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Nuclear role of I kappa B Kinase-gamma/NF-kappa B essential modulator (IKK gamma/NEMO) in NF-kappa B-dependent gene expression.

The I kappa B kinase (IKK) complex, which is composed of the two kinases IKK alpha and IKK beta and the regulatory subunit IKK gamma/nuclear factor-kappa B (NF-kappa B) essential modulator (NEMO), is important in the cytokine-induced activation of the NF-kappa B pathway. In addition to modulation of IKK activity, the NF-kappa B 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-kappa B-dependent promoters. In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of the NF-kappa B pathway. IKK gamma/NEMO was demonstrated to shuttle between the cytoplasm and the nucleus and to interact with the nuclear coactivator cAMP-responsive element-binding protein-binding protein (CBP). Using both in vitro and in vivo analysis, we demonstrated that IKK gamma/NEMO competed with p65 and IKK alpha for binding to the N terminus of CBP, inhibiting CBP-dependent transcriptional activation. These results indicate that, in addition to the key role of IKK gamma/NEMO in regulating cytokine-induced IKK activity, its ability to shuttle between the cytoplasm and the nucleus and to bind to CBP can lead to transcriptional repression of the NF-kappa B pathway.

Pubmed ID: 14597638 RIS Download

Mesh terms: Blotting, Western | Cell Line | Cell Nucleus | Cyclic AMP Response Element-Binding Protein | Cytoplasm | Fatty Acids, Unsaturated | Glutathione Transferase | HeLa Cells | Humans | I-kappa B Kinase | Luciferases | Microscopy, Confocal | Microscopy, Fluorescence | NF-kappa B | Plasmids | Precipitin Tests | Promoter Regions, Genetic | Protein Binding | Protein Processing, Post-Translational | Protein Structure, Tertiary | Protein-Serine-Threonine Kinases | Recombinant Fusion Proteins | Transcription, Genetic | Transcriptional Activation | Transfection

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