Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Feb 27;284(9):5439-43.
doi: 10.1074/jbc.R800008200. Epub 2008 Oct 20.

Integrating computational and biochemical studies to explore mechanisms in NF-{kappa}B signaling

Jeffrey D Kearns  1 , Alexander Hoffmann
Affiliations
Review

Integrating computational and biochemical studies to explore mechanisms in NF-{kappa}B signaling

Jeffrey D Kearns et al. J Biol Chem. .
No abstract available

PubMed Disclaimer

Figures

FIGURE 1.
FIGURE 1.
A, the cell responds to external and internal stimuli through complex signal transduction networks that utilize distinct signaling modules to exact specific cellular responses. The NF-κB signaling module is one such key mediator. IKK is activated in response to cellular stimuli and causes accumulation of the NF-κB transcription factor in the nucleus that drives stimulus-specific gene expression programs. Some of the many connections between stimuli and cellular responses are shown and are illustrative of the combinatorial complexity inherent in the cellular signal transduction network. JNK, Janus kinase; ERK, extracellular signal-regulated protein kinase. AP-1, activator protein 1; ATF, activating transcription factor; IRF, interferon regulatory factor. B, schematic diagram of the components and reactions that are described within the NF-κB computational model. Distinct reactions exist for each IκB isoform (IκBα, IκBβ, and IκBε) and are controlled by isoform-specific reaction rate constants. Reactions control synthesis and degradation of the IκB proteins; association and dissociation of IκB proteins, NF-κB, and IKK; and cellular localization. NF-κB is a product or reactant in multiple reactions and, for clarity, is included once in the middle of the diagram. The temporal profile of IKK activity is used as the model input. C, two examples of the 24 ODEs that are contained within the NF-κB model. The flux for each component is calculated via mass action kinetics by subtracting the sum of the reactions that remove the component from the sum of the reactions that produce the component. Shown first is the equation governing IκBα mRNA expression, which contains the reactions of constitutive and NF-κB-inducible transcription (Txn) and mRNA degradation (Deg.). Shown second is the equation governing the amount of free NF-κB protein in the nucleus (NFκBn), which is controlled by association and dissociation with IκB proteins, protein degradation of NF-κB-bound IκB proteins, and cellular localization reactions.
FIGURE 2.
FIGURE 2.
A, parameter sensitivity analysis reveals the importance of a second IκB protein degradation mechanism (33). Upper, schematic diagram of the four distinct IκB degradation reactions; lower, “spider charts” showing the sensitivity of the model to perturbations of each of the four degradation reaction rate constants from 0.01× to 100×. Each point represents the average of the first hour of NF-κB activity in model simulations with the parameter multiplier indicated on the x axis. The response of the wild-type system (1× multiplier) is shown in the middle of each plot. Upper plot, IKK-dependent IκB degradation rates r1(blue) and r4(light blue); lower plot, IKK-independent IκB degradation rates deg1 (red) and deg4 (pink). B, IκB negative feedback regulates oscillations in NF-κB activity (32). Upper, simulation results with chronic TNF stimulation in Model Version 1.0 (22) with (blue) or without (light blue) IκBβ-regulated NF-κB nuclear export; middle, quantitation of IκBα (pink) and IκBε (red) mRNA expression in response to chronic TNF stimulation in wild-type fibroblast cells as measured by RNase protection assay; lower, simulation results in an updated model (Version 1.2), containing an NF-κB-inducible IκBε synthesis reaction, in wild-type (blue) versus IκBε-deficient (light blue) model systems. NFκBn, free NF-κB protein in the nucleus. C, the IκBδ/p100 IκB isoform mediates cross-talk between inflammatory and developmental signaling pathways (19). Upper, simulation results in Model Version 3.0 show that IκBδ represents a small fraction of the total IκB pool in naïve cells but is increased following priming by transient inflammatory (TNF) stimulation; middle and lower, simulations and cell culture measurements of NF-κB activity by electrophoretic mobility shift assay, respectively, in naïve (light blue) versus TNF-primed (blue) cells in response to developmental (lymphotoxin-β) stimulation. LTβR, lymphotoxin-β receptor.
See this image and copyright information in PMC

References

    1. Palsson, B. (2006) Systems Biology: Properties of Reconstructed Networks, Cambridge University Press, Cambridge
    1. Alon, U. (2007) An Introduction to Systems Biology: Design Principles of Biological Circuits, Chapman & Hall/CRC, Boca Raton, FL
    1. Eungdamrong, N. J., and Iyengar, R. (2004) Trends Cell Biol. 14 661–669 - PMC - PubMed
    1. Kholodenko, B. N. (2006) Nat. Rev. 7 165–176 - PMC - PubMed
    1. Novick, A., and Weiner, M. (1957) Proc. Natl. Acad. Sci. U. S. A. 43 553–566 - PMC - PubMed

Publication types

LinkOut - more resources