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Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20

Werner, Shannon L. and Kearns, Jeffrey D. and Zadorozhnaya, Victoria and Lynch, Candace and O'Dea, Ellen and Boldin, Mark P. and Ma, Averil and Baltimore, David and Hoffmann, Alexander (2008) Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20. Genes and Development, 22 (15). pp. 2093-2101. ISSN 0890-9369. PMCID PMC2492747. doi:10.1101/gad.1680708.

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TNF-induced NF-κB activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two temporal amplification steps—one determined by the obligate negative feedback regulator IκBα—that define the duration of the first phase of NF-κB activity. The second phase is defined by A20, whose inducible expression provides for a rheostat function by which other inflammatory stimuli can regulate TNF responses. Our results delineate the nonredundant functions implied by the knockout phenotypes of iκbα and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.

Item Type:Article
Related URLs:
URLURL TypeDescription Research Data CentralArticle
Boldin, Mark P.0000-0003-4593-0669
Baltimore, David0000-0001-8723-8190
Additional Information:© 2008 by Cold Spring Harbor Laboratory Press. Received April 2, 2008; revised version accepted June 16, 2008. We acknowledge J. Hasty, B. Kholodenko, J. Faeder, and A. Levchenko for insightful discussions. This study was supported by National Institutes of Health R01 grant GM72024. S.L.W. is supported by the NSF Graduate Research Fellowship, and J.D.K. is supported by an American Heart Association Predoctoral Fellowship.
Funding AgencyGrant Number
NIHR01 GM72024
NSF Graduate Research FellowshipUNSPECIFIED
American Heart AssociationUNSPECIFIED
Subject Keywords:NF-κB signaling; negative feedback; computational modeling; temporal control; IκBα; A20
Issue or Number:15
PubMed Central ID:PMC2492747
Record Number:CaltechAUTHORS:20200421-065944620
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102677
Deposited By: Tony Diaz
Deposited On:21 Apr 2020 16:40
Last Modified:16 Nov 2021 18:14

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