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Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex.

Science (New York, N.Y.) | Sep 1, 2000

http://www.ncbi.nlm.nih.gov/pubmed/10968790

Activation of the transcription factor nuclear factor (NF)-kappaB by proinflammatory stimuli leads to increased expression of genes involved in inflammation. Activation of NF-kappaB requires the activity of an inhibitor of kappaB (IkappaB)-kinase (IKK) complex containing two kinases (IKKalpha and IKKbeta) and the regulatory protein NEMO (NF-kappaB essential modifier). An amino-terminal alpha-helical region of NEMO associated with a carboxyl-terminal segment of IKKalpha and IKKbeta that we term the NEMO-binding domain (NBD). A cell-permeable NBD peptide blocked association of NEMO with the IKK complex and inhibited cytokine-induced NF-kappaB activation and NF-kappaB-dependent gene expression. The peptide also ameliorated inflammatory responses in two experimental mouse models of acute inflammation. The NBD provides a target for the development of drugs that would block proinflammatory activation of the IKK complex without inhibiting basal NF-kappaB activity.

Pubmed ID: 10968790 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Anti-Inflammatory Agents, Non-Steroidal | COS Cells | Cells, Cultured | E-Selectin | Endothelium, Vascular | Gene Expression Regulation | HeLa Cells | Humans | I-kappa B Kinase | Inflammation | Mice | Mice, Inbred C57BL | Molecular Sequence Data | Mutation | NF-kappa B | Peptides | Point Mutation | Protein Structure, Tertiary | Protein-Serine-Threonine Kinases | Recombinant Fusion Proteins

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Associated grants

  • Agency: NIAID NIH HHS, Id: AI 33443

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