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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 p53 response to ionizing radiation.(A) The Mdm2-independent flux of p53 is varied between  and  times its wildtype value prior to a step increase in Signal production (model parameter ; light gray to dark gray) [17]. The magnitude of  is plotted as a function of this p53 flux multiplier. Values that give rise to stable oscillations are shaded in blue. At right, representative profiles of phosphorylated p53 are shown for high, wildtype, moderate, and low values of the multiplier. Note that the wildtype flux is indicated by the dashed line in red. (B) As row 1, above, but now the p53-independent flux of Mdm2 is varied between  and  times its wildtype value (light gray to dark gray). Stable oscillations are observed for all values of the Mdm2 flux multiplier. (C) As row 2, above, but for all simulations the flux of p53 is at one-tenth its nominal wildtype value. Instead of sustained oscillations, damped oscillations are observed for all values of the Mdm2 flux multiplier. (D) The flux of p53 is varied between  and  times its wildtype value prior to a 2-hour pulse in Signal production, followed by 22 hours of rest, followed by a second 2-hour pulse. No difference is observed in the amplitude of phosphorylated p53 in response to the first and second pulse. (E) As row 4, above, but now the flux of Mdm2 is varied instead of p53. At lower values of the Mdm2 flux multiplier, a significant difference is observed between the amplitude of phosphorylated p53 in response to the first and second pulse. (F) As row 4, above, but while the p53 flux is allowed to vary, the flux of Mdm2 is held constant at  times its wildtype value. This concomitant reduction of the p53 flux is not able to rescue the Mdm2-compromised response to the second pulse.
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pcbi-1002932-g004: Effects of flux on the p53 response to ionizing radiation.(A) The Mdm2-independent flux of p53 is varied between and times its wildtype value prior to a step increase in Signal production (model parameter ; light gray to dark gray) [17]. The magnitude of is plotted as a function of this p53 flux multiplier. Values that give rise to stable oscillations are shaded in blue. At right, representative profiles of phosphorylated p53 are shown for high, wildtype, moderate, and low values of the multiplier. Note that the wildtype flux is indicated by the dashed line in red. (B) As row 1, above, but now the p53-independent flux of Mdm2 is varied between and times its wildtype value (light gray to dark gray). Stable oscillations are observed for all values of the Mdm2 flux multiplier. (C) As row 2, above, but for all simulations the flux of p53 is at one-tenth its nominal wildtype value. Instead of sustained oscillations, damped oscillations are observed for all values of the Mdm2 flux multiplier. (D) The flux of p53 is varied between and times its wildtype value prior to a 2-hour pulse in Signal production, followed by 22 hours of rest, followed by a second 2-hour pulse. No difference is observed in the amplitude of phosphorylated p53 in response to the first and second pulse. (E) As row 4, above, but now the flux of Mdm2 is varied instead of p53. At lower values of the Mdm2 flux multiplier, a significant difference is observed between the amplitude of phosphorylated p53 in response to the first and second pulse. (F) As row 4, above, but while the p53 flux is allowed to vary, the flux of Mdm2 is held constant at times its wildtype value. This concomitant reduction of the p53 flux is not able to rescue the Mdm2-compromised response to the second pulse.

Mentions: Next we implemented a multiplier of Mdm2-independent p53 flux and let it take values on the interval . For each value we simulated the response to IR using a step function in the production of the upstream Signal molecule, , as previously described [17]. To characterize the p53 response we let be the amplitude of stable oscillations in phosphorylated p53 (Figure 3B), and use this as a metric for p53 sensitivity. Where , we say the module is sensitive to IR stimulation. We find that is greater than zero only when the flux of p53 is near its observed value or higher (Figure 4A). If the flux of p53 is reduced by 2-fold or more, p53 no longer stably oscillates in response to stimulation, but exhibits damped oscillations instead.


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 p53 response to ionizing radiation.(A) The Mdm2-independent flux of p53 is varied between  and  times its wildtype value prior to a step increase in Signal production (model parameter ; light gray to dark gray) [17]. The magnitude of  is plotted as a function of this p53 flux multiplier. Values that give rise to stable oscillations are shaded in blue. At right, representative profiles of phosphorylated p53 are shown for high, wildtype, moderate, and low values of the multiplier. Note that the wildtype flux is indicated by the dashed line in red. (B) As row 1, above, but now the p53-independent flux of Mdm2 is varied between  and  times its wildtype value (light gray to dark gray). Stable oscillations are observed for all values of the Mdm2 flux multiplier. (C) As row 2, above, but for all simulations the flux of p53 is at one-tenth its nominal wildtype value. Instead of sustained oscillations, damped oscillations are observed for all values of the Mdm2 flux multiplier. (D) The flux of p53 is varied between  and  times its wildtype value prior to a 2-hour pulse in Signal production, followed by 22 hours of rest, followed by a second 2-hour pulse. No difference is observed in the amplitude of phosphorylated p53 in response to the first and second pulse. (E) As row 4, above, but now the flux of Mdm2 is varied instead of p53. At lower values of the Mdm2 flux multiplier, a significant difference is observed between the amplitude of phosphorylated p53 in response to the first and second pulse. (F) As row 4, above, but while the p53 flux is allowed to vary, the flux of Mdm2 is held constant at  times its wildtype value. This concomitant reduction of the p53 flux is not able to rescue the Mdm2-compromised response to the second pulse.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585401&req=5

pcbi-1002932-g004: Effects of flux on the p53 response to ionizing radiation.(A) The Mdm2-independent flux of p53 is varied between and times its wildtype value prior to a step increase in Signal production (model parameter ; light gray to dark gray) [17]. The magnitude of is plotted as a function of this p53 flux multiplier. Values that give rise to stable oscillations are shaded in blue. At right, representative profiles of phosphorylated p53 are shown for high, wildtype, moderate, and low values of the multiplier. Note that the wildtype flux is indicated by the dashed line in red. (B) As row 1, above, but now the p53-independent flux of Mdm2 is varied between and times its wildtype value (light gray to dark gray). Stable oscillations are observed for all values of the Mdm2 flux multiplier. (C) As row 2, above, but for all simulations the flux of p53 is at one-tenth its nominal wildtype value. Instead of sustained oscillations, damped oscillations are observed for all values of the Mdm2 flux multiplier. (D) The flux of p53 is varied between and times its wildtype value prior to a 2-hour pulse in Signal production, followed by 22 hours of rest, followed by a second 2-hour pulse. No difference is observed in the amplitude of phosphorylated p53 in response to the first and second pulse. (E) As row 4, above, but now the flux of Mdm2 is varied instead of p53. At lower values of the Mdm2 flux multiplier, a significant difference is observed between the amplitude of phosphorylated p53 in response to the first and second pulse. (F) As row 4, above, but while the p53 flux is allowed to vary, the flux of Mdm2 is held constant at times its wildtype value. This concomitant reduction of the p53 flux is not able to rescue the Mdm2-compromised response to the second pulse.
Mentions: Next we implemented a multiplier of Mdm2-independent p53 flux and let it take values on the interval . For each value we simulated the response to IR using a step function in the production of the upstream Signal molecule, , as previously described [17]. To characterize the p53 response we let be the amplitude of stable oscillations in phosphorylated p53 (Figure 3B), and use this as a metric for p53 sensitivity. Where , we say the module is sensitive to IR stimulation. We find that is greater than zero only when the flux of p53 is near its observed value or higher (Figure 4A). If the flux of p53 is reduced by 2-fold or more, p53 no longer stably oscillates in response to stimulation, but exhibits damped oscillations instead.

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