Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 22 October 2004:
Vol. 306. no. 5696, pp. 704 - 708
DOI: 10.1126/science.1099962
Prev | Table of Contents | Next

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Noisy Paracrine Signal Determines the Cellular NF-{kappa}B Response to Lipopolysaccharide.
T. K. Lee, E. M. Denny, J. C. Sanghvi, J. E. Gaston, N. D. Maynard, J. J. Hughey, and M. W. Covert (2009)
Science Signaling 2, ra65
   Abstract »    Full Text »    PDF »
Nuclear NF-{kappa}B p65 Phosphorylation at Serine 276 by Protein Kinase A Contributes to the Malignant Phenotype of Head and Neck Cancer.
P. Arun, M. S. Brown, R. Ehsanian, Z. Chen, and C. Van Waes (2009)
Clin. Cancer Res. 15, 5974-5984
   Abstract »    Full Text »    PDF »
Multiple roles of the NF-{kappa}B signaling pathway regulated by coupled negative feedback circuits.
D. Kim, W. Kolch, and K.-H. Cho (2009)
FASEB J 23, 2796-2802
   Abstract »    Full Text »    PDF »
Dynamic Advances in NF-{kappa}B Signaling Analysis.
T. Kobayashi and R. Kageyama (2009)
Science Signaling 2, pe47
   Abstract »    Full Text »    PDF »
Pulsatile Stimulation Determines Timing and Specificity of NF-{kappa}B-Dependent Transcription.
L. Ashall, C. A. Horton, D. E. Nelson, P. Paszek, C. V. Harper, K. Sillitoe, S. Ryan, D. G. Spiller, J. F. Unitt, D. S. Broomhead, et al. (2009)
Science 324, 242-246
   Abstract »    Full Text »    PDF »
Loss of p53 enhances catalytic activity of IKK{beta} through O-linked {beta}-N-acetyl glucosamine modification.
K. Kawauchi, K. Araki, K. Tobiume, and N. Tanaka (2009)
PNAS 106, 3431-3436
   Abstract »    Full Text »    PDF »
High Content Cell Screening in a Microfluidic Device.
R. Cheong, C. J. Wang, and A. Levchenko (2009)
Mol. Cell. Proteomics 8, 433-442
   Abstract »    Full Text »    PDF »
Integrating Computational and Biochemical Studies to Explore Mechanisms in NF-{kappa}B Signaling.
J. D. Kearns and A. Hoffmann (2009)
J. Biol. Chem. 284, 5439-5443
   Full Text »    PDF »
The Aryl Hydrocarbon Nuclear Translocator Alters CD30-Mediated NF-{kappa}B-Dependent Transcription.
C. W. Wright and C. S. Duckett (2009)
Science 323, 251-255
   Abstract »    Full Text »    PDF »
Bursting into the Nucleus.
G. R. Crabtree and I. A. Graef (2008)
Science Signaling 1, pe54
   Abstract »    Full Text »    PDF »
Reconstruction of transcriptional dynamics from gene reporter data using differential equations.
B. Finkenstadt, E. A. Heron, M. Komorowski, K. Edwards, S. Tang, C. V. Harper, J. R. E. Davis, M. R. H. White, A. J. Millar, and D. A. Rand (2008)
Bioinformatics 24, 2901-2907
   Abstract »    Full Text »    PDF »
Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear.
S. Ortolano, G. Di Pasquale, G. Crispino, F. Anselmi, F. Mammano, and J. A. Chiorini (2008)
PNAS 105, 18776-18781
   Abstract »    Full Text »    PDF »
Dynamic Effect of Bortezomib on Nuclear Factor-{kappa}B Activity and Gene Expression in Tumor Cells.
M.-H. Sung, L. Bagain, Z. Chen, T. Karpova, X. Yang, C. Silvin, T. C. Voss, J. G. McNally, C. Van Waes, and G. L. Hager (2008)
Mol. Pharmacol. 74, 1215-1222
   Abstract »    Full Text »    PDF »
Homogeneity and persistence of transgene expression by omitting antibiotic selection in cell line isolation.
W. L. Kaufman, I. Kocman, V. Agrawal, H.-P. Rahn, D. Besser, and M. Gossen (2008)
Nucleic Acids Res. 36, e111
   Abstract »    Full Text »    PDF »
NF-{kappa}B Activation Controls Phagolysosome Fusion-Mediated Killing of Mycobacteria by Macrophages.
M. G. Gutierrez, B. B. Mishra, L. Jordao, E. Elliott, E. Anes, and G. Griffiths (2008)
J. Immunol. 181, 2651-2663
   Abstract »    Full Text »    PDF »
Mapping global sensitivity of cellular network dynamics: sensitivity heat maps and a global summation law.
D.A Rand (2008)
J R Soc Interface 5, S59-S69
   Abstract »    Full Text »    PDF »
Encoding NF-{kappa}B temporal control in response to TNF: distinct roles for the negative regulators I{kappa}B{alpha} and A20.
S. L. Werner, J. D. Kearns, V. Zadorozhnaya, C. Lynch, E. O'Dea, M. P. Boldin, A. Ma, D. Baltimore, and A. Hoffmann (2008)
Genes & Dev. 22, 2093-2101
   Abstract »    Full Text »    PDF »
Robust, Tunable Biological Oscillations from Interlinked Positive and Negative Feedback Loops.
T. Y.-C. Tsai, Y. S. Choi, W. Ma, J. R. Pomerening, C. Tang, and J. E. Ferrell Jr. (2008)
Science 321, 126-129
   Abstract »    Full Text »    PDF »
Hydrogen Peroxide Prolongs Nuclear Localization of NF-{kappa}B in Activated Cells by Suppressing Negative Regulatory Mechanisms.
K. Enesa, K. Ito, L. A. Luong, I. Thorbjornsen, C. Phua, Y. To, J. Dean, D. O. Haskard, J. Boyle, I. Adcock, et al. (2008)
J. Biol. Chem. 283, 18582-18590
   Abstract »    Full Text »    PDF »
RelA Ser276 Phosphorylation Is Required for Activation of a Subset of NF-{kappa}B-Dependent Genes by Recruiting Cyclin-Dependent Kinase 9/Cyclin T1 Complexes.
D. E. Nowak, B. Tian, M. Jamaluddin, I. Boldogh, L. A. Vergara, S. Choudhary, and A. R. Brasier (2008)
Mol. Cell. Biol. 28, 3623-3638
   Abstract »    Full Text »    PDF »
Requirements for Two Proximal NF-{kappa}B Binding Sites and I{kappa}B-{zeta} in IL-17A-induced Human {beta}-Defensin 2 Expression by Conducting Airway Epithelium.
C.-Y. Kao, C. Kim, F. Huang, and R. Wu (2008)
J. Biol. Chem. 283, 15309-15318
   Abstract »    Full Text »    PDF »
Identification of a Ligand-induced Transient Refractory Period in Nuclear Factor-{kappa}B Signaling.
B. L. Moss, S. Gross, S. T. Gammon, A. Vinjamoori, and D. Piwnica-Worms (2008)
J. Biol. Chem. 283, 8687-8698
   Abstract »    Full Text »    PDF »
NF-{kappa}B Suppression by the Deubiquitinating Enzyme Cezanne: A NOVEL NEGATIVE FEEDBACK LOOP IN PRO-INFLAMMATORY SIGNALING.
K. Enesa, M. Zakkar, H. Chaudhury, L. A. Luong, L. Rawlinson, J. C. Mason, D. O. Haskard, J. L. E. Dean, and P. C. Evans (2008)
J. Biol. Chem. 283, 7036-7045
   Abstract »    Full Text »    PDF »
Transcriptional Complex Formation of c-Fos, STAT3, and Hepatocyte NF-1{alpha} Is Essential for Cytokine-Driven C-Reactive Protein Gene Expression.
T. Nishikawa, K. Hagihara, S. Serada, T. Isobe, A. Matsumura, J. Song, T. Tanaka, I. Kawase, T. Naka, and K. Yoshizaki (2008)
J. Immunol. 180, 3492-3501
   Abstract »    Full Text »    PDF »
Information-theoretic sensitivity analysis: a general method for credit assignment in complex networks.
N. Ludtke, S. Panzeri, M. Brown, D. S Broomhead, J. Knowles, M. A Montemurro, and D. B Kell (2008)
J R Soc Interface 5, 223-235
   Abstract »    Full Text »    PDF »
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 »
I{kappa}B Genetic Polymorphisms and Invasive Pneumococcal Disease.
S. J. Chapman, C. C. Khor, F. O. Vannberg, A. Frodsham, A. Walley, N. A. Maskell, C. W. H. Davies, S. Segal, C. E. Moore, S. H. Gillespie, et al. (2007)
Am. J. Respir. Crit. Care Med. 176, 181-187
   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
   Abstract »    Full Text »    PDF »
The Hes gene family: repressors and oscillators that orchestrate embryogenesis.
R. Kageyama, T. Ohtsuka, and T. Kobayashi (2007)
Development 134, 1243-1251
   Abstract »    Full Text »    PDF »
Ultradian Oscillators in Somite Segmentation and Other Biological Events.
R. Kageyama, S. Yoshiura, Y. Masamizu, and Y. Niwa (2007)
Cold Spring Harb Symp Quant Biol 72, 451-457
   Abstract »    PDF »
Automated tracking of gene expression in individual cells and cell compartments.
H. Shen, G. Nelson, D. E Nelson, S. Kennedy, D. G Spiller, T. Griffiths, N. Paton, S. G Oliver, M. R.H White, and D. B Kell (2006)
J R Soc Interface 3, 787-794
   Abstract »    Full Text »    PDF »
Minimal model of spiky oscillations in NF-{kappa}B signaling.
S. Krishna, M. H. Jensen, and K. Sneppen (2006)
PNAS 103, 10840-10845
   Abstract »    Full Text »    PDF »
Oxidative stress and redox regulation of lung inflammation in COPD..
I. Rahman and I. M. Adcock (2006)
Eur. Respir. J. 28, 219-242
   Abstract »    Full Text »    PDF »
I{kappa}B{varepsilon} provides negative feedback to control NF-{kappa}B oscillations, signaling dynamics, and inflammatory gene expression.
J. D. Kearns, S. Basak, S. L. Werner, C. S. Huang, and A. Hoffmann (2006)
J. Cell Biol. 173, 659-664
   Abstract »    Full Text »    PDF »
Inhibition of the NF-{kappa}B Pathway by Varicella-Zoster Virus In Vitro and in Human Epidermal Cells In Vivo..
J. O. Jones and A. M. Arvin (2006)
J. Virol. 80, 5113-5124
   Abstract »    Full Text »    PDF »
Rac1 and RhoA as regulators of endothelial phenotype and barrier function in hypoxia-induced neonatal pulmonary hypertension.
B. Wojciak-Stothard, L. Y. F. Tsang, E. Paleolog, S. M. Hall, and S. G. Haworth (2006)
Am J Physiol Lung Cell Mol Physiol 290, L1173-L1182
   Abstract »    Full Text »    PDF »
Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells.
G. Cattoretti, M. Buttner, R. Shaknovich, E. Kremmer, B. Alobeid, and G. Niedobitek (2006)
Blood 107, 3967-3975
   Abstract »    Full Text »    PDF »
NF-{kappa}B is essential for the progression of KSHV- and EBV-infected lymphomas in vivo.
S. A. Keller, D. Hernandez-Hopkins, J. Vider, V. Ponomarev, E. Hyjek, E. J. Schattner, and E. Cesarman (2006)
Blood 107, 3295-3302
   Abstract »    Full Text »    PDF »
Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways.
A. Tedgui and Z. Mallat (2006)
Physiol Rev 86, 515-581
   Abstract »    Full Text »    PDF »
NF-{kappa}B activation as a pathological mechanism of septic shock and inflammation.
S. F. Liu and A. B. Malik (2006)
Am J Physiol Lung Cell Mol Physiol 290, L622-L645
   Abstract »    Full Text »    PDF »
Inducible Phosphorylation of NF-{kappa}B p65 at Serine 468 by T Cell Costimulation Is Mediated by IKK{epsilon}.
I. Mattioli, H. Geng, A. Sebald, M. Hodel, C. Bucher, M. Kracht, and M. L. Schmitz (2006)
J. Biol. Chem. 281, 6175-6183
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor-{alpha} Activates the Human Prolactin Gene Promoter via Nuclear Factor-{kappa}B Signaling.
S. Friedrichsen, C. V. Harper, S. Semprini, M. Wilding, A. D. Adamson, D. G. Spiller, G. Nelson, J. J. Mullins, M. R. H. White, and J. R. E. Davis (2006)
Endocrinology 147, 773-781
   Abstract »    Full Text »    PDF »
Host and parasite-derived IKK activities direct distinct temporal phases of NF-{kappa}B activation and target gene expression following Toxoplasma gondii infection.
R. E. Molestina and A. P. Sinai (2005)
J. Cell Sci. 118, 5785-5796
   Abstract »    Full Text »    PDF »
Prevention of NF-{kappa}B activation in vivo by a cell-permeable NF-{kappa}B inhibitor peptide.
A. L. Mora, J. LaVoy, M. McKean, A. Stecenko, K. L. Brigham, R. Parker, and M. Rojas (2005)
Am J Physiol Lung Cell Mol Physiol 289, L536-L544
   Abstract »    Full Text »    PDF »
Achieving Stability of Lipopolysaccharide-Induced NF-{kappa}B Activation.
M. W. Covert, T. H. Leung, J. E. Gaston, and D. Baltimore (2005)
Science 309, 1854-1857
   Abstract »    Full Text »    PDF »
Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of IKK Activity.
S. L. Werner, D. Barken, and A. Hoffmann (2005)
Science 309, 1857-1861
   Abstract »    Full Text »    PDF »
Systems biology in the cell nucleus.
S. Gorski and T. Misteli (2005)
J. Cell Sci. 118, 4083-4092
   Abstract »    Full Text »    PDF »
Coactivators and Corepressors of NF-{kappa}B in I{kappa}B{alpha} Gene Promoter.
Z. Gao, P. Chiao, X. Zhang, X. Zhang, M. A. Lazar, E. Seto, H. A. Young, and J. Ye (2005)
J. Biol. Chem. 280, 21091-21098
   Abstract »    Full Text »    PDF »
Comment on "Oscillations in NF-{kappa}B Signaling Control the Dynamics of Gene Expression".
D. Barken, C. J. Wang, J. Kearns, R. Cheong, A. Hoffmann, and A. Levchenko (2005)
Science 308, 52a
   Full Text »    PDF »
Response to Comment on "Oscillations in NF-{kappa}B Signaling Control the Dynamics of Gene Expression".
D. E. Nelson, C. A. Horton, V. See, J. R. Johnson, G. Nelson, D. G. Spiller, D. B. Kell, and M. R. H. White (2005)
Science 308, 52b
   Full Text »    PDF »
The Strength of Indecisiveness: Oscillatory Behavior for Better Cell Fate Determination.
G. Lahav (2004)
Sci. STKE 2004, pe55
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)