CONTROL OF THE THROMBOSPONDIN-1 GENE BY MYC ONCOPROTEINS

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THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OF AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEAD ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE APPLICATION BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. The transforming potential of Myc oncoproteins depends upon their ability to regulate gene expression. For instance, Myc might trigger neoplastic transformation by activating certain tumor susceptibility or repressing certain tumor suppressor gene(s). Indeed, our data have demonstrated that retrovirally encoded Myc proteins profoundly downregulate thrombospondin- 1 (tsp-1), a potent inhibitor of tumor neovascularization, growth, and metastasis. This proposal primarily seeks to delineate the role of tsp-1 and other genes in Myc-induced neoplastic transformation. It will be examined whether constitutive expression of tsp-1 in cultured cells can restore the normal phenotype or whether retroviruses expressing tsp-1 can render animals resistant to Myc-induced tumorigenesis. An antisense RNA- based approach and gene targeting via homologous recombination will be employed to relate inactivation of tsp-1 and acquisition of various traits of the transformed phenotype. To dissect the molecular mechanisms of transcriptional repression by Myc, transient expression system will be set up. The roles of cis-elements in the tsp-promoter and trans- elements within Myc as well as the contributions of Myc heterodimeric partner Max will be assessed. Further experiments will be performed to determine whether viral Myc regulates the ornithine decarboxylase, cyclin D1, and other genes implicated in Myc normal functions. In addition the search for more Myc gene targets will be undertaken using new screening approaches.