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Science 324 (5924): 242-246

Copyright © 2009 by the American Association for the Advancement of Science

Pulsatile Stimulation Determines Timing and Specificity of NF-{kappa}B-Dependent Transcription

Louise Ashall,1* Caroline A. Horton,1* David E. Nelson,1* Pawel Paszek,1* Claire V. Harper,1 Kate Sillitoe,1 Sheila Ryan,1 David G. Spiller,1 John F. Unitt,2 David S. Broomhead,3 Douglas B. Kell,4 David A. Rand,5 Violaine Sée,1 Michael R. H. White1{dagger}

Abstract: The nuclear factor {kappa}B (NF-{kappa}B) transcription factor regulates cellular stress responses and the immune response to infection. NF-{kappa}B activation results in oscillations in nuclear NF-{kappa}B 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-{kappa}B 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-{kappa}B–dependent gene expression, which supports the idea that oscillation frequency has 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.

{dagger} To whom correspondence should be addressed. E-mail: mwhite{at}

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   Abstract »    Full Text »    PDF »
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B. M. Grabias and K. Konstantopoulos (2014)
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   Abstract »    Full Text »    PDF »
On the dephasing of genetic oscillators.
D. A. Potoyan and P. G. Wolynes (2014)
PNAS 111, 2391-2396
   Abstract »    Full Text »    PDF »
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J. Schaber, A. Lapytsko, and D. Flockerzi (2014)
J R Soc Interface 11, 20130971
   Abstract »    Full Text »    PDF »
Peptides genetically selected for NF-{kappa}B activation cooperate with oncogene Ras and model carcinogenic role of inflammation.
V. Natarajan, A. P. Komarov, T. Ippolito, K. Bonneau, A. A. Chenchik, and A. V. Gudkov (2014)
PNAS 111, E474-E483
   Abstract »    Full Text »    PDF »
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M.-H. Sung, N. Li, Q. Lao, R. A. Gottschalk, G. L. Hager, and I. D. C. Fraser (2014)
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   Abstract »    Full Text »    PDF »
Stimulus-induced modulation of transcriptional bursting in a single mammalian gene.
N. Molina, D. M. Suter, R. Cannavo, B. Zoller, I. Gotic, and F. Naef (2013)
PNAS 110, 20563-20568
   Abstract »    Full Text »    PDF »
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J. H. Levine, Y. Lin, and M. B. Elowitz (2013)
Science 342, 1193-1200
   Abstract »    Full Text »    PDF »
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H. Chang and A. Levchenko (2013)
Phil Trans R Soc B 368, 20130117
   Abstract »    Full Text »    PDF »
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B. M. Grabias and K. Konstantopoulos (2013)
Am J Physiol Renal Physiol 305, F123-F133
   Abstract »    Full Text »    PDF »
A hierarchical model of transcriptional dynamics allows robust estimation of transcription rates in populations of single cells with variable gene copy number.
D. J. Woodcock, K. W. Vance, M. Komorowski, G. Koentges, B. Finkenstadt, and D. A. Rand (2013)
Bioinformatics 29, 1519-1525
   Abstract »    Full Text »    PDF »
Tuning the auxin transcriptional response.
E. Pierre-Jerome, B. L. Moss, and J. L. Nemhauser (2013)
J. Exp. Bot. 64, 2557-2563
   Abstract »    Full Text »    PDF »
Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis.
W. Alazawi, H. Heath, J. A. Waters, A. Woodfin, A. J. O'Brien, A. J. Scarzello, B. Ma, Y. Lopez-Otalora, M. Jacobs, G. Petts, et al. (2013)
PNAS 110, 8656-8661
   Abstract »    Full Text »    PDF »
Promoter type influences transcriptional topography by targeting genes to distinct nucleoplasmic sites.
J. D. Larkin, A. Papantonis, and P. R. Cook (2013)
J. Cell Sci. 126, 2052-2059
   Abstract »    Full Text »    PDF »
Circuit-level input integration in bacterial gene regulation.
L. Espinar, M. Dies, T. Cagatay, G. M. Suel, and J. Garcia-Ojalvo (2013)
PNAS 110, 7091-7096
   Abstract »    Full Text »    PDF »
Rate of environmental change determines stress response specificity.
J. W. Young, J. C. W. Locke, and M. B. Elowitz (2013)
PNAS 110, 4140-4145
   Abstract »    Full Text »    PDF »
Direct observation of frequency modulated transcription in single cells using light activation.
D. R. Larson, C. Fritzsch, L. Sun, X. Meng, D. S. Lawrence, and R. H. Singer (2013)
eLife Sci 2, e00750
   Abstract »    Full Text »    PDF »
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A. Papantonis, T. Kohro, S. Baboo, J. D. Larkin, B. Deng, P. Short, S. Tsutsumi, S. Taylor, Y. Kanki, M. Kobayashi, et al. (2012)
EMBO J. 31, 4404-4414
   Abstract »    Full Text »    PDF »
Epithelial-mesenchymal transition and fibrosis are mutually exclusive reponses in shear-activated proximal tubular epithelial cells.
B. M. Grabias and K. Konstantopoulos (2012)
FASEB J 26, 4131-4141
   Abstract »    Full Text »    PDF »
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B. L. Moss, A. Elhammali, T. Fowlkes, S. Gross, A. Vinjamoori, C. H. Contag, and D. Piwnica-Worms (2012)
J. Biol. Chem. 287, 31359-31370
   Abstract »    Full Text »    PDF »
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J. E. Purvis, K. W. Karhohs, C. Mock, E. Batchelor, A. Loewer, and G. Lahav (2012)
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   Abstract »    Full Text »    PDF »
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S.-T. Chen, J.-Y. Li, Y. Zhang, X. Gao, and H. Cai (2012)
J. Immunol. 188, 668-677
   Abstract »    Full Text »    PDF »
How to infer gene networks from expression profiles, revisited.
C. A. Penfold and D. L. Wild (2011)
Interface Focus 1, 857-870
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. Cheong, A. Rhee, C. J. Wang, I. Nemenman, and A. Levchenko (2011)
Science 334, 354-358
   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 286, 36076-36085
   Abstract »    Full Text »    PDF »
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U. Bruning, L. Cerone, Z. Neufeld, S. F. Fitzpatrick, A. Cheong, C. C. Scholz, D. A. Simpson, M. O. Leonard, M. M. Tambuwala, E. P. Cummins, et al. (2011)
Mol. Cell. Biol. 31, 4087-4096
   Abstract »    Full Text »    PDF »
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J. W. Moore, G. J. Loake, and S. H. Spoel (2011)
PLANT CELL 23, 2809-2820
   Abstract »    Full Text »    PDF »
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A. Colleran, A. Ryan, A. O'Gorman, C. Mureau, C. Liptrot, P. Dockery, H. Fearnhead, and L. J. Egan (2011)
J. Biol. Chem. 286, 22886-22893
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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A. D. Adamson, D. Jackson, and J. R. E. Davis (2011)
J. Endocrinol. 208, 193-206
   Abstract »    Full Text »    PDF »
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Development 138, 601-607
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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