REGULATION OF ONCOGENIC ACTIVITY BY DBL FAMILY PROTEINS

描述：（改编自申请人摘要）Dbl 相关癌基因 编码一个结构相关的生长调节蛋白大家族 最初被鉴定为转化或入侵诱导（例如，Dbs、Lfc 和LSC）。 因此，人们普遍认为，放松管制 Dbl 家族蛋白的表达可能导致异常生长， 肿瘤细胞的侵袭性和转移潜力。 Dbl 蛋白是 Rho 家族 GTPases 的激活剂，其转化特性已被 归因于 Rho 活性的异常上调。 数量大 最近描述的 Dbl 蛋白，以及不断增加的 他们的 GPTase 靶标数量，充分证明了重要的 这些蛋白质将在多种生物中发挥调节作用 流程。 然而，关于其机制仍有很多需要了解的地方 哪些 Dbl 蛋白介导其生物活性，以及 这些活动对人类恶性肿瘤的贡献。 三具体 提出的目标是直接解决这两个重要问题。 首先， 尽管一些研究表明 Rho 蛋白是直接的 Dbl 蛋白转化活性的目标，目前还有限 对 Dbl 中催化活性的作用进行基于结构的分析 蛋白质转化。 在具体目标 1 中，作者将确定 Lfc 是否 转化取决于其结合和激活 RhoA 的能力。 这个 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 RhoA 激活。 其次，尽管申请人最近表明 Dbl 蛋白质具有激活多种信号通路的共同能力 （例如，JNK、p38、SRF 和 NFKB），任何这些途径对 Dbl 介导的转化尚不清楚。 在具体目标 2 中，他直接 评估 JNK、p38 和 NFKB 对转化活性的贡献 Dbs 蛋白。 最后，Dbl 蛋白的转化研究依赖于 很大程度上依赖于成纤维细胞系统。 因此，贡献 Dbl 蛋白对人类的致癌作用目前尚不清楚。 具体目标 3 Lfc、Lsc 和 Dbs 蛋白在介导分化和分化中的作用 T47D人乳腺上皮细胞系的侵袭潜力将是 检查了。 根据他的初步数据，他预计 T47D 将 解决 Dbl 家族蛋白贡献的重要系统 至上皮细胞转化。 综合来看，调查者认为 这些研究将极大地有助于理解 Dbl 蛋白促进异常细胞生长的机制 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.