PMID:18234968
| Citation |
D'Arcy, P, Maruwge, W, Ryan, BA and Brodin, B (2008) The oncoprotein SS18-SSX1 promotes p53 ubiquitination and degradation by enhancing HDM2 stability. Mol. Cancer Res. 6:127-38 |
|---|---|
| Abstract |
Mutations of the p53 gene are uncommon in synovial sarcoma, a high-grade tumor genetically characterized by the chromosomal translocation t:(X;18), which results in the fusion of SS18 with members of SSX gene family. Although implicated in tumorigenesis, the mechanisms by which SS18-SSX promotes tumor growth and cell survival are poorly defined. Here, we show that SS18-SSX1 negatively regulates the stability of the tumor suppressor p53 under basal conditions. Overexpression of SS18-SSX1 enhanced p53 ubiquitination and degradation in a manner dependent on the ubiquitin ligase activity of HDM2. The negative effect of SS18-SSX1 expression on p53 was mediated by its ability to promote HDM2 stabilization through inhibition of HDM2 autoubiquitination. Furthermore, SS18-SSX1 expression altered the induction of p53-regulated genes in response to cellular stress by abrogating the transactivation of HDM2, PUMA, and NOXA but not p21. Our data uncover a novel mechanism whereby SS18-SSX1 can negatively regulate p53 tumor-suppressive function by increasing the stability of its negative regulator HDM2 and suggest that chemical compounds that target the p53-HDM2 regulatory axis may be of therapeutic benefit for the treatment of synovial sarcoma. |
| Links |
PubMed Online version:10.1158/1541-7786.MCR-07-0176 |
| Keywords |
Active Transport, Cell Nucleus; Apoptosis; Cell Line, Tumor; Cell Nucleus/metabolism; Cell Survival; DNA Damage; Gene Expression Regulation, Neoplastic; Half-Life; Humans; Oncogene Proteins, Fusion/genetics; Oncogene Proteins, Fusion/metabolism; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-mdm2/metabolism; Thermodynamics; Tumor Suppressor Protein p53/metabolism; Ubiquitination |
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