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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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