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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

Authors

  • Verma UN
  • Yamamoto Y
  • Prajapati S
  • Gaynor RB

Journal

The Journal of biological chemistry

Publication Data

January 30, 2004

Associated Grants

None

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