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PMID:19838211

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Citation

Allende-Vega, N, Sparks, A, Lane, DP and Saville, MK (2010) MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 29:432-41

Abstract

It has previously been shown that ubiquitin-specific protease 2a (USP2a) is a regulator of the Mdm2/p53 pathway. USP2a binds to Mdm2 and can deubiquitinate Mdm2 without reversing Mdm2-mediated p53 ubiquitination. Overexpression of USP2a causes accumulation of Mdm2 and promotes p53 degradation. We now show that MdmX is also a substrate for USP2a. MdmX associates with USP2a independently of Mdm2. Ectopic expression of wild-type USP2a but not a catalytic mutant prevents Mdm2-mediated degradation of MdmX. This correlates with the ability of wild-type USP2a to deubiquitinate MdmX. siRNA-mediated knockdown of USP2a in NTERA-2 testicular embryonal carcinoma cells and MCF7 breast cancer cells causes destabilization of MdmX and results in a decrease in MdmX protein levels, showing that endogenous USP2a participates in the regulation of MdmX stability. The therapeutic drug, cisplatin decreases MdmX protein expression. USP2a mRNA and protein levels were also reduced after cisplatin exposure. The magnitude and time course of USP2a downregulation suggests that the reduction in USP2a levels could contribute to the decrease in MdmX expression following treatment with cisplatin. Knockdown of USP2a increases the sensitivity of NTERA-2 cells to cisplatin, raising the possibility that suppression of USP2a in combination with cisplatin may be an approach for cancer therapy.

Links

PubMed Online version:10.1038/onc.2009.330

Keywords

Antineoplastic Agents/pharmacology; Blotting, Western; Catalytic Domain/genetics; Cell Line, Tumor; Cisplatin/pharmacology; Down-Regulation/drug effects; Endopeptidases/genetics; Endopeptidases/metabolism; Humans; Immunoprecipitation; Mutation; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Protein Binding; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-mdm2/genetics; Proto-Oncogene Proteins c-mdm2/metabolism; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Substrate Specificity; Transfection; Ubiquitination

Significance

Annotations

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

HUMAN:UBP2

involved_in

GO:0016579: protein deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP2

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:UBP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15151

F

Seeded From UniProt

complete

HUMAN:MDM4

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75604

F

Seeded From UniProt

complete

Notes

See also

References

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