Homeostatic controllers compensating for growth and perturbations

Ruoff, Peter; Agafonov, Oleg; Tveit, Daniel Myklatun; Thorsen, Kristian; Drengstig, Tormod

doi:10.1371/journal.pone.0207831

Cited by 11 publications

(20 citation statements)

References 44 publications

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“…The simulations also demonstrate that during the growth phase, growth associated offsets from steady state values associated with constant volume are observed, and that these offsets appears to be caused by set-point changes that are dependent on the growth rate. Importantly, investigations into control mechanisms similar to the ones identified in this paper, have shown that growth associated offsets become negligible if the kinetics of the controller species behave on a timescale much faster than cell growth (9,10,(73)(74)(75). These control mechanisms, called ICMs, achieve robust homeostatic control due to a negative feedback structure that includes integral action.…”

Section: Modeling Glucose Uptake In Cancermentioning

confidence: 64%

“…Investigations into ICMs have shown that growth associated offsets becomes negligible if the rates of the controller reactions, i.e. the generation and degradation of GLUT1 and HK2, are much faster compared to the rate of dilution (9,10,(73)(74)(75). In our model, enzymes responsible for generating and removing the controller species (E i , i = 1, 2, 3, 4) are present in constant amounts only, meaning that their concentrations simply dilute with increasing volume.…”

Section: Resultsmentioning

confidence: 94%

“…However, most protein and mRNA concentrations are independent of cell size, and therefore it is likely that the concentrations E,i (i = 1, 2, 3, 4) should be considered constant (7). In this case, it has been shown that regulation is possible even in the presence of dilution in an exponentially increasing cell volume (9,10).…”

Section: Resultsmentioning

confidence: 99%

“…The first term of Eq. 4 is identical to the time derivative of x in a constant volume, while the second term represents the dilution of x (10). We will call this the dilution term.…”

Section: Modeling Rate Expressions In a Changing Volumementioning

confidence: 99%

“…Although most proteins are maintained at constant concentrations in growing cells, owing to mRNA amounts and number of ribosomes increasing with cell size, we lack an understanding of the molecular mechanisms that coordinate biosynthesis to achieve constant protein concentrations during growth (7,8). Investigations into the performance of so-called integral control motifs (ICMs) have revealed mechanisms by which robustness to dilution can be achieved (9,10). In this paper, we look into homeostatic mechanisms regulating glucose uptake in rapidly growing cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Exploring Mechanisms of Glucose Uptake Regulation and Dilution Resistance in Growing Cancer Cells

Tveit

Fjeld

Drengstig

et al. 2020

Preprint

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Most cancer cells rely on aerobic glycolysis and increased glucose uptake for the production of biosynthetic precursors needed to support rapid proliferation. Increased glucose uptake and glycolytic activity may result in intracellular acidosis and increase of osmotically active substances, leading to cell swelling. This causes dilution of cellular constituents, which can markedly influence cellular reactions and the function of proteins, and hence, control mechanisms used by cancer cells to maintain a highly glycolytic phenotype must be robust to dilution. In this paper, we review the literature on cancer cell metabolism and glucose uptake, and employ mathematical modeling to examine control mechanisms in cancer cell metabolism that show robust homeostatic control in the presence of dilution. Using differential gene expression data from the Expression Atlas database, we identify the key components of glucose uptake in cancer, in order to guide the construction of a mathematical model. By simulations of this model we show that while negative feedback from downstream glycolytic metabolites to glucose transporters is sufficient for homeostatic control of glycolysis in a constant cellular volume, it is necessary to control intermediate glycolytic enzymes in order to achieve homeostatic control during growth. With a focus on glucose uptake in cancer, we demonstrate a systems biology approach to the identification, reduction, and analysis of complex regulatory systems. SIGNIFICANCE Rapid proliferation and increased glycolytic activity in cancer cells lead to dilution of cellular constituents, which can markedly influence cellular reactions and the function of proteins. Therefore, control mechanisms used by cancer cells to maintain a highly glycolytic phenotype must be robust to dilution. We construct a mathematical model of glucose uptake in cancer, and using a systems biology approach to the analysis of regulatory networks, identify the presence of integral control motifs as a means for achieving dilution resistance. Furthermore, we show that while negative feedback from downstream glycolytic metabolites to glucose transporters is sufficient for homeostatic control of glycolysis in a constant cellular volume, it is necessary to control intermediate glycolytic enzymes to achieve homeostatic control during growth.

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Section: Modeling Glucose Uptake In Cancermentioning

confidence: 64%

Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

“…The first term of Eq. 4 is identical to the time derivative of x in a constant volume, while the second term represents the dilution of x (10). We will call this the dilution term.…”

Section: Modeling Rate Expressions In a Changing Volumementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exploring Mechanisms of Glucose Uptake Regulation and Dilution Resistance in Growing Cancer Cells

Tveit

Fjeld

Drengstig

et al. 2020

Preprint

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Robust adaptation of PKC ζ-IRS1 insulin signaling pathways through integral feedback control

Joshi¹,

Patel²,

Bhatt³

2021

Biomed. Phys. Eng. Express

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Insulin signaling pathways in muscle tissue play a major role in maintaining glucose homeostasis. Dysregulation in these pathways results in the onset of serious metabolic disorders like type 2 diabetes. Robustness is an essential characteristic of insulin signaling pathways that ensures reliable signal transduction in the presence of perturbations as a result of several feedback mechanisms. Integral control, according to control engineering, provides reliable setpoint tracking and disturbance rejection. The presence of negative feedback and integrating process is crucial for biological processes to achieve integral control. The existence of an integral controller leads to the rejection of perturbations which resulted in the robust regulation of biochemical entities within acceptable levels. In the present in silico research work, the presence of integral control in the protein kinase C ζ -insulin receptor substrate-1 (PKC ζ-IRS1) pathway is identified, verified mathematically and model is simulated in Cell Designer. The data is exported to Minitab software and robustness analysis is carried out statistically using the Mann-Whitney test. The p-value of the results obtained with given parameters perturbed by ±1% is greater than the significance level of 0.05 (0.2132 for 1% error in k7(rate constant of IRS1 phosphorylation), 0.2096 for −1% error in k7, 0.9037 for both ±1% error in insulin and 0.9037 for ±1% error in k1(association rate constant of the first molecule of insulin to bind the insulin receptor), indicated that our hypothesis is proved The results satisfactorily indicate that even when perturbations are present, glucose homeostasis in muscle tissue is robust due to the presence of integral regulation in the PKC ζ-IRS1 insulin signaling pathways. In this paper, we have analysed the findings from the framework of robust control theory, which has allowed us to examine that how PKC ζ-IRS1 insulin signaling pathways produces desired output in presence of perturbations.

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Frequency switching between oscillatory homeostats and the regulation of p53

Ruoff

Nishiyama

2020

Preprint

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1Homeostasis is an essential concept to understand the stability of organisms and their 2 adaptive behaviors when coping with external and internal assaults. Many hormones 3 that take part in homeostatic control come in antagonistic pairs, such as glucagon and 4 insulin reflecting the inflow and outflow compensatory mechanisms to control a certain 5 internal variable, such as blood sugar levels. By including negative feedback loops 6 homeostatic controllers can exhibit oscillations with characteristic frequencies. In this 7 paper we demonstrate the associated frequency changes in homeostatic systems when 8 individual controllers in a set of interlocked feedback loops gain control in response to 9 environmental changes. Taking p53 as an example, we show how the Per2, ATM and 10 Mdm2 feedback loops -interlocked with p53-gain individual control in dependence to 11 DNA damage and how each of these controllers provide certain functionalities in their 12 regulation of p53. In unstressed cells, the circadian regulator Per2 ensures a basic p53 13 level to allow its rapid up-regulation in case of DNA damage. When DNA damage 14 occurs the ATM controller increases the level of p53 and defends it towards uncontrolled 15 degradation, which despite DNA damage, would drive p53 to lower values and p53 16dysfunction. Mdm2 on its side keeps p53 at a maximum level to avoid premature 17 apoptosis. However, with on-going DNA damage the Mdm2 set-point is increased by 18 HSP90 and other p53 stabilizers leading finally to apoptosis. An essential aspect in p53 19 regulation at occurring cell stress is the coordinated inhibition of ubiquitin-independent 20 and ubiquitin-dependent degradation reactions and the increasing stabilizing 21 mechanisms of p53. Whether oscillations serve a function or are merely a by-product of 22 the controllers are discussed in view of the finding that homeostatic control of p53, as 23 indicated above, does in principle not require oscillatory homeostats. 24 30 control [8], alongside with integral feedback [9][10][11], and systems biology methods [12, 13]. 31 It became clear that certain reaction kinetic conditions are necessary for the occurrence 32December 24, 2019 1/17 of integral control leading to the robustness of the feedback controller. These conditions 33 include zero-order kinetics [9, 10,[14][15][16][17][18][19], autocatalysis [20][21][22], and second-order 34 (bimolecular/antithetic) reaction [23, 24], which were implemented into various controller 35 motifs, synthetic gene networks, and other negative feedback structures [18,[25][26][27]. 36A particular interesting aspect is that, under certain conditions, the homeostatic 37 controllers may become oscillatory and preserve, if integral control is present, their 38 homeostatic property by keeping the average value of the controlled variable at its 39 set-point [28]. While the occurrence of oscillations is generally avoided in control 40 engineering, natural systems show generally oscillatory behaviors, as found in circadian 41 or ultradian rhythms ...

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Homeostatic controllers compensating for growth and perturbations

Cited by 11 publications

References 44 publications

Exploring Mechanisms of Glucose Uptake Regulation and Dilution Resistance in Growing Cancer Cells

Exploring Mechanisms of Glucose Uptake Regulation and Dilution Resistance in Growing Cancer Cells

Robust adaptation of PKC ζ-IRS1 insulin signaling pathways through integral feedback control

Frequency switching between oscillatory homeostats and the regulation of p53

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