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

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, Deltap53(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 Deltap53(145-164) results in accumulation of endogenous p53.
Mesh Terms:
Amino Acid Sequence, Binding Sites, DNA, DNA-Binding Proteins, HL-60 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Multiprotein Complexes, Mutagenesis, Site-Directed, Peptide Hydrolases, Phosphorylation, Proteasome Endopeptidase Complex, Proteins, Proto-Oncogene Proteins p21(ras), Signal Transduction, Threonine, Transcription Factors, Tumor Suppressor Protein p53, Ubiquitins, Valine
EMBO J.
Date: Apr. 02, 2001
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