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.

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Mitochondrial apoptotic module. The levels of p53killer and Aktu are considered as pro-apoptotic input signals. Total level of Akt is assumed constant and, since the phosphorylated Akt is anti-apoptotic, the unphosphorylated Akt is considered as the pro-apoptotic input (associated with e.g. growth factor withdrawal). Phosphorylated Akt phosphorylates Bad, which then remains bound to Scaffold14-3-3. When dephosphorylated, Bad binds to Bcl-xL, leading to the dissociation of Bax from its complexes with Bcl-xL. Free Bax (via the omitted process of cytochrome c release) turns pro-caspases into active caspases (module output) which induce apoptosis. Arrow-headed lines indicate protein transformations, circle-headed lines – activating (including transcription) or inactivating influence. Light red color indicates pro-apoptotic, and light blue – anti-apoptotic proteins. Symbol Ø is used to denote sink or source.
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Figure 2: Mitochondrial apoptotic module. The levels of p53killer and Aktu are considered as pro-apoptotic input signals. Total level of Akt is assumed constant and, since the phosphorylated Akt is anti-apoptotic, the unphosphorylated Akt is considered as the pro-apoptotic input (associated with e.g. growth factor withdrawal). Phosphorylated Akt phosphorylates Bad, which then remains bound to Scaffold14-3-3. When dephosphorylated, Bad binds to Bcl-xL, leading to the dissociation of Bax from its complexes with Bcl-xL. Free Bax (via the omitted process of cytochrome c release) turns pro-caspases into active caspases (module output) which induce apoptosis. Arrow-headed lines indicate protein transformations, circle-headed lines – activating (including transcription) or inactivating influence. Light red color indicates pro-apoptotic, and light blue – anti-apoptotic proteins. Symbol Ø is used to denote sink or source.

Mentions: In the model (Figure 2), levels of phosphorylated Akt (named here Aktp) and p53 in its killer form (i.e. p53 phosphorylated at Ser15, Ser20 and Ser46; denoted p53killer) will serve as inputs. Surviving cells are characterized by high level of Aktp and lack (or very low level) of p53killer. In these cells, most of Bad remains in the phosphorylated form (denoted Badp) bound to Scaffold14-3-3, while Bax is inhibited (sequestered) by Bcl-xL[44]. Unphosphorylated Bad (Badu) may bind to Bcl-xL, which limits the amount of Bcl-xL protein available for inhibiting Bax. The steady state is controlled by the total levels of Bad (Badtot) and Bcl-xL (Bcl-xL tot), which will be considered as parameters in the model. The fraction of Bcl-xL bound to Bad increases with Badtot rendering cells of high Bad level more prone to apoptosis. (Protein levels, written in italics, are given in molecules per cell; for disambiguation, levels of protein complexes will be written in curly braces.)


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)

Mitochondrial apoptotic module. The levels of p53killer and Aktu are considered as pro-apoptotic input signals. Total level of Akt is assumed constant and, since the phosphorylated Akt is anti-apoptotic, the unphosphorylated Akt is considered as the pro-apoptotic input (associated with e.g. growth factor withdrawal). Phosphorylated Akt phosphorylates Bad, which then remains bound to Scaffold14-3-3. When dephosphorylated, Bad binds to Bcl-xL, leading to the dissociation of Bax from its complexes with Bcl-xL. Free Bax (via the omitted process of cytochrome c release) turns pro-caspases into active caspases (module output) which induce apoptosis. Arrow-headed lines indicate protein transformations, circle-headed lines – activating (including transcription) or inactivating influence. Light red color indicates pro-apoptotic, and light blue – anti-apoptotic proteins. Symbol Ø is used to denote sink or source.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Mitochondrial apoptotic module. The levels of p53killer and Aktu are considered as pro-apoptotic input signals. Total level of Akt is assumed constant and, since the phosphorylated Akt is anti-apoptotic, the unphosphorylated Akt is considered as the pro-apoptotic input (associated with e.g. growth factor withdrawal). Phosphorylated Akt phosphorylates Bad, which then remains bound to Scaffold14-3-3. When dephosphorylated, Bad binds to Bcl-xL, leading to the dissociation of Bax from its complexes with Bcl-xL. Free Bax (via the omitted process of cytochrome c release) turns pro-caspases into active caspases (module output) which induce apoptosis. Arrow-headed lines indicate protein transformations, circle-headed lines – activating (including transcription) or inactivating influence. Light red color indicates pro-apoptotic, and light blue – anti-apoptotic proteins. Symbol Ø is used to denote sink or source.
Mentions: In the model (Figure 2), levels of phosphorylated Akt (named here Aktp) and p53 in its killer form (i.e. p53 phosphorylated at Ser15, Ser20 and Ser46; denoted p53killer) will serve as inputs. Surviving cells are characterized by high level of Aktp and lack (or very low level) of p53killer. In these cells, most of Bad remains in the phosphorylated form (denoted Badp) bound to Scaffold14-3-3, while Bax is inhibited (sequestered) by Bcl-xL[44]. Unphosphorylated Bad (Badu) may bind to Bcl-xL, which limits the amount of Bcl-xL protein available for inhibiting Bax. The steady state is controlled by the total levels of Bad (Badtot) and Bcl-xL (Bcl-xL tot), which will be considered as parameters in the model. The fraction of Bcl-xL bound to Bad increases with Badtot rendering cells of high Bad level more prone to apoptosis. (Protein levels, written in italics, are given in molecules per cell; for disambiguation, levels of protein complexes will be written in curly braces.)

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