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Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics.

Cancer cell | Mar 20, 2012

Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.

Pubmed ID: 22439931 RIS Download

Mesh terms: Activating Transcription Factor 2 | Animals | Antineoplastic Agents | Apoptosis | Cell Line, Tumor | Cell Proliferation | Gene Expression Regulation, Neoplastic | Gene Knockdown Techniques | HEK293 Cells | Histone Deacetylase Inhibitors | Humans | Mice | Oncogene Proteins, Fusion | RNA, Small Interfering | Repressor Proteins | Sarcoma, Synovial | Translocation, Genetic

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Associated grants

  • Agency: NCI NIH HHS, Id: K08 CA138764
  • Agency: NIGMS NIH HHS, Id: R01 GM021168
  • Agency: NCI NIH HHS, Id: K08CA138764

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