Synovial sarcoma is a soft tissue cancer of the joints that affects young adults. It is characterized by a chromosomal rearrangement between the SYT gene on chromosome 18 and the SSX gene on chromosome x, which results in a fusion product, SYT/SSX. In synovial sarcomas, wt SYT expression from the intact allele is suppressed, and therefore, with the other allele engaged in expressing SYT/SSX, the tumor almost entirely lacks intact SYT function. This could mean that SYT contributes to maintaining normal homeostasis, and losing its function could, at least in part, contribute to tumor formation. Elucidating SYT in vivo function, therefore, is of great importance to the understanding of synovial sarcoma development. One biological event SYT appears to contribute to, is proper cell adhesion, by sending a nuclear to cytoplasm signal. The ability of the cell to adhere to its extracellular matrix is crucial for normal growth and other cellular functions, and loss of such property is one of the prominent features of tumorigenesis and invasiveness. The objective of this application is to gain an in-depth knowledge about the mechanism of cell adhesion control by SYT. One important approach toward this goal is to study the biological consequences in development and adult tissue formation when the SYT gene is targeted in a mouse model. SYT will also be deleted in vitro, by RNAi, in primary and immortalized cell lines, where the integrity of proper adhesion will be investigated. Such events normally involve the ability of the cells to migrate in the wounds for repair, to form polarized epithelial layers, to differentiate on basement membranes, and to adhere to the extracellular matrix for normal division. The recent finding that SYT regulates (-catenin function is of particular interest, since beta-catenin is a major component of cell adhesion-related processes. One of the objectives of this application is to elucidate the biological significance of the SYT/beta-catenin interaction and whether such association is part of SYT nuclear signaling in cell adhesion control. Finally, in order to decipher the basic mechanism of SYT function, protein purification experiments will be conducted in order to isolate and characterize the total cellular complexes in which SYT exists, and through which it sends its efferent signal to mediate proper cell adhesion.
