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Pulsatile Stimulation Determines Timing and Specificity of NF-B-Dependent Transcription
Louise Ashall,1*Caroline A. Horton,1*David E. Nelson,1*Pawel Paszek,1*Claire V. Harper,1Kate Sillitoe,1Sheila Ryan,1David G. Spiller,1John F. Unitt,2David S. Broomhead,3Douglas B. Kell,4David A. Rand,5Violaine Sée,1Michael R. H. White1
The nuclear factor B (NF-B) transcription factor regulates cellularstress responses and the immune response to infection. NF-Bactivation results in oscillations in nuclear NF-B abundance.To define the function of these oscillations, we treated cellswith repeated short pulses of tumor necrosis factor– atvarious intervals to mimic pulsatile inflammatory signals. Atall pulse intervals that were analyzed, we observed synchronouscycles of NF-B nuclear translocation. Lower frequency stimulationsgave repeated full-amplitude translocations, whereas higherfrequency pulses gave reduced translocation, indicating a failureto reset. Deterministic and stochastic mathematical models predictedhow negative feedback loops regulate both the resetting of thesystem and cellular heterogeneity. Altering the stimulationintervals gave different patterns of NF-B–dependent geneexpression, which supports the idea that oscillation frequencyhas a functional role.
1 Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Crown Street, Liverpool, L69 7ZB, UK. 2 Molecular Biology Department, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK. 3 School of Mathematics, The Alan Turing Building, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK. 4 Manchester Centre for Integrative Systems Biology, School of Chemistry, and Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester, M1 7DN. 5 Warwick Systems Biology, Coventry House, University of Warwick, Coventry CV4 7AL, UK.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: mwhite{at}liv.ac.uk
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Dynamic Advances in NF-{kappa}B Signaling Analysis.
B-Dependent Transcription
B (NF-
at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-
To whom correspondence should be addressed. E-mail: 
