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Harmonic oscillations in homeostatic controllers: Dynamics of the p53 regulatory system.

ABSTRACT: Homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Previously, we have described molecular mechanisms that lead to robust homeostasis/adaptation under inflow or outflow perturbations. Here we report that harmonic oscillations occur in models of such homeostatic controllers and that a close relationship exists between the control of the p53/Mdm2 system and that of a homeostatic inflow controller. This homeostatic control model of the p53 system provides an explanation why large fluctuations in the amplitude of p53/Mdm2 oscillations may arise as part of the homeostatic regulation of p53 by Mdm2 under DNA-damaging conditions. In the presence of DNA damage p53 is upregulated, but is subject to a tight control by Mdm2 and other factors to avoid a premature apoptotic response of the cell at low DNA damage levels. One of the regulatory steps is the Mdm2-mediated degradation of p53 by the proteasome. Oscillations in the p53/Mdm2 system are considered to be part of a mechanism by which a cell decides between cell cycle arrest/DNA repair and apoptosis. In the homeostatic inflow control model, harmonic oscillations in p53/Mdm2 levels arise when the binding strength of p53 to degradation complexes increases. Due to the harmonic character of the oscillations rapid fluctuating noise can lead, as experimentally observed, to large variations in the amplitude of the oscillation but not in their period, a behavior which has been difficult to simulate by deterministic limit-cycle models. In conclusion, the oscillatory response of homeostatic controllers may provide new insights into the origin and role of oscillations observed in homeostatically controlled molecular networks.

SUBMITTER: Jolma IW

PROVIDER: S-EPMC2830462 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Harmonic oscillations in homeostatic controllers: Dynamics of the p53 regulatory system.

Jolma Ingunn W IW Ni Xiao Yu XY Rensing Ludger L Ruoff Peter P

Biophysical journal 20100301 5

Homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Previously, we have described molecular mechanisms that lead to robust homeostasis/adaptation under inflow or outflow perturbations. Here we report that harmonic oscillations occur in models of such homeostatic controllers and that a close relationship exists between the control of the p53/Mdm2 system and that of a homeostatic inflow controller. This homeostatic control ...[more]

PMID: 20197027

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Project description:Cells and organisms have developed homeostatic mechanisms which protect them against a changing environment. How growth and homeostasis interact is still not well understood, but of increasing interest to the molecular and synthetic biology community to recognize and design control circuits which can oppose the diluting effects of cell growth. In this paper we describe the performance of selected negative feedback controllers in response to different applied growth laws and time dependent outflow perturbations of a controlled variable. The approach taken here is based on deterministic mass action kinetics assuming that cell content is instantaneously mixed. All controllers behave ideal in the sense that they for step-wise perturbations in volume and a controlled compound A are able to drive A precisely back to the controllers' theoretical set-points. The applied growth kinetics reflect experimentally observed growth laws, which range from surface to volume ratio growth to linear and exponential growth. Our results show that the kinetic implementation of integral control and the structure of the negative feedback loop are two properties which affect controller performance. Best performance is observed for controllers based on derepression kinetics and controllers with an autocatalytic implementation of integral control. Both are able to defend exponential growth and perturbations, although the autocatalytic controller shows an offset from its theoretical set-point. Controllers with activating signaling using zero-order or bimolecular (antithetic) kinetics for integral control behave very similar but less well. Their performance can be improved by implementing negative feedback structures having repression/derepression steps or by increasing controller aggressiveness. Our results provide a guide what type of feedback structures and integral control kinetics are suitable to oppose the dilution effects by different growth laws and time dependent perturbations on a deterministic level.

Project description:In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage. Its negative regulator Mdm2 also demonstrates oscillatory behaviour. Attempts have been made recently to explain this behaviour by mathematical models but these have not addressed explicit molecular mechanisms. We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop. Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage. The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53. The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation. The models can readily be modified as further information becomes available, and linked to other models of cellular ageing.The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists. It also predicts that if there is a gradual accumulation of DNA damage, such as may occur in ageing, oscillations break out once a threshold level of damage is acquired. The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop. The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values. This may account for the large variability seen in the experimental data which so far has examined ARF negative cells.The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions. Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer.

Project description:ObjectiveThe stage of sleep is a known modulator of high-frequency oscillations (HFOs). For instance, high amplitude slow waves during NREM sleep and the subtypes of REM sleep were shown to contribute to a better separation between physiological and pathological HFOs. This study investigated rates and spatial spread of the different HFO types (physiological and pathological ripples in the 80-250 Hz frequency band, and fast ripples above 250 Hz) depending on time spent in sleep across the different sleep cycles.MethodsFifteen patients with focal pharmaco-resistant epilepsy underwent one night of video-polysomnography during chronic intracranial EEG recording for presurgical epilepsy evaluation. The HFO rate and spread across the different sleep cycles were determined with an automatic HFO detector. We built models to explain the observed rate and spread based on time in sleep and other variables i.e. sleep stage, delta band and sigma band activity, and slow wave amplitude. Statistical significance of the different variables was determined by a model comparison using the Akaike information criterion.ResultsThe rate of HFOs depends significantly on the accumulated time of sleep. As the night advanced, the rate of pathological ripples and fast ripples decreased during NREM sleep (up to 15% per hour spent in the respective sleep stages), while the rate of physiological ripples increased during REM sleep (8% per hour spent in REM sleep). Interestingly, the stage of sleep but not the sleep cycle determined the extent of spread of HFOs, showing a larger field during NREM sleep and a more restricted field during REM sleep.ConclusionThe different dependence with sleep time for physiological and pathological ripples is in keeping with their distinct underlying generating mechanisms. From a practical point of view, the first sleep cycle seems to be best suitable for studying HFOs in epilepsy, given that the contrast between physiological and pathological ripple rates is largest during this time.

Dataset Information

Harmonic oscillations in homeostatic controllers: Dynamics of the p53 regulatory system.

Publications

Harmonic oscillations in homeostatic controllers: Dynamics of the p53 regulatory system.

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