COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system

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Item Type:	Article
Title:	COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system
Creators Name:	Bech-Otschir, D., Kraft, R., Huang, X.H., Henklein, P., Kapelari, B., Pollmann, C. and Dubiel, W.
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 Δp53(145-164) results in accumulation of endogenous p53.
Keywords:	COP9 Signalosome, Jab1, Mdm2, Proteasome, Ubiquitin
Source:	EMBO Journal
ISSN:	0261-4189
Publisher:	Oxford University Press
Volume:	20
Number:	7
Page Range:	1630-1639
Date:	1 January 2001
Official Publication:	https://doi.org/10.1093/emboj/20.7.1630
PubMed:	View item in PubMed

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