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  COP9 Signalosome-specific Phosphorylation Targets p53 to Degradation by the Ubiquitin System

Bech-Otschir, D., Kraft, R., Huang, X., Henklein, P., Kapelari, B., Pollmann, C., et al. (2001). COP9 Signalosome-specific Phosphorylation Targets p53 to Degradation by the Ubiquitin System. EMBO J., 20(7), 1630-1639.

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Bech-Otschir, D., Author
Kraft, R., Author
Huang, X.H., Author
Henklein, P., Author
Kapelari, B.1, Author              
Pollmann, C., Author
Dubiel, W., Author
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1External Organizations, ou_persistent22              

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Free keywords: COP9 signalosome; Jab1; Mdm2; proteasome; ubiquitin
 Abstract: In higher eukaryotic cells, the p53 protein is degraded by the ubiquitin–26S proteasome system mediated by Mdm2 or the human papilloma virus E6 protein. Here we show that COP9 signalosome (CSN)-specific phosphorylation targets human p53 to ubiquitin–26S proteasome-dependent degradation. As visualized by electron microscopy, p53 binds with high affinity to the native CSN complex. p53 interacts via its N-terminus with CSN subunit 5/Jab1 as shown by far-western and pull-down assays. The CSN-specific phosphorylation sites were mapped to the core domain of p53 including Thr155. A phosphorylated peptide, [Delta]p53(145–164), specifically inhibits CSN-mediated phosphorylation and p53 degradation. Curcumin, a CSN kinase inhibitor, blocks E6-dependent p53 degradation in reticulocyte lysates. Mutation of Thr155 to valine is sufficient to stabilize p53 against E6-dependent degradation in reticulocyte lysates and to reduce binding to Mdm2. The p53T155V mutant accumulates in both HeLa and HL 60 cells and exhibits a mutant (PAb 240+) conformation. It induces the cyclin-dependent inhibitor p21. In HeLa and MCF-7 cells, inhibition of CSN kinase by curcumin or [Delta]p53(145–164) results in accumulation of endogenous p53.

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 Dates: 2001
 Publication Status: Published in print
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 Identifiers: eDoc: 318670
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Title: EMBO J.
Source Genre: Journal
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Pages: - Volume / Issue: 20 (7) Sequence Number: - Start / End Page: 1630 - 1639 Identifier: -