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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 paired positive (+) and negative (−) flux motif controls stimulus-sensitivity in the p53 and NFkB stress response pathways.(A) For p53, the (+) flux is formed by the synthesis and degradation of p53 itself. The (−) flux is formed by synthesis and degradation of Mdm2. Together these fluxes control the sensitivity of p53 to IR-stimulation, which acts by inducing the synthesis of p53 and the degradation of Mdm2. (B) For NFkB, the (+) flux is formed by association and dissociation of NFkB from its negative regulator, IκB. The (−) flux is formed by synthesis and degradation of IκB. These fluxes control the sensitivity of NFkB to TNF-stimulation, which induces the dissociation of NFκB from IκB, and UV-stimulation, which inhibits the synthesis of IκB.
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pcbi-1002932-g008: A paired positive (+) and negative (−) flux motif controls stimulus-sensitivity in the p53 and NFkB stress response pathways.(A) For p53, the (+) flux is formed by the synthesis and degradation of p53 itself. The (−) flux is formed by synthesis and degradation of Mdm2. Together these fluxes control the sensitivity of p53 to IR-stimulation, which acts by inducing the synthesis of p53 and the degradation of Mdm2. (B) For NFkB, the (+) flux is formed by association and dissociation of NFkB from its negative regulator, IκB. The (−) flux is formed by synthesis and degradation of IκB. These fluxes control the sensitivity of NFkB to TNF-stimulation, which induces the dissociation of NFκB from IκB, and UV-stimulation, which inhibits the synthesis of IκB.

Mentions: For p53 and NFkB, we show that stimulus sensitivity can be controlled by a paired positive and negative regulatory flux. We propose that this pairing may constitute a common regulatory motif in cell signaling. In contrast to other regulatory motifs [75], [76], the “flux motif” described here does not have a unique structure. The positive p53 flux, for example, is formed by the synthesis and degradation of p53 itself, while the positive flux in the NFκB system includes the nuclear import of free NFκB and export of NFκB bound to IκB. For p53, the negative flux is formed by synthesis and degradation of Mdm2, while for NFκB it is formed by the synthesis, shuttling, and degradation of cytoplasmic and nuclear IκB. Thus the reaction structure for each flux is quite different, but they nevertheless form a regulatory motif that is common to both pathways (Figure 8). And since the mathematical models used here are only abstractions of the underlying network, the true structure of the p53 and NFκB flux motifs are in reality even more complex.


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

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

A paired positive (+) and negative (−) flux motif controls stimulus-sensitivity in the p53 and NFkB stress response pathways.(A) For p53, the (+) flux is formed by the synthesis and degradation of p53 itself. The (−) flux is formed by synthesis and degradation of Mdm2. Together these fluxes control the sensitivity of p53 to IR-stimulation, which acts by inducing the synthesis of p53 and the degradation of Mdm2. (B) For NFkB, the (+) flux is formed by association and dissociation of NFkB from its negative regulator, IκB. The (−) flux is formed by synthesis and degradation of IκB. These fluxes control the sensitivity of NFkB to TNF-stimulation, which induces the dissociation of NFκB from IκB, and UV-stimulation, which inhibits the synthesis of IκB.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002932-g008: A paired positive (+) and negative (−) flux motif controls stimulus-sensitivity in the p53 and NFkB stress response pathways.(A) For p53, the (+) flux is formed by the synthesis and degradation of p53 itself. The (−) flux is formed by synthesis and degradation of Mdm2. Together these fluxes control the sensitivity of p53 to IR-stimulation, which acts by inducing the synthesis of p53 and the degradation of Mdm2. (B) For NFkB, the (+) flux is formed by association and dissociation of NFkB from its negative regulator, IκB. The (−) flux is formed by synthesis and degradation of IκB. These fluxes control the sensitivity of NFkB to TNF-stimulation, which induces the dissociation of NFκB from IκB, and UV-stimulation, which inhibits the synthesis of IκB.
Mentions: For p53 and NFkB, we show that stimulus sensitivity can be controlled by a paired positive and negative regulatory flux. We propose that this pairing may constitute a common regulatory motif in cell signaling. In contrast to other regulatory motifs [75], [76], the “flux motif” described here does not have a unique structure. The positive p53 flux, for example, is formed by the synthesis and degradation of p53 itself, while the positive flux in the NFκB system includes the nuclear import of free NFκB and export of NFκB bound to IκB. For p53, the negative flux is formed by synthesis and degradation of Mdm2, while for NFκB it is formed by the synthesis, shuttling, and degradation of cytoplasmic and nuclear IκB. Thus the reaction structure for each flux is quite different, but they nevertheless form a regulatory motif that is common to both pathways (Figure 8). And since the mathematical models used here are only abstractions of the underlying network, the true structure of the p53 and NFκB flux motifs are in reality even more complex.

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