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Title: Molecular mechanisms underlying the oncogeneic function of SS18 & SSX.
Authors: D'Arcy, Pádraig
Year: 4-Jan-2008
Publisher: Institutionen för onkologi-patologi / Department of Oncology-Pathology
Description: The SS18 and SSX genes were initially identified based on their reoccurrence as fusion partners in synovial sarcoma. As a result of the specific chromosomal translocation t(X:18), the SS18 gene from chromosome 18 becomes fused with members of the SSX gene family on the X chromosome resulting in the generation of a novel chimeric fusion gene SS18-SSX. The SS18 gene encodes a ubiquitously expressed transcriptional activator, whereas the SSX gene encodes a transcriptional repressor whose expression is restricted to germ cells and numerous cancers. Thus, the resultant SS18-SSX fusion gene encodes a transcription factor with dual trans activation and repression properties; the expression of which is the initiating event of synovial sarcoma. We present the findings that SSX, along with several other members of the CT-antigen family is expressed in mesenchymal stem cells and their expression is down regulated following differentiation. Knockdown of SSX could effectively impair cell migration, a phenotype associated with down regulation of MMP2 expression adding a functional role for SSX in stem and tumor cell migration. We further explored the potential oncogenic mechanism of SSX expression by investigating the in vitro and in vivo role of SSX in altering cell growth and cell cycle progression. Using an inducible siRNA system we show that knockdown of endogenously expressed SSX can inhibit cell proliferation and tumor growth of in vivo xenographs. We demonstrate that SS18-SSX induces p53 ubiquitination, degradation and prevents the transactivation of p53 target genes following the induction of a stress response. The negative effect on p53 function was attributed to the ability of SS18-SSX to stabilize HDM2. We developed this notion by studying the p53 pathway in synovial sarcoma cell lines expressing wild type p53. We show that these cells were defective for inducing p53 trans activation in response to genotoxic stress; however treatment with the HDM2 antagonist nutlin-3A can could effectively restore p53 trans activation and apoptosis, suggesting that targeting the p53- HDM2 auto regulatory loop may be of therapeutic benefit for synovial sarcoma.
Standard no: 978-91-7357-481-5
Appears in Collections:Dept of Oncology-Pathology

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