Oscillations in NF-κB Signaling Control the Dynamics of Gene Expression

Nelson, David E.; Ihekwaba, Adaoha E. C.; Elliott, Malcolm C.; Johnson, James R.; Gibney, C. A.; Foreman, Bo; Nelson, Glyn; Sée, Violaine; Horton, Caroline A.; Spiller, David G.; Edwards, Steven W.; McDowell, Heather P.; Unitt, John; Sullivan, Elaine; Grimley, Rachel L.; Benson, Neil; Broomhead, D. S.; Kell, Douglas B.; White, Mike

doi:10.1126/science.1099962

Cited by 1,103 publications

(1,234 citation statements)

References 28 publications

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“…Research using real-time single-cell imaging has shown NF!B shuttling in and out of the nucleus under an inflammatory stimulus such as TNF!, matched with firefly-luciferase activity [40]. Here we show that the data from a Gaussia luciferase reporter under the control of NF!B is a valid measure of the dynamics of transcriptional activity due to NF!B stimulation in a cell population.…”

Section: Discussionmentioning

confidence: 74%

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Brüning

Fitzpatrick

Frank

et al. 2011

Cell. Mol. Life Sci.

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The oxygen-sensitive transcription factor Hypoxia Inducible Factor (HIF) is a key regulator of gene expression during adaptation to hypoxia. Crucially, inflamed tissue often displays regions of prominent hypoxia. Recent studies have shown HIF signalling is intricately linked to that of the pro-inflammatory transcription factor Nuclear factor kappa B (NF!B) during hypoxic inflammation. Here we describe the relative temporal contributions of each to hypoxia-induced inflammatory gene expression and investigate the level of crosstalk between the two pathways using a novel Gaussia princeps luciferase (Gluc) reporter system. Under the control of an active promoter, Gluc is expressed and secreted into the cell culture media, where it can be sampled and measured over time. Thus Gluc constructs under the control of either HIF or NF!B were used to resolve their temporal transcriptional dynamics in response to hypoxia and to cytokine stimuli respectively. We also investigated the interactions between HIF and NF!B activities using a construct containing the sequence from the promoter of the inflammatory gene cyclooxygenase 2 (COX-2), which includes functionally active binding sites for both HIF and NF!B. Finally, based on our experimental data, we constructed a mathematical model of the binding affinities of HIF and NF!B to their respective response elements to analyse transcriptional crosstalk. Taken together, these data reveal distinct temporal HIF and NF!B transcriptional activities in response to hypoxic inflammation. Furthermore, we demonstrate synergistic activity between these two transcription factors on the regulation of the COX-2 promoter, implicating a coordinated role for both HIF and NF!B in the expression of COX-2 in hypoxic inflammation.

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Section: Discussionmentioning

confidence: 74%

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Brüning

Fitzpatrick

Frank

et al. 2011

Cell. Mol. Life Sci.

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“…The experimental results in Ref. [5] show only few periods of the oscillations, making it difficult to decide whether one deals with sustained or damped oscillations. The same may be said for the results in [2].…”

Section: Comparison With Experimental Resultsmentioning

confidence: 99%

“…The three proteins Hes1, p53, and NF-κB are transcriptionally regulated by short negative feedback loops and actual experiments have revealed that their genes show an oscillatory expression [1,2,3,4,5]. In the vertebrate segmentation clock several cycling genes are involved in an oscillatory mechanism driving somite segmentation [6].…”

Section: Introductionmentioning

confidence: 99%

“…In the vertebrate segmentation clock several cycling genes are involved in an oscillatory mechanism driving somite segmentation [6]. Mathematical models have been established for the regulation of these proteins [1,2,3,5,7,8,9,10,11,12] where the authors of [7,8,9,10] have introduced a discrete time delay to describe the time lag between transcription factor binding and gene transcription. Analytical and numerical results have shown that these models, which display damped oscillations for small positive delay times, can pass a Hopf bifurcation at a critical delay time where the stable steady state becomes unstable and a stable limit cycle oscillator emerges [7,8,9,10].…”

Section: Introductionmentioning

confidence: 99%

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Intracellular delay limits cyclic changes in gene expression

Rateitschak

Wolkenhauer

2007

Mathematical Biosciences

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Based on previously published experimental observations and mathematical models for Hes1, p53 and NF-κB gene expression, we improve these models through a distributed delay formulation of the time lag between transcription factor binding and mRNA production. This description of natural variability for delays introduces a transition from a stable steady state to limit cycle oscillations and then a second transition back to a stable steady state which has not been observed in previously published models. On the basis of our results and following recent discussions about the role of delay-induced oscillations in gene transcription we establish the hypothesis that the period of the delay-induced cyclic changes should be characterized by an upper bound so that it cannot be greater then the period of fundamental biological cycles. We demonstrate our approach for two models. The first model describes Hes1 autorepression with equations for Hes1 mRNA production and Hes1 protein translation. The second model describes Hes1 repression by the protein complex Gro/TLE1/Hes1, where Gro/TLE1 is activated by Hes1 phosphorylation.

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“…These initial studies utilized IkB-deficient cell lines and observed that continual application of TNF resulted in extended oscillations of NF-kB activity in IkBe À/À b À/À cells owing to the powerful negative feedback of NF-kBcontrolled IkBa expression. Similarly, overexpression of RelA and RelA-responsive IkBa by transient transfection resulted in oscillatory activity in single cells as revealed by video microscopy in single cells (Nelson et al, 2004), although the resulting increase in the green fluorescence protein-fusion effector molecules can alter the dynamic behavior . However, in wild-type cells, NF-kB activity is subject to other negative feedback mechanisms.…”

Section: Transcriptional Specificity As Determined By Nf-jb Dynamicsmentioning

confidence: 99%

Transcriptional regulation via the NF-κB signaling module

2006

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Stimulus-induced nuclear factor-jB (NF-jB) activity, the central mediator of inflammatory responses and immune function, comprises a family of dimeric transcription factors that regulate diverse gene expression programs consisting of hundreds of genes. A family of inhibitor of jB (IjB) proteins controls NF-jB DNA-binding activity and nuclear localization. IjB protein metabolism is intricately regulated through stimulus-induced degradation and feedback re-synthesis, which allows for dynamic control of NF-jB activity. This network of interactions has been termed the NF-jB signaling module. Here, we summarize the current understanding of the molecular structures and biochemical mechanisms that determine NF-jB dimer formation and the signal-processing characteristics of the signaling module. We identify NF-jB-jB site interaction specificities and dynamic control of NF-jB activity as mechanisms that generate specificity in transcriptional regulation. We discuss examples of gene regulation that illustrate how these mechanisms may interface with other transcription regulators and promoter-associated events, and how these mechanisms suggest regulatory principles for NF-jB-mediated gene activation.

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Oscillations in NF-κB Signaling Control the Dynamics of Gene Expression

Cited by 1,103 publications

References 28 publications

NFκB and HIF display synergistic behaviour during hypoxic inflammation

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Intracellular delay limits cyclic changes in gene expression

Transcriptional regulation via the NF-κB signaling module

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