecules) for gate AND (Figure 5A). Size of the Bcl-xL buffer determines cell susceptibility to apoptosis: small buffer renders cells more prone to apoptosis.

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