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.


Logo for

PNAS 106 (45): 18972-18977

Copyright © 2009 by the National Academy of Sciences.


Regulation of NF-{kappa}B activity through lysine monomethylation of p65

Chee-Kwee Ea David Baltimore1

Division of Biology, California Institute of Technology, 330 Braun, 1200 East California Boulevard, Pasadena, CA 91125

Contributed by David Baltimore, September 14, 2009

Received for publication July 31, 2009.

Abstract: NF-{kappa}B is a key activator of inflammatory and immune responses with important pathological roles in cancer, heart disease, and autoimmune diseases. Transcriptional activity of NF-{kappa}B is regulated by different posttranslational modifications. Here, we report a novel mechanism of NF-{kappa}B regulation through lysine monomethylation by SET9 methyltransferase. Set9 specifically methylates p65 at lysine 37. Both TNF{alpha} and IL-1β treatments induced methylation of p65. Methylated p65 is restricted to the nucleus and this modification regulates the promoter binding of p65. Moreover, Set9 mediated methylation of p65 is required for the expression of a subset of NF-{kappa}B target genes in response to TNF{alpha} stimulation.

Key Words: methylation • SET9

Freely available online through the PNAS open access option.

Author contributions: C.-K.E. and D.B. designed research; C.-K.E. performed research; C.-K.E. and D.B. analyzed data; and C.-K.E. and D.B. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: baltimo{at}

The functional diversity of protein lysine methylation.
S. Lanouette, V. Mongeon, D. Figeys, and J.-F. Couture (2014)
Mol Syst Biol 10, 724
   Abstract »    Full Text »    PDF »
Activation of the Transcriptional Function of the NF-{kappa}B Protein c-Rel by O-GlcNAc Glycosylation.
P. Ramakrishnan, P. M. Clark, D. E. Mason, E. C. Peters, L. C. Hsieh-Wilson, and D. Baltimore (2013)
Science Signaling 6, ra75
   Abstract »    Full Text »    PDF »
Role of lysine methylation of NF-{kappa}B in differential gene regulation.
T. Lu, M. Yang, D.-B. Huang, H. Wei, G. H. Ozer, G. Ghosh, and G. R. Stark (2013)
PNAS 110, 13510-13515
   Abstract »    Full Text »    PDF »
PRMT5 dimethylates R30 of the p65 subunit to activate NF-{kappa}B.
H. Wei, B. Wang, M. Miyagi, Y. She, B. Gopalan, D.-B. Huang, G. Ghosh, G. R. Stark, and T. Lu (2013)
PNAS 110, 13516-13521
   Abstract »    Full Text »    PDF »
EHMT1 Protein Binds to Nuclear Factor-{kappa}B p50 and Represses Gene Expression.
C.-K. Ea, S. Hao, K. S. Yeo, and D. Baltimore (2012)
J. Biol. Chem. 287, 31207-31217
   Abstract »    Full Text »    PDF »
Distinguishing Hyperglycemic Changes by Set7 in Vascular Endothelial Cells.
J. Okabe, C. Orlowski, A. Balcerczyk, C. Tikellis, M. C. Thomas, M. E. Cooper, and A. El-Osta (2012)
Circ. Res. 110, 1067-1076
   Abstract »    Full Text »    PDF »
Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death.
Q. Xie, Y. Hao, L. Tao, S. Peng, C. Rao, H. Chen, H. You, M.-q. Dong, and Z. Yuan (2012)
EMBO Rep. 13, 371-377
   Abstract »    Full Text »    PDF »
NF-{kappa}B, the first quarter-century: remarkable progress and outstanding questions.
M. S. Hayden and S. Ghosh (2012)
Genes & Dev. 26, 203-234
   Abstract »    Full Text »    PDF »
Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization.
L. T. Donlin, C. Andresen, S. Just, E. Rudensky, C. T. Pappas, M. Kruger, E. Y. Jacobs, A. Unger, A. Zieseniss, M.-W. Dobenecker, et al. (2012)
Genes & Dev. 26, 114-119
   Abstract »    Full Text »    PDF »
Lysine methylation: beyond histones.
X. Zhang, H. Wen, and X. Shi (2012)
Acta Biochim Biophys Sin 44, 14-27
   Abstract »    Full Text »    PDF »
Targeting protein lysine methylation and demethylation in cancers.
Y. He, I. Korboukh, J. Jin, and J. Huang (2012)
Acta Biochim Biophys Sin 44, 70-79
   Abstract »    Full Text »    PDF »
Fluorescence-Based Methods for Screening Writers and Readers of Histone Methyl Marks.
A. Allali-Hassani, G. A. Wasney, A. Siarheyeva, T. Hajian, C. H. Arrowsmith, and M. Vedadi (2012)
J Biomol Screen 17, 71-84
   Abstract »    Full Text »    PDF »
Epigenetic Mechanisms: Critical Contributors to Long-Term Memory Formation.
F. D. Lubin, S. Gupta, R. R. Parrish, N. M. Grissom, and R. L. Davis (2011)
Neuroscientist 17, 616-632
   Abstract »    PDF »
Ranpirnase Interferes with NF-{kappa}B Pathway and MMP9 Activity, Inhibiting Malignant Mesothelioma Cell Invasiveness and Xenograft Growth.
M. Nasu, M. Carbone, G. Gaudino, B. H. Ly, P. Bertino, D. Shimizu, P. Morris, H. I. Pass, and H. Yang (2011)
Genes & Cancer 2, 576-584
   Abstract »    Full Text »    PDF »
Regulation of the androgen receptor by SET9-mediated methylation.
L. Gaughan, J. Stockley, N. Wang, S. R. C. McCracken, A. Treumann, K. Armstrong, F. Shaheen, K. Watt, I. J. McEwan, C. Wang, et al. (2011)
Nucleic Acids Res. 39, 1266-1279
   Abstract »    Full Text »    PDF »
A Nuclear Inhibitor of NF-{kappa}B Encoded by a Poxvirus.
D. G. Diel, S. Luo, G. Delhon, Y. Peng, E. F. Flores, and D. L. Rock (2011)
J. Virol. 85, 264-275
   Abstract »    Full Text »    PDF »
Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes.
J. Yang, J. Huang, M. Dasgupta, N. Sears, M. Miyagi, B. Wang, M. R. Chance, X. Chen, Y. Du, Y. Wang, et al. (2010)
PNAS 107, 21499-21504
   Abstract »    Full Text »    PDF »
Epigenetics: Mechanisms and Implications for Diabetic Complications.
M. E. Cooper and A. El-Osta (2010)
Circ. Res. 107, 1403-1413
   Abstract »    Full Text »    PDF »
Epigenetic Histone Methylation Modulates Fibrotic Gene Expression.
G. Sun, M. A. Reddy, H. Yuan, L. Lanting, M. Kato, and R. Natarajan (2010)
J. Am. Soc. Nephrol. 21, 2069-2080
   Abstract »    Full Text »    PDF »
Methylation of the Retinoblastoma Tumor Suppressor by SMYD2.
L. A. Saddic, L. E. West, A. Aslanian, J. R. Yates III, S. M. Rubin, O. Gozani, and J. Sage (2010)
J. Biol. Chem. 285, 37733-37740
   Abstract »    Full Text »    PDF »
SET7/9 Catalytic Mutants Reveal the Role of Active Site Water Molecules in Lysine Multiple Methylation.
P. A. Del Rizzo, J.-F. Couture, L. M. A. Dirk, B. S. Strunk, M. S. Roiko, J. S. Brunzelle, R. L. Houtz, and R. C. Trievel (2010)
J. Biol. Chem. 285, 31849-31858
   Abstract »    Full Text »    PDF »
Specification of the NF-{kappa}B transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK{varepsilon}.
R. Moreno, J.-M. Sobotzik, C. Schultz, and M. L. Schmitz (2010)
Nucleic Acids Res. 38, 6029-6044
   Abstract »    Full Text »    PDF »
Regulation of NF-{kappa}B by NSD1/FBXL11-dependent reversible lysine methylation of p65.
T. Lu, M. W. Jackson, B. Wang, M. Yang, M. R. Chance, M. Miyagi, A. V. Gudkov, and G. R. Stark (2010)
PNAS 107, 46-51
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882