1. | Ashall L.♦, Horton Caroline A.♦, Nelson David E.♦, Paszek P.♦, Harper Claire V.V.♦, Sillitoe K.♦, Ryan S.♦, Spiller David G.♦, Unitt John F.♦, Broomhead David S.♦, Kell Douglas B.♦, Rand David A.A.♦, Sée V.♦, White Michael R.R.♦, Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription, Science, ISSN: 0036-8075, DOI: 10.1126/science.1164860, Vol.324, No.5924, pp.242-246, 2009Abstract:The nuclear factor κB (NF-κB) transcription factor regulates cellular stress responses and the immune response to infection. NF-κB activation results in oscillations in nuclear NF-κB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor–α at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-κB 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-κB–dependent gene expression, which supports the idea that oscillation frequency has a functional role. Affiliations:Ashall L. | - | other affiliation | Horton Caroline A. | - | other affiliation | Nelson David E. | - | other affiliation | Paszek P. | - | other affiliation | Harper Claire V.V. | - | University of Manchester
(GB) | Sillitoe K. | - | other affiliation | Ryan S. | - | other affiliation | Spiller David G. | - | other affiliation | Unitt John F. | - | other affiliation | Broomhead David S. | - | other affiliation | Kell Douglas B. | - | other affiliation | Rand David A.A. | - | University of Warwick (GB) | Sée V. | - | other affiliation | White Michael R.R. | - | University of Manchester
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