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Minimal model of spiky oscillations in NF-kappaB signaling.

ABSTRACT: The NF-kappaB signaling system is involved in a variety of cellular processes including immune response, inflammation, and apoptosis. Recent experiments have found oscillations in the nuclear-cytoplasmic translocation of the NF-kappaB transcription factor [Hoffmann, A., et al. (2002) Science 298, ; Nelson, D. E., et al. (2004) Science 306, .] How the cell uses the oscillations to differentiate input conditions and send specific signals to downstream genes is an open problem. We shed light on this issue by examining the small core network driving the oscillations, which we show is designed to produce periodic spikes in nuclear NF-kappaB concentration. The presence of oscillations is extremely robust to variation of parameters, depending mainly on the saturation of the active degradation rate of IkappaB, an inhibitor of NF-kappaB. The oscillations can be used to regulate downstream genes in a variety of ways. In particular, we show that genes to whose operator sites NF-kappaB binds and dissociates fast can respond very sensitively to changes in the input signal, with effective Hill coefficients of >20.

SUBMITTER: Krishna S

PROVIDER: S-EPMC1544135 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Minimal model of spiky oscillations in NF-kappaB signaling.

Krishna Sandeep S Jensen Mogens H MH Sneppen Kim K

Proceedings of the National Academy of Sciences of the United States of America 20060707 29

The NF-kappaB signaling system is involved in a variety of cellular processes including immune response, inflammation, and apoptosis. Recent experiments have found oscillations in the nuclear-cytoplasmic translocation of the NF-kappaB transcription factor [Hoffmann, A., et al. (2002) Science 298, ; Nelson, D. E., et al. (2004) Science 306, .] How the cell uses the oscillations to differentiate input conditions and send specific signals to downstream genes is an open problem. We shed light on thi ...[more]

PMID: 16829571

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Project description:BackgroundThe nuclear factor-kappaB (NF-kappaB) family of transcription factors plays a role in a wide range of cellular processes including the immune response and cellular growth. In addition, deregulation of the NF-kappaB system has been associated with a number of disease states, including cancer. Therefore, insight into the regulation of NF-kappaB activation has crucial medical relevance, holding promise for novel drug target discovery. Transcription of NF-kappaB-induced genes is regulated by differential dynamics of single NF-kappaB subunits, but only a few methods are currently being applied to study dynamics. In particular, while oscillations of NF-kappaB activation have been observed in response to the cytokine tumor necrosis factor alpha (TNFalpha), little is known about the occurrence of oscillations in response to bacterial infections.ResultsTo quantitatively assess NF-kappaB dynamics we generated human and murine monoclonal cell lines that stably express the NF-kappaB subunit p65 fused to GFP. Furthermore, a high-throughput assay based on automated microscopy coupled to image analysis to quantify p65-nuclear translocation was established. Using this assay, we demonstrate a stimulus- and cell line-specific temporal control of p65 translocation, revealing, for the first time, oscillations of p65 translocation in response to bacterial infection. Oscillations were detected at the single-cell level using real-time microscopy as well as at the population level using high-throughput image analysis. In addition, mathematical modeling of NF-kappaB dynamics during bacterial infections predicted masking of oscillations on the population level in asynchronous activations, which was experimentally confirmed.ConclusionsTaken together, this simple and cost effective assay constitutes an integrated approach to infer the dynamics of NF-kappaB kinetics in single cells and cell populations. Using a single system, novel factors modulating NF-kappaB can be identified and analyzed, providing new possibilities for a wide range of applications from therapeutic discovery and understanding of disease to host-pathogen interactions.

Dataset Information

Minimal model of spiky oscillations in NF-kappaB signaling.

Publications

Minimal model of spiky oscillations in NF-kappaB signaling.

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