ETS DOMAIN PROTEIN, LIN1

高度保守的Ras信号通路在发育过程中决定细胞命运中起着重要作用，并且ras原癌基因的突变通常在人类癌症中发现。ETS结构域蛋白似乎是Ras信号传导的保守介质，并且确定ETS转录因子如何受Ras信号传导调节以及它们在各种发育过程中作为效应子的功能是一个重要目标。 我建议联合收割机在C.线虫外阴发育的生物化学研究，以阐明ETS结构域蛋白，LIN-1的功能。LIN-1的DNA结合活性和转录激活潜力将被确定，LIN-1调控的靶基因将通过生物化学方法鉴定。 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，含有这种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周围的基因网络中的突变将通过使用遗传筛选来鉴定和表征。 这些调查将提供重要的线索，保守的作用ETS结构域蛋白作为效应细胞增殖和命运的决定。

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.