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Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase.
- Source :
-
The EMBO journal [EMBO J] 1997 Nov 03; Vol. 16 (21), pp. 6486-94. - Publication Year :
- 1997
-
Abstract
- Activation of the transcription factor NF-kappa B is a paradigm for signal transduction through the ubiquitin-proteasome pathway: ubiquitin-dependent degradation of the transcriptional inhibitor I kappa B in response to cell stimulation. A major issue in this context is the nature of the recognition signal and the targeting enzyme involved in the proteolytic process. Here we show that following a stimulus-dependent phosphorylation, and while associated with NF-kappa B, I kappa B is targeted by a specific ubiquitin-ligase via direct recognition of the signal-dependent phosphorylation site; phosphopeptides corresponding to this site specifically inhibit ubiquitin conjugation of I kappa B and its subsequent degradation. The ligase recognition signal is functionally conserved between I kappa B alpha and I kappa B beta, and does not involve the nearby ubiquitination site. Microinjection of the inhibitory peptides into stimulated cells abolished NF-kappa B activation in response to TNF alpha and the consequent expression of E-selectin, an NF-kappa B-dependent cell-adhesion molecule. Inhibition of NF-kappa B function by specific blocking of ubiquitin ligase activity provides a novel approach for intervening in cellular processes via regulation of unique proteolytic events.
- Subjects :
- Amino Acid Sequence
Biological Transport
Cell Nucleus metabolism
Cells, Cultured
Cytoplasm metabolism
E-Selectin biosynthesis
E-Selectin genetics
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
HeLa Cells drug effects
HeLa Cells metabolism
Humans
Jurkat Cells drug effects
Jurkat Cells metabolism
Ligases physiology
Molecular Sequence Data
Peptide Fragments pharmacology
Phosphorylation drug effects
Proteasome Endopeptidase Complex
Signal Transduction physiology
Transcription Factor RelB
Ubiquitin-Protein Ligases
Umbilical Veins
Cysteine Endopeptidases metabolism
Ligases antagonists & inhibitors
Multienzyme Complexes metabolism
NF-kappa B antagonists & inhibitors
Protein Processing, Post-Translational drug effects
Proto-Oncogene Proteins metabolism
Signal Transduction drug effects
Transcription Factors
Transcription, Genetic drug effects
Ubiquitins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0261-4189
- Volume :
- 16
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 9351830
- Full Text :
- https://doi.org/10.1093/emboj/16.21.6486