CONTROL OF THE THROMBOSPONDIN-1 GENE BY MYC ONCOPROTEINS

这是香农奖，为这项研究提供部分支持 项目低于指定研究所的资助范围，但 都在最优秀的边缘。香农奖旨在提供 支持测试该方法的可行性；开发进一步的测试 改进研究方法；对可用的数据进行二次分析 数据集；或执行可演示PI的离散项目 研究能力或导致额外的重量已经有价值的 申请。以下应用程序取自原始文档 由首席调查员提交。 Myc癌蛋白的转化能力取决于它们的能力 来调控基因的表达。例如，Myc可能会引发肿瘤 通过激活某些肿瘤敏感性或抑制而转化 某些肿瘤抑制基因(S)。事实上，我们的数据已经证明了 逆转录病毒编码的Myc蛋白显著下调血栓反应蛋白- 1(TSP-1)，一种有效的肿瘤新生血管、生长和 转移。这项提议主要是为了界定TSP-1的作用 以及Myc诱导的肿瘤转化中的其他基因。会是 检测TSP-1在培养细胞中的组成性表达是否 恢复正常表型或表达TSP-1的逆转录病毒是否可以 使动物对Myc诱导的肿瘤形成产生抗药性。一种反义RNA- 基于同源重组的方法和基因靶向将是 用来联系TSP-1的失活和各种 转化后的表型性状。剖析分子机制 Myc转录抑制，瞬时表达系统将 被陷害了。顺式元件在TSP启动子和反式启动子中的作用 Myc中的元素以及Myc异二聚体的贡献 将对合作伙伴MAX进行评估。将进行进一步的实验，以 确定病毒Myc是否调节鸟氨酸脱羧酶、细胞周期蛋白 和其他与Myc正常功能有关的基因。此外， 将使用新的筛查方法搜索更多Myc基因靶点 接近了。

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.