Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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

The EMBO journal | Apr 2, 2001

http://www.ncbi.nlm.nih.gov/pubmed/11285227

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.

Pubmed ID: 11285227 RIS Download

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