Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription

Louise Ashall, Caroline A Horton, David E Nelson, Pawel Paszek, Claire V Harper, Kate Sillitoe, Sheila Ryan, David G Spiller, John F Unitt, David S Broomhead, Douglas B Kell, David A Rand, Violaine Sée, Michael R H White

Research output: Contribution to journalArticle

378 Citations (Scopus)

Abstract

The nuclear factor kappaB (NF-kappaB) transcription factor regulates cellular stress responses and the immune response to infection. NF-kappaB activation results in oscillations in nuclear NF-kappaB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor-alpha at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-kappaB nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-kappaB-dependent gene expression, which supports the idea that oscillation frequency has a functional role.

Original languageEnglish
Pages (from-to)242-6
Number of pages5
JournalScience
Volume324
Issue number5924
DOIs
Publication statusPublished - 10 Apr 2009

Keywords

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus/metabolism
  • Cytoplasm/metabolism
  • Feedback, Physiological
  • Gene Expression
  • Humans
  • I-kappa B Proteins/metabolism
  • Mice
  • Models, Biological
  • Models, Statistical
  • NF-KappaB Inhibitor alpha
  • NF-kappa B/metabolism
  • Phosphorylation
  • Recombinant Fusion Proteins/metabolism
  • Stochastic Processes
  • Transcription Factor RelA/metabolism
  • Transcription, Genetic
  • Transfection
  • Tumor Necrosis Factor-alpha/metabolism

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  • Cite this

    Ashall, L., Horton, C. A., Nelson, D. E., Paszek, P., Harper, C. V., Sillitoe, K., Ryan, S., Spiller, D. G., Unitt, J. F., Broomhead, D. S., Kell, D. B., Rand, D. A., Sée, V., & White, M. R. H. (2009). Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription. Science, 324(5924), 242-6. https://doi.org/10.1126/science.1164860