ETS DOMAIN PROTEIN, LIN1

高度保守的Ras信号通路在细胞发育过程中起着决定细胞命运的重要作用，Ras原癌基因的突变在人类癌症中很常见。ETS结构域蛋白似乎是Ras信号的保守介质，确定ETS转录因子如何受Ras信号调控及其在各种发育过程中的效应作用是一个重要的目标。我建议将线虫外阴发育过程中ras介导的信号传导的遗传分析与生化研究相结合，以阐明ETS结构域蛋白LIN-1的功能。确定LIN-1的DNA结合活性和转激活电位，并通过生化方法鉴定LIN-1调控的靶基因。ERK MAP激酶对接位点在体内调节ets结构域转录因子中的作用将被确定，并且含有此类对接位点的肽将被开发为ras介导的事件（如肿瘤发生）的潜在抑制剂。lin-1周围基因网络中的突变将通过使用遗传筛选来识别和表征。这些研究将为了解ets结构域蛋白作为细胞增殖和命运决定效应器的保守作用提供重要线索。

The highly conserved Ras signaling pathway plays a major role in the determination of cell fates during development, and mutations in the ras proto-oncogene are commonly found in human cancers. ETS-domain proteins appear to be conserved mediators of Ras signaling, and the determination of how ETS transcription factors are regulated by Ras signaling and their function as effectors in various developmental processes is an important goal. I propose to combine genetic analyses of Ras-mediated signaling during C. elegans vulval development with biochemical investigations to elucidate the function of the ETS domain protein, LIN-1. The DNA binding activity and transactivation potential of LIN-1 will be ascertained, and target genes regulated by LIN-1 will be identified by biochemical methods. The role of ERK MAP kinase docking sites in the regulation of ETS-domain transcription factors in vivo will be ascertained, and peptides containing such docking sites will be developed as potential inhibitors of Ras-mediated events such as oncogenesis. Mutations in the network of genes surrounding lin-1 will be identified and characterized through the use of a genetic screen. These investigations will provide important clues about the conserved role of ETS-domain proteins as effectors of cell proliferation and fate determination.