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Papers In Press, published online ahead of print November 3, 2003
Medicine, UT Southwestern, Dallas, Texas 75235-8594
Corresponding Author: gaynor_richard{at}lilly.com
The IkB kinase (IKK) complex comprised of the two kinases, IKKa and IKKb, and a regulatory subunit IKKg/NEMO is important in the cytokine-induced activation of the NF-kB pathway. In addition to modulation of IKK activity, the NF-kB pathway is also regulated by other processes including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-kB dependent promoters. In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of NF-kB pathway. IKKg/NEMO was demonstrated to shuttle between the cytoplasm and the nucleus and interact with the nuclear coactivator CBP. Using both in vitro and in vivo analysis, we demonstrated that IKKg/NEMO competed with p65 and IKKa for binding to the amino-terminus of CBP to inhibit CBP-dependent transcriptional activation. These results indicate that in addition to the key role of IKKg/NEMO in regulating cytokine-induced IKK activity, its ability to shuttle between the cytoplasm and nucleus and bind to CBP can lead to transcriptional repression of the NF-kB pathway.
J. Biol. Chem, 10.1074/jbc.M309300200
Submitted on August 21, 2003
Revised on October 27, 2003
Accepted on November 3, 2003
Nuclear role of IKK
/NEMO in NF-
B-dependent gene expression
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