Oscillations in NF-κB Signaling Control the Dynamics of Gene Expression
Abstract
Signaling by the transcription factor nuclear factor kappa B (NF-κB) involves its release from inhibitor kappa B (IκB) in the cytosol, followed by translocation into the nucleus. NF-κB regulation of IκBα transcription represents a delayed negative feedback loop that drives oscillations in NF-κB translocation. Single-cell time-lapse imaging and computational modeling of NF-κB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IκBα transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-κB signaling may thus depend on number, period, and amplitude of oscillations.
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In the NF-κB system, NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB; pro-inflammatory cytokines such as TNF-α, LPS and IL-1 act by binding to receptors at the cell surface and initiating signalling pathways that lead to activation of IKK; IKK phosphorylates IκB causing its release and degradation, allowing NF-κB to translocate to the nucleus where it can activate a
“In the NF-κB system (e.g. [2020-2024]) (Fig 8), NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB (often IκBα). Pro-inflammatory cytokines such as TNF-α, LPS [2025-2030] and IL-1 [2031] act by binding to receptors at the cell surface and initiating signalling pathways that lead to the activation of a particular kinase, IκB kinase or IKK. This kinase phosphorylates the”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [2022]
Specificity of NF-κB activity is likely to come in part via frequency encoding.
“Specificity is likely to come, in part, via the frequency encoding of NF-κB activity”
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- Authors
- Nelson, D. E., Ihekwaba, A. E. C., Elliott, M., Johnson, J. R., Gibney, C. A., Foreman, B. E., Nelson, G., See, V., Horton, C. A., Spiller, D. G., Edwards, S. W., McDowell, H. P., Unitt, J. F., Sullivan, E., Grimley, R., Benson, N., Broomhead, D., Kell, D. B., & White, M. R. H.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Crown Street, Liverpool, L69 7ZB, UK.
- Corresponding author
- White, M. R. H.
- ORCID
- Venue
- Science
- Published
- 2004-10-22
- Volume
- 306
- Issue
- 5696
- Pages
- 704-708
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2125937596
- Cited by
- 1,186
- References
- 29
- Citations by year
- 2026: 30 · 2025: 28 · 2024: 30 · 2023: 39 · 2022: 37 · 2021: 48 · 2020: 45 · 2019: 61 · 2018: 51 · 2017: 62 · 2016: 54 · 2015: 69 · 2014: 69 · 2013: 76 · 2012: 65
- FWCI
- 20.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Engineering and Physical Sciences Research Council (GR/R60621/01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- NF-κB signaling, NF-κB oscillations, negative feedback loop, p65 phosphorylation, nuclear translocation, gene expression dynamics, single-cell time-lapse imaging, computational modeling, asynchronous oscillations, signal transduction
- MeSH terms
- NF-KappaB Inhibitor alpha, Cell Nucleus, Computer Simulation, Cytoplasm, Etoposide, Gene Expression Regulation, HeLa Cells, Humans, Models, Biological, Phosphorylation, Recombinant Fusion Proteins, Transcription, Genetic, Transfection, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, I-kappa B Proteins, Active Transport, Cell Nucleus, Feedback, Physiological, Cell Line, Tumor, Transcription Factor RelA
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