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Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module
Many cellular stress-responsive signaling systems exhibit highly dynamic behavior with oscillatory features mediated by delayed negative feedback loops. What remains unclear is whether oscillatory behavior is the basis for a signaling code based on frequency modulation (FM) or whether the negative f...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694842/ https://www.ncbi.nlm.nih.gov/pubmed/23825938 http://dx.doi.org/10.1371/journal.pcbi.1003112 |
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author | Longo, Diane M. Selimkhanov, Jangir Kearns, Jeffrey D. Hasty, Jeff Hoffmann, Alexander Tsimring, Lev S. |
author_facet | Longo, Diane M. Selimkhanov, Jangir Kearns, Jeffrey D. Hasty, Jeff Hoffmann, Alexander Tsimring, Lev S. |
author_sort | Longo, Diane M. |
collection | PubMed |
description | Many cellular stress-responsive signaling systems exhibit highly dynamic behavior with oscillatory features mediated by delayed negative feedback loops. What remains unclear is whether oscillatory behavior is the basis for a signaling code based on frequency modulation (FM) or whether the negative feedback control modules have evolved to fulfill other functional requirements. Here, we use experimentally calibrated computational models to interrogate the negative feedback loops that regulate the dynamic activity of the transcription factor NF-[Image: see text]B. Linear stability analysis of the model shows that oscillatory frequency is a hard-wired feature of the primary negative feedback loop and not a function of the stimulus, thus arguing against an FM signaling code. Instead, our modeling studies suggest that the two feedback loops may be tuned to provide for rapid activation and inactivation capabilities for transient input signals of a wide range of durations; by minimizing late phase oscillations response durations may be fine-tuned in a graded rather than quantized manner. Further, in the presence of molecular noise the dual delayed negative feedback system minimizes stochastic excursions of the output to produce a robust NF-[Image: see text]B response. |
format | Online Article Text |
id | pubmed-3694842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36948422013-07-03 Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module Longo, Diane M. Selimkhanov, Jangir Kearns, Jeffrey D. Hasty, Jeff Hoffmann, Alexander Tsimring, Lev S. PLoS Comput Biol Research Article Many cellular stress-responsive signaling systems exhibit highly dynamic behavior with oscillatory features mediated by delayed negative feedback loops. What remains unclear is whether oscillatory behavior is the basis for a signaling code based on frequency modulation (FM) or whether the negative feedback control modules have evolved to fulfill other functional requirements. Here, we use experimentally calibrated computational models to interrogate the negative feedback loops that regulate the dynamic activity of the transcription factor NF-[Image: see text]B. Linear stability analysis of the model shows that oscillatory frequency is a hard-wired feature of the primary negative feedback loop and not a function of the stimulus, thus arguing against an FM signaling code. Instead, our modeling studies suggest that the two feedback loops may be tuned to provide for rapid activation and inactivation capabilities for transient input signals of a wide range of durations; by minimizing late phase oscillations response durations may be fine-tuned in a graded rather than quantized manner. Further, in the presence of molecular noise the dual delayed negative feedback system minimizes stochastic excursions of the output to produce a robust NF-[Image: see text]B response. Public Library of Science 2013-06-27 /pmc/articles/PMC3694842/ /pubmed/23825938 http://dx.doi.org/10.1371/journal.pcbi.1003112 Text en © 2013 Longo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Longo, Diane M. Selimkhanov, Jangir Kearns, Jeffrey D. Hasty, Jeff Hoffmann, Alexander Tsimring, Lev S. Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module |
title | Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module |
title_full | Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module |
title_fullStr | Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module |
title_full_unstemmed | Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module |
title_short | Dual Delayed Feedback Provides Sensitivity and Robustness to the NF-κB Signaling Module |
title_sort | dual delayed feedback provides sensitivity and robustness to the nf-κb signaling module |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694842/ https://www.ncbi.nlm.nih.gov/pubmed/23825938 http://dx.doi.org/10.1371/journal.pcbi.1003112 |
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