Dataset Information

Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses.

ABSTRACT:

Background

Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.

Objectives

Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data.

Methods

Here we have examined dose-response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures.

Discussion and conclusion

Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC4256703 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Publications

Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses.

Zhang Qiang Q Bhattacharya Sudin S Conolly Rory B RB Clewell Harvey J HJ Kaminski Norbert E NE Andersen Melvin E ME

Environmental health perspectives 20140812 12

<h4>Background</h4>Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.<h4>Objectives</h4>Cellular response behaviors depend on the molecular pathway and circuitr ...[more]

PMID: 25117432

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Project description:BackgroundWith increasing knowledge about the potential mechanisms underlying cellular functions, it is becoming feasible to predict the response of biological systems to genetic and environmental perturbations. Due to the lack of homogeneity in living tissues it is difficult to estimate the physiological effect of chemicals, including potential toxicity. Here we investigate a biologically motivated model for estimating tissue level responses by aggregating the behavior of a cell population. We assume that the molecular state of individual cells is independently governed by discrete non-deterministic signaling mechanisms. This results in noisy but highly reproducible aggregate level responses that are consistent with experimental data.ResultsWe developed an asynchronous threshold Boolean network simulation algorithm to model signal transduction in a single cell, and then used an ensemble of these models to estimate the aggregate response across a cell population. Using published data, we derived a putative crosstalk network involving growth factors and cytokines - i.e., Epidermal Growth Factor, Insulin, Insulin like Growth Factor Type 1, and Tumor Necrosis Factor α - to describe early signaling events in cell proliferation signal transduction. Reproducibility of the modeling technique across ensembles of Boolean networks representing cell populations is investigated. Furthermore, we compare our simulation results to experimental observations of hepatocytes reported in the literature.ConclusionA systematic analysis of the results following differential stimulation of this model by growth factors and cytokines suggests that: (a) using Boolean network ensembles with asynchronous updating provides biologically plausible noisy individual cellular responses with reproducible mean behavior for large cell populations, and (b) with sufficient data our model can estimate the response to different concentrations of extracellular ligands. Our results suggest that this approach is both quantitative, allowing statistical verification and calibration, and extensible, allowing modification and revision as guided by experimental evidence. The simulation methodology is part of the US EPA Virtual Liver, which is investigating the effects of everyday contaminants on living tissues. Future models will incorporate additional crosstalk surrounding proliferation as well as the putative effects of xenobiotics on these signaling cascades within hepatocytes.

Dataset Information

Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses.

Background

Objectives

Methods

Discussion and conclusion

Publications

Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses.

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