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

Item Type:Article
Title:COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system
Creators Name:Bech-Otschir, D. and Kraft, R. and Huang, X.H. and Henklein, P. and Kapelari, B. and 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:Nature Publishing Group (U.S.A.)
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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