Review Advance Publication
Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses
This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.
Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell III HJ, Kaminski NE, Andersen ME. Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1408244.
Received: 7 February 2014
Accepted: 12 August 2014
Advance Publication: 12 August 2014
Background: Increasingly, there is a move toward using in vitro toxicity testing for assessment of human health risk by chemicals. 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.
Notice of Intent to RecruitThe National Institute of Environmental Health Sciences will soon announce a search for candidates for the position of Supervisory Technical Editor (Operations Manager) for EHP. The Operations Manager will report directly to the Editor-in-Chief of EHP. To learn more, read the full notice of intent to recruit.
CEHN October 2014 Article of the Month“Maternal Exposure to Criteria Air Pollutants and Congenital Heart Defects in Offspring: Results from the National Birth Defects Prevention Study” (Environ Health Perspect; DOI:10.1289/ehp.1307289) has been selected by the Children’s Environmental Health Network (CEHN) as its October 2014 Article of the Month. These CEHN summaries discuss the potential policy implications of current children’s environmental health research.
Sign Up to Receive E-mail Alerts
Recent Advance Publications
A Targeted Health Risk Assessment Following the Deep Water Horizon Oil Spill: Polycyclic Aromatic Hydrocarbon Exposure in Vietnamese-American Shrimp Consumers
Commuting-Adjusted Short-Term Health Impact Assessment of Airborne Fine Particles with Uncertainty Quantification via Monte Carlo Simulation
Effects of Benzo[a]pyrene Exposure on Human Hepatocellular Carcinoma Cell Angiogenesis, Metastasis, and NF-κB Signaling
Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh
Prenatal Exposure to Maternal Cigarette Smoking and DNA Methylation: Epigenome-Wide Association in a Discovery Sample of Adolescents and Replication in an Independent Cohort at Birth through 17 Years of Age