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...

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Autores principales:	Diane M Longo, Jangir Selimkhanov, Jeffrey D Kearns, Jeff Hasty, Alexander Hoffmann, Lev S Tsimring
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d46deef5c1d24267890fa77561ef3eea
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spelling	oai:doaj.org-article:d46deef5c1d24267890fa77561ef3eea2021-11-18T05:52:03ZDual delayed feedback provides sensitivity and robustness to the NF-κB signaling module.1553-734X1553-735810.1371/journal.pcbi.1003112https://doaj.org/article/d46deef5c1d24267890fa77561ef3eea2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23825938/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Many 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-κB. 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-κB response.Diane M LongoJangir SelimkhanovJeffrey D KearnsJeff HastyAlexander HoffmannLev S TsimringPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 6, p e1003112 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Diane M Longo Jangir Selimkhanov Jeffrey D Kearns Jeff Hasty Alexander Hoffmann Lev S Tsimring Dual delayed feedback provides sensitivity and robustness to the NF-κB signaling module.
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-κB. 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-κB response.
format	article
author	Diane M Longo Jangir Selimkhanov Jeffrey D Kearns Jeff Hasty Alexander Hoffmann Lev S Tsimring
author_facet	Diane M Longo Jangir Selimkhanov Jeffrey D Kearns Jeff Hasty Alexander Hoffmann Lev S Tsimring
author_sort	Diane M Longo
title	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_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_sort	dual delayed feedback provides sensitivity and robustness to the nf-κb signaling module.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/d46deef5c1d24267890fa77561ef3eea
work_keys_str_mv	AT dianemlongo dualdelayedfeedbackprovidessensitivityandrobustnesstothenfkbsignalingmodule AT jangirselimkhanov dualdelayedfeedbackprovidessensitivityandrobustnesstothenfkbsignalingmodule AT jeffreydkearns dualdelayedfeedbackprovidessensitivityandrobustnesstothenfkbsignalingmodule AT jeffhasty dualdelayedfeedbackprovidessensitivityandrobustnesstothenfkbsignalingmodule AT alexanderhoffmann dualdelayedfeedbackprovidessensitivityandrobustnesstothenfkbsignalingmodule AT levstsimring dualdelayedfeedbackprovidessensitivityandrobustnesstothenfkbsignalingmodule
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Dual delayed feedback provides sensitivity and robustness to the NF-κB signaling module.

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