This project explores the molecular mechanisms involved in cellular transformation by the chimeric transcriptional regulatory protein TLS-CHOP that is encoded by the t(12:16) chromosomal rearrangement common to most myxoid and round cell liposarcomas. It is hypothesized that transformation in liposarcoma proceeds by two parallel pathways: (1) The CHOP component of the oncoprotein directs it to one set of target genes, and the TLS component deregulates their expression; (2) TLS-CHOP impinges on the normal function of the RNA-binding protein TLS, interfering with the proper expression of another set of target genes. The second component is predicted to be common to sarcomas that contain a TLS (or EWS) component in their causative oncoprotein. Members of both sets of target genes are hypothesized to function as effectors of the process of transformation. The goals of this project are, thus, to identify TLS-CHOP target genes, delineate the mechanism of their deregulation in liposarcoma, and determine their role in transformation. This will involve identifying genes contacted by TLS-CHOP and genes that are normally regulated by TLS, as well as identifying proteins that participate as partners in the process by which TLS-CHOP carried out its function. The latter include the direct cellular contingents of TLS and CHOP, as well as the products of genes that modify transformation indirectly. The identification of TLS-CHOP and TLS target genes will rely on the comparative analysis of the expression pattern of genes in cells that do and do not contain active forms of these regulators. The direct contingents of TLS and CHOP will be identified by biochemical and genetic means, whereas the identification of genes that modify the process of transformation by TLS-CHOP will be attained by a genetic screen of tumors derived in genetically-modified mice that will be developed as animal models for tumorigenesis by the oncoprotein.
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