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A protein turnover signaling motif controls the stimulus-sensitivity of stress response pathways.

Loriaux PM, Hoffmann A - PLoS Comput. Biol. (2013)

Bottom Line: In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR.In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF.Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NFκB, IκBα. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NFκB signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

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A prototypical negative feedback module.(A) In this simple model of negative feedback control, an activator X is constitutively produced but catalytically degraded by an inhibitor, Y. Y is constitutively degraded but its synthesis requires X. Each of these four reactions is modeled using mass action kinetics. To stimulate the model and activate X, the steady-state abundance of Y is instantaneously depleted. (B) In response to stimulation, the abundance of X increases until activator-induced synthesis of Y forces a return to steady-state. This response can be characterized by , the maximum abundance of X following stimulation, and , the time at which  is observed. Parameters were chosen for this model such that the steady state abundances of X and Y equal one arbitrary unit and the stimulus-induced amplitude of X is  at time . The rates of activator synthesis (C), inhibitor synthesis (D), activator degradation (E), and inhibitor degradation (F) were multiplied by  (gray) to  (blue) prior to stimulation as described above. For each multiplier, the dynamics of the activator response are plotted on the right. Similar plots were generated by multiplying the flux of the activator (G), and the flux of the inhibitor (H), as described in Methods.
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pcbi-1002932-g001: A prototypical negative feedback module.(A) In this simple model of negative feedback control, an activator X is constitutively produced but catalytically degraded by an inhibitor, Y. Y is constitutively degraded but its synthesis requires X. Each of these four reactions is modeled using mass action kinetics. To stimulate the model and activate X, the steady-state abundance of Y is instantaneously depleted. (B) In response to stimulation, the abundance of X increases until activator-induced synthesis of Y forces a return to steady-state. This response can be characterized by , the maximum abundance of X following stimulation, and , the time at which is observed. Parameters were chosen for this model such that the steady state abundances of X and Y equal one arbitrary unit and the stimulus-induced amplitude of X is at time . The rates of activator synthesis (C), inhibitor synthesis (D), activator degradation (E), and inhibitor degradation (F) were multiplied by (gray) to (blue) prior to stimulation as described above. For each multiplier, the dynamics of the activator response are plotted on the right. Similar plots were generated by multiplying the flux of the activator (G), and the flux of the inhibitor (H), as described in Methods.

Mentions: To examine the effects of flux on stimulus-responsiveness, we built a prototypical negative feedback model reminiscent of the p53 or NFκB stress-response pathways (Figure 1A). In it, an activator “X” is constitutively expressed but catalytically degraded by an inhibitor, “Y”. The inhibitor is constitutively degraded but its synthesis requires X. Activation is achieved by instantaneous depletion of Y, the result of which is accumulation of X until negative feedback forces a return to steady state. The dynamics of this response can be described by two values: , the amplitude or maximum value of X after stimulation, and , the time at which is observed (Figure 1B). Parameters for this model were chosen such that the abundances of both X and Y are one arbitrary unit and X achieves its maximum value of at time , where the units of time are also arbitrary.


A protein turnover signaling motif controls the stimulus-sensitivity of stress response pathways.

Loriaux PM, Hoffmann A - PLoS Comput. Biol. (2013)

A prototypical negative feedback module.(A) In this simple model of negative feedback control, an activator X is constitutively produced but catalytically degraded by an inhibitor, Y. Y is constitutively degraded but its synthesis requires X. Each of these four reactions is modeled using mass action kinetics. To stimulate the model and activate X, the steady-state abundance of Y is instantaneously depleted. (B) In response to stimulation, the abundance of X increases until activator-induced synthesis of Y forces a return to steady-state. This response can be characterized by , the maximum abundance of X following stimulation, and , the time at which  is observed. Parameters were chosen for this model such that the steady state abundances of X and Y equal one arbitrary unit and the stimulus-induced amplitude of X is  at time . The rates of activator synthesis (C), inhibitor synthesis (D), activator degradation (E), and inhibitor degradation (F) were multiplied by  (gray) to  (blue) prior to stimulation as described above. For each multiplier, the dynamics of the activator response are plotted on the right. Similar plots were generated by multiplying the flux of the activator (G), and the flux of the inhibitor (H), as described in Methods.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585401&req=5

pcbi-1002932-g001: A prototypical negative feedback module.(A) In this simple model of negative feedback control, an activator X is constitutively produced but catalytically degraded by an inhibitor, Y. Y is constitutively degraded but its synthesis requires X. Each of these four reactions is modeled using mass action kinetics. To stimulate the model and activate X, the steady-state abundance of Y is instantaneously depleted. (B) In response to stimulation, the abundance of X increases until activator-induced synthesis of Y forces a return to steady-state. This response can be characterized by , the maximum abundance of X following stimulation, and , the time at which is observed. Parameters were chosen for this model such that the steady state abundances of X and Y equal one arbitrary unit and the stimulus-induced amplitude of X is at time . The rates of activator synthesis (C), inhibitor synthesis (D), activator degradation (E), and inhibitor degradation (F) were multiplied by (gray) to (blue) prior to stimulation as described above. For each multiplier, the dynamics of the activator response are plotted on the right. Similar plots were generated by multiplying the flux of the activator (G), and the flux of the inhibitor (H), as described in Methods.
Mentions: To examine the effects of flux on stimulus-responsiveness, we built a prototypical negative feedback model reminiscent of the p53 or NFκB stress-response pathways (Figure 1A). In it, an activator “X” is constitutively expressed but catalytically degraded by an inhibitor, “Y”. The inhibitor is constitutively degraded but its synthesis requires X. Activation is achieved by instantaneous depletion of Y, the result of which is accumulation of X until negative feedback forces a return to steady state. The dynamics of this response can be described by two values: , the amplitude or maximum value of X after stimulation, and , the time at which is observed (Figure 1B). Parameters for this model were chosen such that the abundances of both X and Y are one arbitrary unit and X achieves its maximum value of at time , where the units of time are also arbitrary.

Bottom Line: In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR.In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF.Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NFκB, IκBα. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NFκB signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

Show MeSH
Related in: MedlinePlus