Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses.
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 ma...
| Publicado en: | Environmental Health Perspectives Vol. 122; no. 12; pp. 1261 - 1271 |
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| Autores principales: | , , , , , |
| Formato: | tables/charts Journal Article |
| Publicado: |
National Institute of Environmental Health Sciences
Dec2014
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=103921759&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 103921759 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00916765 3B5 jtl: Environmental Health Perspectives issn: 00916765 maglogo: N pubinfo: dt: Dec2014 vid: 122 iid: 12 pid: 56539 pub: National Institute of Environmental Health Sciences place: Research Triangle Park, North Carolina artinfo: ui: 103921759 99739988 10.1289/ehp.1408244 NLM25117432 103921759 ppf: 1261 ppct: 10 formats: fmt: @attributes: type: P tig: atl: Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses. aug: au: Qiang Zhang Bhattacharya, Sudin Conolly, Rory B. Clewell III, Harvey J. Kaminski, Norbert E. Andersen, Melvin E. affil: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA sug: subj: Signal Transduction Cell Physiology Dose-Response Relationship Metabolic Networks and Pathways Toxicity Tests Homeostasis Cell Differentiation Adaptation, Physiological Apoptosis In Vitro Studies ab: 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. pubtype: Academic Journal doctype: tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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