Minimal model of spiky oscillations in NF-κB signaling

Krishna, Sandeep; Jensen, Mogens H.; Sneppen, Kim

doi:10.1073/pnas.0604085103

Cited by 149 publications

(177 citation statements)

References 34 publications

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“…Far from being restricted to circadian rhythms such negative autoregulation is indeed encountered in other oscillatory systems such as Hes1 or NFκB (Monk 2003;Krishna et al 2006), which are characterized by an ultradian period in the range of a few hours. The Hes1 oscillatory system is closely related to the segmentation clock that controls somitogenesis.…”

Section: Discussionmentioning

confidence: 99%

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

Gérard

Gonze

Goldbeter

2009

Phil. Trans. R. Soc. A.

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Circadian rhythms, which occur spontaneously with a period of about 24 h in a variety of organisms, allow their adaptation to the periodic variations of the environment. These rhythms are generated by a genetic regulatory network involving a negative feedback loop on transcription. Mathematical models based on the negative autoregulation of gene expression by the protein product of a clock gene account for the occurrence of selfsustained circadian oscillations. These models differ by their degree of complexity and, hence, by the number of variables considered. Some of these models can be considered as minimal because they contain a reduced number of biochemical processes and variables capable of producing sustained oscillations. In three of these minimal models, the period of the oscillations significantly changes with the rate of degradation of the clock protein. However, depending on the model considered, the period increases, decreases or passes through a maximum as a function of the protein degradation rate. We clarify the bases for these markedly different results by bringing to light the roles of (i) protein phosphorylation, which is required for protein degradation, and (ii) the velocity and degree of saturation of mRNA and protein degradation. Changes in the parameter values of the more complex of the minimal models can produce the period profiles observed in the other two models. The analysis allows us to reconcile the contradictory predictions for the dependence of the period on the clock protein degradation rate in three minimal models used to describe circadian rhythms.

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Section: Discussionmentioning

confidence: 99%

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

Gérard

Gonze

Goldbeter

2009

Phil. Trans. R. Soc. A.

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“…In fact, oscillations in protein concentration have been observed in a number of important systems (figure 2), such as the tumour-suppressor protein p53 [4], proteins involved in embryonal somite segmentation such as Hes1, Axin, Notch, Wnt [6,9] and in immune response as NFkB [7]. In all these cases, the very physical reason for time oscillations was found to be a delay in some elements of the control network of these proteins [10][11][12] (for a review, see refs. [13,14]).…”

Section: Introductionmentioning

confidence: 99%

“…Under specific conditions, nuclear/cytoplasmic NFkB has been observed to undergo time oscillations [7,8], whereas its total amount is almost constant on the experimental time scale. The oscillations of nuclear/cytoplasmic NFkB have been well described in terms of shape, phase, time period and frequency response by the rate equations [12] (figure 1e)…”

Section: Systems With Implicit Delaymentioning

confidence: 99%

The dynamics of genetic control in the cell: the good and bad of being late

Tiana

Jensen

2013

Phil. Trans. R. Soc. A.

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One contribution of 15 to a Theme Issue 'Dynamics, control and information in delay-coupled systems' . The expression of genes in the cell is controlled by a complex interaction network involving proteins, RNA and DNA. The molecular events associated with the nodes of such a network take place on a variety of time scales, and thus cannot be regarded as instantaneous. In many cases, the cell is robust with respect to the delay in gene expression control, behaving as if it were instantaneous. However, there are specific cases in which delay gives rise to temporal oscillations. This is the case, for example, of the expression of tumoursuppressor protein p53, of protein Hes1, involved in the differentiation of stem cells, of NFkB and Wnt, in which case delay arises implicitly from the structure of the associated network. By means of delay rate equations, we study the kinetics of small regulatory networks, emphasizing the role of delay in an evolutionary context. These models suggest that oscillations are a typical outcome of the dynamics of regulatory networks, and evolution has to work to avoid them when not required (and not vice versa).

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“…Krishna et al [45] showed that three ODEs with a negative feedback loop are sufficient to simulate the observed oscillatory behavior. Zambrano et al [48] also developed a relatively simple model with 11 ODEs and 14 parameters.…”

Section: Modelingmentioning

confidence: 99%

“…In the modeling approaches, some groups have included only parts of the NF-κB network that are sufficient to explain the dynamical behavior measured in in vitro experiments [45][46][47][48] or have developed methods to reduce complex models [49]. Krishna et al [45] showed that three ODEs with a negative feedback loop are sufficient to simulate the observed oscillatory behavior.…”

Section: Modelingmentioning

confidence: 99%

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Kuijper

Yang

Water

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs. ARTICLE HISTORY

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Minimal model of spiky oscillations in NF-κB signaling

Cited by 149 publications

References 34 publications

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

Dependence of the period on the rate of protein degradation in minimal models for circadian oscillations

The dynamics of genetic control in the cell: the good and bad of being late

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

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