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Science 22 October 2004:
Vol. 306. no. 5696, pp. 704 - 708
DOI: 10.1126/science.1099962
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Reports

Oscillations in NF-{kappa}B Signaling Control the Dynamics of Gene Expression

D. E. Nelson,1 A. E. C. Ihekwaba,2 M. Elliott,1 J. R. Johnson,1 C. A. Gibney,1 B. E. Foreman,1 G. Nelson,1 V. See,1 C. A. Horton,1 D. G. Spiller,1 S. W. Edwards,1 H. P. McDowell,4 J. F. Unitt,5 E. Sullivan,6 R. Grimley,7 N. Benson,7 D. Broomhead,3 D. B. Kell,2 M. R. H. White1*

Signaling by the transcription factor nuclear factor kappa B (NF-{kappa}B) involves its release from inhibitor kappa B (I{kappa}B) in the cytosol, followed by translocation into the nucleus. NF-{kappa}B regulation of I{kappa}B{alpha} transcription represents a delayed negative feedback loop that drives oscillations in NF-{kappa}B translocation. Single-cell time-lapse imaging and computational modeling of NF-{kappa}B (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased I{kappa}B{alpha} transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-{kappa}B signaling may thus depend on number, period, and amplitude of oscillations.

1 Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Crown Street, Liverpool, L69 7ZB, UK.
2 Department of Chemistry, University of Manchester Institute of Science and Technology, P.O. Box 88, Sackville Street, Manchester, M60 1QD, UK.
3 Department of Mathematics, University of Manchester Institute of Science and Technology, P.O. Box 88, Sackville Street, Manchester, M60 1QD, UK.
4 Royal Liverpool Children's National Health Service Trust, Alder Hey Hospital, Eaton Road, Liverpool, L12 2AP, UK.
5 Molecular Biology Department, AstraZeneca Research and Development Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
6 Advanced Science and Technology Laboratory, AstraZeneca Research and Development Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
7 Pfizer Central Research, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.

* To whom correspondence should be addressed. E-mail: mwhite{at}liv.ac.uk

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