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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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Effects of flux on the dynamic response to stimulation.(A) The magnitude of the activator flux is varied between  (light gray) and  (dark gray) times its nominal steady-state value prior to stimulation. The peak amplitude  of X in response to stimulation is observed to increase with the flux of X while the time  at which the peak occurs is observed to decrease. Representative profiles of the activator at low, wildtype, and high values of the flux are shown at right. The dashed red line indicates the nominal wildtype response. (B) The magnitude of the inhibitor flux is varied between  and  times its nominal steady-state value prior to stimulation. Both  and  are observed to decrease. (C) The fluxes of both X and Y are varied simultaneously between  and  times their nominal wildtype values. As a result,  is held constant while  is reduced. (D) The magnitude of the inhibitor flux is varied between  and  times its nominal steady-state value prior to stimulation. For each value of this flux, the value of activator flux is calculated such that  is held constant. As in row 2 above,  is observed to decrease as the magnitude of the flux of Y increases.
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pcbi-1002932-g002: Effects of flux on the dynamic response to stimulation.(A) The magnitude of the activator flux is varied between (light gray) and (dark gray) times its nominal steady-state value prior to stimulation. The peak amplitude of X in response to stimulation is observed to increase with the flux of X while the time at which the peak occurs is observed to decrease. Representative profiles of the activator at low, wildtype, and high values of the flux are shown at right. The dashed red line indicates the nominal wildtype response. (B) The magnitude of the inhibitor flux is varied between and times its nominal steady-state value prior to stimulation. Both and are observed to decrease. (C) The fluxes of both X and Y are varied simultaneously between and times their nominal wildtype values. As a result, is held constant while is reduced. (D) The magnitude of the inhibitor flux is varied between and times its nominal steady-state value prior to stimulation. For each value of this flux, the value of activator flux is calculated such that is held constant. As in row 2 above, is observed to decrease as the magnitude of the flux of Y increases.

Mentions: To further characterize the effects of flux on the activator's response to stimulation, we applied systematic changes to the fluxes of X and Y prior to stimulation and plotted the resulting values of and . Multiplying the flux of X over the interval showed, as expected, that the value of increases while the value of deceases (Figure 2A). In other words, a high activator flux results in a strong, fast response to stimulation. If we repeat the process with the inhibitor, we find that both and decrease as the flux increases; a high inhibitor flux results in a fast but weak response (Figure 2B). This result illustrates that fluxes of different regulators can have different but complementary effects on stimulus-induced signaling dynamics.


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

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

Effects of flux on the dynamic response to stimulation.(A) The magnitude of the activator flux is varied between  (light gray) and  (dark gray) times its nominal steady-state value prior to stimulation. The peak amplitude  of X in response to stimulation is observed to increase with the flux of X while the time  at which the peak occurs is observed to decrease. Representative profiles of the activator at low, wildtype, and high values of the flux are shown at right. The dashed red line indicates the nominal wildtype response. (B) The magnitude of the inhibitor flux is varied between  and  times its nominal steady-state value prior to stimulation. Both  and  are observed to decrease. (C) The fluxes of both X and Y are varied simultaneously between  and  times their nominal wildtype values. As a result,  is held constant while  is reduced. (D) The magnitude of the inhibitor flux is varied between  and  times its nominal steady-state value prior to stimulation. For each value of this flux, the value of activator flux is calculated such that  is held constant. As in row 2 above,  is observed to decrease as the magnitude of the flux of Y increases.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002932-g002: Effects of flux on the dynamic response to stimulation.(A) The magnitude of the activator flux is varied between (light gray) and (dark gray) times its nominal steady-state value prior to stimulation. The peak amplitude of X in response to stimulation is observed to increase with the flux of X while the time at which the peak occurs is observed to decrease. Representative profiles of the activator at low, wildtype, and high values of the flux are shown at right. The dashed red line indicates the nominal wildtype response. (B) The magnitude of the inhibitor flux is varied between and times its nominal steady-state value prior to stimulation. Both and are observed to decrease. (C) The fluxes of both X and Y are varied simultaneously between and times their nominal wildtype values. As a result, is held constant while is reduced. (D) The magnitude of the inhibitor flux is varied between and times its nominal steady-state value prior to stimulation. For each value of this flux, the value of activator flux is calculated such that is held constant. As in row 2 above, is observed to decrease as the magnitude of the flux of Y increases.
Mentions: To further characterize the effects of flux on the activator's response to stimulation, we applied systematic changes to the fluxes of X and Y prior to stimulation and plotted the resulting values of and . Multiplying the flux of X over the interval showed, as expected, that the value of increases while the value of deceases (Figure 2A). In other words, a high activator flux results in a strong, fast response to stimulation. If we repeat the process with the inhibitor, we find that both and decrease as the flux increases; a high inhibitor flux results in a fast but weak response (Figure 2B). This result illustrates that fluxes of different regulators can have different but complementary effects on stimulus-induced signaling dynamics.

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