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PMID:17290220

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Citation

Stevenson, LF, Sparks, A, Allende-Vega, N, Xirodimas, DP, Lane, DP and Saville, MK (2007) The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 26:976-86

Abstract

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.

Links

PubMed PMC1852834 Online version:10.1038/sj.emboj.7601567

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:UBP2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP2

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q00987

F

Seeded From UniProt

complete

HUMAN:UBP2

involved_in

GO:0050821: protein stabilization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP2

involved_in

GO:0045931: positive regulation of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP2

involved_in

GO:0016579: protein deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP2

enables

GO:0004843: thiol-dependent deubiquitinase

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:UBP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q00987

F

Seeded From UniProt

complete

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0CG48

F

Seeded From UniProt

complete

HUMAN:UBC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:UBC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q00987

F

Seeded From UniProt

complete

HUMAN:MDM2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75604

F

Seeded From UniProt

complete

HUMAN:MDM2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0CG48

F

Seeded From UniProt

complete

HUMAN:MDM2

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75604

F

Seeded From UniProt

complete

HUMAN:MDM2

involved_in

GO:0045931: positive regulation of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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