Biology subjects

Drengstig, T.

Publications and source records attributed to Drengstig, T..

3 recordsLinked to original sources

bioRxiv2020

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

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. SIGNIFICANCERapid 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.

cancer biology↗

bioRxiv2018

Homeostatic Controllers Compensating for Growth and Perturbations

Cells and organisms have developed homeostatic mechanisms to maintain internal stabilities which protect them against a changing environment. How cellular growth and homeostasis interact is still not well understood, but of increasing interest to the synthetic and molecular biology community where molecular control circuits are sought and tried to maintain homeostasis that opposes the diluting effects of cell growth. In this paper we describe the performance of four negative feedback (inflow) controllers, which, for different observed growth laws (time-dependent increase in the cellular volume V) are able to compensate for various time-dependent removals of the controlled variable A. The four implementations of integral control are based on zero-order, first-order autocatalytic, second-order (antithetic), and derepressing inhibition kinetics. All controllers behave ideal in the sense that they for step-wise perturbations in V and A are able to drive the controlled variable precisely back to the controllers theoretical set-point [Formula] The applied increase in cellular volume includes linear, exponential and saturating growth and reflect experimentally observed growth laws of single cell organisms and other cell types. During the increase in V, additional linear or exponential time-dependent perturbations which remove A are applied, and controllers are tested with respect to their ability to compensate for both the increase in volume V and the applied perturbations removing A. Our results show that the way how integral control is kinetically implemented and the structure of the negative feedback loop are essential determinants of a controllers performance. The results provide a ranking between the four tested controller types. Considering exponential volume increases together with an exponentially increasing removal rate of A controllers based on derepression kinetics perform best, but break down when the control-inhibitors concentration gets too low. The first-order autocatalytic controller is able to defend time-dependent exponential growth and removals in A, but generally with a certain offset below its theoretical set-point [Formula] The controllers based on zero-order and second-order (antithetic) integral feedback can only manage linear increases in V and removals in A, in dependence of the controllers aggressiveness. Our results provide a theoretical basis what controller kinetics are needed in order to compensate for different growth laws.

biophysics↗

bioRxiv2018

Antagonistic regulation with a unique setpoint, integral and double integral action

Several biochemical species are in organisms controlled in a pairwise manner i.e., two different species (e.g., hormone, enzyme, transporter protein) work to control the concentration of a third chemical species. Such pairs are often antagonistic, meaning that one of the controller species acts to increase whereas the other controller species acts to decrease the amount of the controlled species. How antagonistic systems interact to achieve regulation and to avoid competing against each other is not fully understood. An issue is how two antagonistic hormones can agree upon one common setpoint. We present here a new type of antagonistic regulatory system that has a single unique setpoint inherently defined by the system. The regulatory system controls the concentration of a chemical species with both integral and double integral action, achieving tight control. We show by the use of an analytical stability analysis, using the principle of vanishing perturbations, that the setpoint is asymptotically stable. Finally the prospect of treating the presented system as a part of a larger family of antagonistic regulatory systems with unique setpoints, integral and double integral action is discussed.

systems biology↗