REGULATION OF ONCOGENIC ACTIVITY BY DBL FAMILY PROTEINS

描述：(摘自申请者摘要)与DBL相关的癌基因 编码一个结构上相关的生长调节蛋白大家族 最初被识别为转型或入侵诱导(例如，DBS、LFC 和LSC)。因此，人们普遍认为，放松管制的人 DBL家族蛋白的表达可促进异常生长， 肿瘤细胞的侵袭性和转移潜能。DBL蛋白是 Rho家族GTP酶激活剂及其转化特性 归因于它们对Rho活性的异常上调。庞大的数字 最近描述的DBL蛋白的种类，以及不断增加的 其GPTase靶标的数量，是重要的充分证据 这些蛋白质将在多种生物中发挥调节作用 流程。然而，关于这些机制仍有许多需要通过 哪些DBL蛋白介导它们的生物学活性，以及关于 这些活动对人类恶性肿瘤的贡献。三个具体的 AIMS的提出是为了直接解决这两个重要问题。第一, 尽管有几项研究表明Rho蛋白是直接的 DBL蛋白转化活性的靶点一直是有限的 催化剂活性在DBL中作用的结构分析 蛋白质转化。在具体目标1中，作者将确定LFC是否 转化依赖于其结合和激活RhoA的能力。这 该方法还将产生有价值的试剂，可用于确定 如果LFC是细胞外信号通路和细胞外信号通路之间的关键环节 RhoA激活。第二，尽管申请人最近表明DBL 蛋白质具有共同的激活多条信号通路的能力 (例如，JNK、p38、SRF和NFKB)，这些途径中的任何一个对 DBL介导的转化，都是未知的。在特定的目标2，他直接 评估JNK、p38和NFKB在细胞转化活性中的作用 星展银行的蛋白质。最后，对DBL蛋白的转化研究依赖于 严重依赖成纤维细胞系统。其结果是， DBL蛋白对人类致癌作用尚不清楚。在特定目标中3 LFC、LSC和DBS蛋白在细胞分化和分化中的作用 人乳腺上皮细胞株T47D的侵袭潜能 检查过了。根据他的初步数据，他预计T47D将是 一个解决DBL家族蛋白贡献的重要系统 到上皮细胞转化。综上所述，调查员觉得 这些研究将大大有助于理解 DBL蛋白促进细胞异常生长的机制 人类癌症的发展。

DESCRIPTION: (dapted from applicant abstract) The Dbl-related oncogenes encode a large, structurally related family of growth regulatory proteins originally identified as transforming or invasion inducing(e.g., Dbs, Lfc and Lsc). Consequently , it is widely believed that the deregulated expression of Dbl family proteins can contribute to the aberrant growth, invasiveness and metastatic potential of tumor cells. Dbl proteins are activators of Rho family GTPases, and their transforming properties has been attributed to their aberrant upregulation of Rho activity. The large number of Dbl proteins that have been recently described, as well as the increasing number of their GPTase targets, is ample evidence of the important regulatory roles that these proteins will play in a multitude of biological processes. However, much remains to be learned about the mechanisms through which Dbl proteins mediate their biological activities, and about the contributions of these activities to human malignancies. Three specific aims are proposed to directly address these two important issues. First, although several studies have implicated the Rho proteins as the immediate targets of the Dbl protein transforming activity, there have been limited structure-based analyses done on the role of the catalytic activity in Dbl protein transformation. In specific Aim 1 the author will determine if Lfc transformation is dependent on its ability to bind, and activate RhoA. This approach will also generate valuable reagents that can be used to determine if Lfc is the critical link between extracellular signaling pathways and RhoA activation. Second, although the applicant has recently shown that Dbl proteins share a common ability to activate multiple signaling pathways (e.g., JNK, p38, SRF and NFKB), the contribution of any of these pathways to Dbl-mediated transformation, are unknown. In Specific Aim 2 he directly assess the contribution of JNK, p38 and NFKB to the transforming activity of the Dbs protein. Finally, transformation studies on Dbl protein have relied heavily on fibroblast cell systems. As a consequence the contribution of Dbl proteins to human carcinogenesis is still not known. In Specific Aim 3 the role of Lfc, Lsc and Dbs proteins in mediating the differentiation and invasive potential of the T47D human breast epithelial cell line will be examined. Based on his preliminary data, he anticipates that T47D will be an important system to address the contribution of the Dbl family proteins to epithelial cell transformation. Taken together, the investigator feels that these studies will contribute significantly to understand the mechanisms through which Dbl proteins contribute to aberrant cell growth and the development of human cancers.