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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 model of p53 oscillations in response to ionizing radiation.(A) The model shown here is structurally identical to [17], but parameter values have been scaled to match published rates of synthesis and degradation for p53 and Mdm2 as well as their steady-state abundances (see Methods). (B) Ionizing radiation is modeled as an increase in synthesis of the Signal molecule (left; model parameter ) [17]. In response to a step increase in Signal production, phosphorylated p53 is observed to oscillate. We define  to be the amplitude of the stable oscillations. In response to a 2-hour pulse in Signal production (right), p53 exhibits a transient peak in phosphorylation, as does Mdm2. We define  to be the amplitude of phosphorylated p53, and  to be its amplitude in response to a second, identical pulse, 22 hours after the first pulse.
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pcbi-1002932-g003: A model of p53 oscillations in response to ionizing radiation.(A) The model shown here is structurally identical to [17], but parameter values have been scaled to match published rates of synthesis and degradation for p53 and Mdm2 as well as their steady-state abundances (see Methods). (B) Ionizing radiation is modeled as an increase in synthesis of the Signal molecule (left; model parameter ) [17]. In response to a step increase in Signal production, phosphorylated p53 is observed to oscillate. We define to be the amplitude of the stable oscillations. In response to a 2-hour pulse in Signal production (right), p53 exhibits a transient peak in phosphorylation, as does Mdm2. We define to be the amplitude of phosphorylated p53, and to be its amplitude in response to a second, identical pulse, 22 hours after the first pulse.

Mentions: Given that flux precisely controls the dynamic response to stimulation in a prototypical signaling module, we hypothesized that for p53, oscillations in response to DNA damage require the high rates of turnover reported for p53 and Mdm2. To test this, we applied our method to a published model of p53 activation in response to ionizing gamma radiation (IR), a common DNA damaging agent (Figure 3A) [17]. Because the model uses arbitrary units, we rescaled it so that the steady state abundances of p53 and Mdm2, as well as their rates of synthesis and degradation, matched published values (see Table S1). We note that these values are also in good agreement with the consensus parameters reported in [16].


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

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

A model of p53 oscillations in response to ionizing radiation.(A) The model shown here is structurally identical to [17], but parameter values have been scaled to match published rates of synthesis and degradation for p53 and Mdm2 as well as their steady-state abundances (see Methods). (B) Ionizing radiation is modeled as an increase in synthesis of the Signal molecule (left; model parameter ) [17]. In response to a step increase in Signal production, phosphorylated p53 is observed to oscillate. We define  to be the amplitude of the stable oscillations. In response to a 2-hour pulse in Signal production (right), p53 exhibits a transient peak in phosphorylation, as does Mdm2. We define  to be the amplitude of phosphorylated p53, and  to be its amplitude in response to a second, identical pulse, 22 hours after the first pulse.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002932-g003: A model of p53 oscillations in response to ionizing radiation.(A) The model shown here is structurally identical to [17], but parameter values have been scaled to match published rates of synthesis and degradation for p53 and Mdm2 as well as their steady-state abundances (see Methods). (B) Ionizing radiation is modeled as an increase in synthesis of the Signal molecule (left; model parameter ) [17]. In response to a step increase in Signal production, phosphorylated p53 is observed to oscillate. We define to be the amplitude of the stable oscillations. In response to a 2-hour pulse in Signal production (right), p53 exhibits a transient peak in phosphorylation, as does Mdm2. We define to be the amplitude of phosphorylated p53, and to be its amplitude in response to a second, identical pulse, 22 hours after the first pulse.
Mentions: Given that flux precisely controls the dynamic response to stimulation in a prototypical signaling module, we hypothesized that for p53, oscillations in response to DNA damage require the high rates of turnover reported for p53 and Mdm2. To test this, we applied our method to a published model of p53 activation in response to ionizing gamma radiation (IR), a common DNA damaging agent (Figure 3A) [17]. Because the model uses arbitrary units, we rescaled it so that the steady state abundances of p53 and Mdm2, as well as their rates of synthesis and degradation, matched published values (see Table S1). We note that these values are also in good agreement with the consensus parameters reported in [16].

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