Synovial sarcoma (SS) is a rare but aggressive malignancy that is typically diagnosed in adolescents and young adults. These tumors are characterized by the presence of a specific chromosomal translocation t(X;18)(p11.2;q11.2) resulting in the fusion of the SYT gene from chromosome 18 with one of the SSX genes located on the X chromosome. The wild-type SYT and SSX proteins function as a transcriptional co-activator and transcriptional co-repressor, respectively, thus it is believed that the tumorigenic activity of the resultant SYT-SSX fusion protein is based on transcriptional deregulation. Moreover, it has been hypothesized that SS arises from an undifferentiated cell type. Here we show that SYT-SSX2 expression in mesenchymal stem and progenitor cells results in the aberrant activation of a neural program through the direct targeting of genes involved in the differentiation and function of this lineage. In addition, this phenotype is dependent on signaling through Fgfr2, a gene that is also directly occupied and upregulated by the chimeric protein. Genome-wide binding and expression studies included in this work reveal that SYT-SSX2 may reverse the transcriptional activity, whether silent or expressed, of its target genes. These analyses also demonstrate that SYT-SSX2 is primarily recruited to genes regulated by Polycomb repressive complexes and antagonizes their silencing function. At the molecular level this may be mediated by the opposition of the ubiquitin E3-ligase activity of Ring1b, a core component of Polycomb Repressive Complex 1, by SYT-SSX2 and/or the proteins with which it interacts. Overall, the data presented here indicate that by altering lineage-specific factors, signaling pathways, and epigenetic regulators, SYT-SSX2 mediates transformation through aberrant cellular reprogramming.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09222011-192110 |
| Date | 26 September 2011 |
| Creators | Garcia, Christina Valerie Boma |
| Contributors | Barbara Fingleton, Josiane Eid, P. Anthony Weil, Stephen Brandt |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-09222011-192110/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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