CONTROL OF THE THROMBOSPONDIN-1 GENE BY MYC ONCOPROTEINS

这是一个香农奖提供部分支持的研究 项目不属于指定机构的资助范围，但 在优秀的边缘。香农奖旨在提供 支持测试方法的可行性;支持进一步测试 和完善研究技术;对现有的 数据集;或进行可以证明PI的离散项目 研究能力或导致额外的重量已经优秀 应用程序.下面的应用程序是从原始文件 由主要经销商提交。 Myc癌蛋白的转化潜力取决于它们的能力， 来调节基因表达。例如，Myc可能会引发肿瘤 通过激活某些肿瘤易感性或抑制 某些肿瘤抑制基因。事实上，我们的数据表明， 逆转录病毒编码的Myc蛋白深刻下调血小板反应蛋白， 1（tsp-1），一种有效的肿瘤新生血管形成、生长抑制剂， 转移这项建议主要是为了界定tsp-1的作用 和其他基因在Myc诱导的肿瘤转化中的作用。将 检测培养细胞中tsp-1的组成型表达是否 恢复正常表型或表达tsp-1的逆转录病毒是否能 使动物对Myc诱导的肿瘤发生具有抗性。反义RNA- 基于方法和基因靶向通过同源重组将是 用于将tsp-1的失活与各种 转化表型的性状。来剖析 由于Myc的转录抑制作用，瞬时表达系统将 被设置。探讨了tsp启动子顺式元件和反式元件的作用。 Myc内的元件以及Myc异二聚体的贡献 麦克斯搭档将接受评估将进行进一步的实验， 确定病毒Myc是否调节鸟氨酸脱羧酶、细胞周期蛋白 D1和其他与Myc正常功能有关的基因。此外 将使用新的筛选方法寻找更多的Myc基因靶点 接近。

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.