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Science 306 (5696): 704-708

Copyright © 2004 by the American Association for the Advancement of Science

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*

Abstract: 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}

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J R Soc Interface 5, 223-235
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Vasoactive Hormone Adrenomedullin and Its Binding Protein: Anti-Inflammatory Effects by Up-Regulating Peroxisome Proliferator-Activated Receptor-{gamma}.
M. Miksa, R. Wu, X. Cui, W. Dong, P. Das, H. H. Simms, T. S. Ravikumar, and P. Wang (2007)
J. Immunol. 179, 6263-6272
   Abstract »    Full Text »    PDF »
Bayesian inference for dynamic transcriptional regulation; the Hes1 system as a case study.
E. A. Heron, B. Finkenstadt, and D. A. Rand (2007)
Bioinformatics 23, 2596-2603
   Abstract »    Full Text »    PDF »
Beyond I{kappa}Bs: alternative regulation of NF-{kappa}B activity.
M. Neumann and M. Naumann (2007)
FASEB J 21, 2642-2654
   Abstract »    Full Text »    PDF »
Antiapoptotic Effects of Progastrin on Pancreatic Cancer Cells Are Mediated by Sustained Activation of Nuclear Factor-{kappa}B.
W. Rengifo-Cam, S. Umar, S. Sarkar, and P. Singh (2007)
Cancer Res. 67, 7266-7274
   Abstract »    Full Text »    PDF »
Ultradian oscillations of Stat, Smad, and Hes1 expression in response to serum.
S. Yoshiura, T. Ohtsuka, Y. Takenaka, H. Nagahara, K. Yoshikawa, and R. Kageyama (2007)
PNAS 104, 11292-11297
   Abstract »    Full Text »    PDF »
Sustained Induction of NF-{kappa}B Is Required for Efficient Expression of Latent Human Immunodeficiency Virus Type 1.
S. A. Williams, H. Kwon, L.-F. Chen, and W. C. Greene (2007)
J. Virol. 81, 6043-6056
   Abstract »    Full Text »    PDF »
Oscillation patterns in negative feedback loops.
S. Pigolotti, S. Krishna, and M. H. Jensen (2007)
PNAS 104, 6533-6537
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