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Signaling and Regulation

The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability

¹ Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden and ² Department of Biological Sciences, Dublin Institute of Technology, Dublin, Ireland

Requests for reprints: Bertha Brodin, Department of Oncology-Pathology, Cancer Center Karolinska R8:04, Karolinska Institute, Stockholm 17176, Sweden. Phone: 46-8-51775244; Fax: 46-8-321047. E-mail: Bertha.Brodin{at}ki.se

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. (Mol Cancer Res 2008;6(1):127–38)

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