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The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2.

The EMBO journal | Feb 21, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17290220

Mdm2 is an E3 ubiquitin ligase that promotes its own ubiquitination and also ubiquitination of the p53 tumour suppressor. In a bacterial two-hybrid screen, using Mdm2 as bait, we identified an Mdm2-interacting peptide that bears sequence similarity to the deubiquitinating enzyme USP2a. We have established that full-length USP2a associates with Mdm2 in cells where it can deubiquitinate Mdm2 while demonstrating no deubiquitinating activity towards p53. Ectopic expression of USP2a causes accumulation of Mdm2 in a dose-dependent manner and consequently promotes Mdm2-mediated p53 degradation. This differs from the behaviour of HAUSP, which deubiquitinates p53 in addition to Mdm2 and thus protects p53 from Mdm2-mediated degradation. We further demonstrate that suppression of endogenous USP2a destabilises Mdm2 and causes accumulation of p53 protein and activation of p53. Our data identify the deubiquitinating enzyme USP2a as a novel regulator of the p53 pathway that acts through its ability to selectively target Mdm2.

Pubmed ID: 17290220 RIS Download

Mesh terms: Amino Acid Sequence | Blotting, Western | Cell Line, Tumor | Endopeptidases | Enzyme-Linked Immunosorbent Assay | Flow Cytometry | Green Fluorescent Proteins | Humans | Immunoprecipitation | Molecular Sequence Data | Peptides | Proto-Oncogene Proteins c-mdm2 | RNA Interference | Signal Transduction | Tumor Suppressor Protein p53 | Two-Hybrid System Techniques | Ubiquitin

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Associated grants

  • Agency: Cancer Research UK, Id: A6613

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