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Science 293 (5535): 1653-1657

Copyright © 2001 by the American Association for the Advancement of Science

Duration of Nuclear NF-kappa B Action Regulated by Reversible Acetylation

Lin-feng Chen,1 Wolfgang Fischle,1 Eric Verdin,12 Warner C. Greene123*

The nuclear expression and action of the nuclear factor kappa B (NF-kappa B) transcription factor requires signal-coupled phosphorylation and degradation of the Ikappa B inhibitors, which normally bind and sequester this pleiotropically active factor in the cytoplasm. The subsequent molecular events that regulate the termination of nuclear NF-kappa B action remain poorly defined, although the activation of de novo Ikappa Balpha gene expression by NF-kappa B likely plays a key role. Our studies now demonstrate that the RelA subunit of NF-kappa B is subject to inducible acetylation and that acetylated forms of RelA interact weakly, if at all, with Ikappa Balpha . Acetylated RelA is subsequently deacetylated through a specific interaction with histone deacetylase 3 (HDAC3). This deacetylation reaction promotes effective binding to Ikappa Balpha and leads in turn to Ikappa Balpha -dependent nuclear export of the complex through a chromosomal region maintenance-1 (CRM-1)-dependent pathway. Deacetylation of RelA by HDAC3 thus acts as an intranuclear molecular switch that both controls the duration of the NF-kappa B transcriptional response and contributes to the replenishment of the depleted cytoplasmic pool of latent NF-kappa B-Ikappa Balpha complexes.

1 Gladstone Institute of Virology and Immunology,
2 Department of Medicine,
3 Department of Microbiology and Immunology, University of California, San Francisco, CA 94141, USA.
*   To whom correspondence should be addressed. E-mail: wgreene{at}

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Interleukin-8 Expression Is Regulated by Histone Deacetylases through the Nuclear Factor-{kappa}B Pathway in Breast Cancer.
C. Chavey, M. Muhlbauer, C. Bossard, A. Freund, S. Durand, C. Jorgensen, C. Jobin, and G. Lazennec (2008)
Mol. Pharmacol. 74, 1359-1366
   Abstract »    Full Text »    PDF »
Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain.
M. J. Bottomley, P. Lo Surdo, P. Di Giovine, A. Cirillo, R. Scarpelli, F. Ferrigno, P. Jones, P. Neddermann, R. De Francesco, C. Steinkuhler, et al. (2008)
J. Biol. Chem. 283, 26694-26704
   Abstract »    Full Text »    PDF »
PKC{beta}II Augments NF-{kappa}B-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation.
D. L. Clarke, A. Sutcliffe, K. Deacon, D. Bradbury, L. Corbett, and A. J. Knox (2008)
J. Immunol. 181, 3503-3514
   Abstract »    Full Text »    PDF »
c-Rel, an NF-{kappa}B family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation.
H. J. Ahn, C. M. Hernandez, J. M. Levenson, F. D. Lubin, H.-C. Liou, and J. D. Sweatt (2008)
Learn. Mem. 15, 539-549
   Abstract »    Full Text »    PDF »
Histone Deacetylase Inhibitors Exert Time-Dependent Effects on Nuclear Factor-{kappa}B but Consistently Suppress the Expression of Proinflammatory Genes in Human Myometrial Cells.
T. M. Lindstrom, A. R. Mohan, M. R. Johnson, and P. R. Bennett (2008)
Mol. Pharmacol. 74, 109-121
   Abstract »    Full Text »    PDF »
Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling.
W. Cao, C. Bao, E. Padalko, and C. J. Lowenstein (2008)
J. Exp. Med. 205, 1491-1503
   Abstract »    Full Text »    PDF »
Inhibition of Transcription and DNA Replication by the Papillomavirus E8^E2C Protein Is Mediated by Interaction with Corepressor Molecules.
I. Ammermann, M. Bruckner, F. Matthes, T. Iftner, and F. Stubenrauch (2008)
J. Virol. 82, 5127-5136
   Abstract »    Full Text »    PDF »
Substance P enhances NF-{kappa}B transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways.
J. Sun, R. D. Ramnath, L. Zhi, R. Tamizhselvi, and M. Bhatia (2008)
Am J Physiol Cell Physiol 294, C1586-C1596
   Abstract »    Full Text »    PDF »
Cigarette smoke-mediated inflammatory and oxidative responses are strain-dependent in mice.
H. Yao, I. Edirisinghe, S. Rajendrasozhan, S.-R. Yang, S. Caito, D. Adenuga, and I. Rahman (2008)
Am J Physiol Lung Cell Mol Physiol 294, L1174-L1186
   Abstract »    Full Text »    PDF »
Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice.
R. Glauben, A. Batra, T. Stroh, U. Erben, I. Fedke, H. A. Lehr, F. Leoni, P. Mascagni, C. A. Dinarello, M. Zeitz, et al. (2008)
Gut 57, 613-622
   Abstract »    Full Text »    PDF »
AKIP1 Enhances NF-{kappa}B-dependent Gene Expression by Promoting the Nuclear Retention and Phosphorylation of p65.
N. Gao, K. Asamitsu, Y. Hibi, T. Ueno, and T. Okamoto (2008)
J. Biol. Chem. 283, 7834-7843
   Abstract »    Full Text »    PDF »
Histone deacetylase 3 localizes to the mitotic spindle and is required for kinetochore-microtubule attachment.
S. Ishii, Y. Kurasawa, J. Wong, and L.-y. Yu-Lee (2008)
PNAS 105, 4179-4184
   Abstract »    Full Text »    PDF »
Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65.
C. Buerki, K. M. Rothgiesser, T. Valovka, H. R. Owen, H. Rehrauer, M. Fey, W. S. Lane, and M. O. Hottiger (2008)
Nucleic Acids Res. 36, 1665-1680
   Abstract »    Full Text »    PDF »

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