BIOLOGIC CHARACTERIZATION OF A NOVEL SHC-LIKE GENE

Ras癌基因编码一种小分子量的gtp酶，参与一种 过多的信号通路。RAS的突变是一个反复出现的主题 人类的恶性肿瘤。大约30%的人类肿瘤含有突变的ras。 90%以上胰腺癌ras阳性的等位基因 突变。因此，了解RAS信号的调节是 对设计潜在的治疗方法很重要 RAS阳性肿瘤。最近，一些RAS调节蛋白已经 被隔离了。这些物质包括GTP酶激活蛋白(GAP)、鸟嘌呤 核苷酸交换或释放因子(GEF)和适配蛋白 作为Grb2和Shc，它们将RAS与其上游监管机构联系起来。目标是 这一建议的目的是描述一种新的类Shc基因(SLI)，该基因是 最近确定并确定了其在监管 RAS信号转导级联反应。这项建议的目标是(1) 确定SLI和Shc在以下方面的异同 它们的序列和表达模式；(2)测定生化 SLI和Shc之间的冗余；(3)考察SLI在 转变和分化；(4)考察SLI在其中的作用 同源敲除基因的发育过程 重组。 在这里提出的研究将开始阐明一个功能 潜在的新型RAS调节蛋白SLI，进一步促进了我们的 了解RAS信号。反过来，这可能会导致更多的 合理设计癌症的治疗方法。

The ras oncogene encodes a small, molecular weight GTPase involved in a plethora of signaling pathways. Mutation of ras is a recurring theme in human malignancies. Approximately 30% of human tumors harbor mutant ras alleles with greater than 90% of pancreatic cancers positive for ras mutations. Therefore, understanding the regulation of the Ras signal is important for the design of potential therapeutic treatments of ras-positive tumors. Recently, a number of Ras regulatory proteins have been isolated. These include GTPase activating proteins (GAPs), guanine nucleotide exchange or releasing factors (GEFs) and adapter proteins such as Grb2 and Shc which link Ras to its upstream regulators. The objective of this proposal is to characterize a novel Shc-like gene (Sli) which I have recently identified and determine its role in the regulation of the Ras signal transduction cascade. The goals of this proposal are to (1) determine the similarities and differences between Sli and Shc in terms of their sequence and expression patterns; (2) determine the biochemical redundancy between Sli and Shc; (3) examine the role of Sli in transformation and differentiation; (4) examine the role of Sli in developmental processes through knocking out the gene by homologous recombination. The studies proposed here will begin to elucidate the function of a potentially novel Ras regulatory protein, Sli, furthering our understanding of Ras signaling. This, in turn, and may lead to a more rational design of therapeutic treatments for cancer.