Integration of Ras, Myc and E2F Signaling Pathways

产品说明： （申请人提供）三大细胞信号通路 在控制细胞生长和细胞增殖中起关键作用 命运的决定 这些途径包括c-Myc转录因子， Ras信号分子和G1细胞周期蛋白激酶/视网膜母细胞瘤/E2 F通路。 总之，这些通路中的病变可以解释 几乎所有的人类肿瘤。 分析这些 分子途径相互作用和协同作用来控制细胞生长是必不可少的 帮助我们理解癌症的发展， 成功的治疗。 我们实验室最近的工作建立了 这三种细胞调节途径之间的重要联系。 我们有 表明Ras激活导致稳定和积累 转录 活性Myc蛋白，我们已经确定了E2 F 转录因子作为介导c-Myc的重要下游效应子 功能 本拨款申请中概述的研究旨在进一步 我们对这些细胞信号通路如何相互作用的理解。 我们提出 以下具体目标。 1)研究介导 Ras诱导的c-Myc稳定化，并确定其对Myc功能的影响。 2)鉴定特异性参与靶向c-Myc的F-box蛋白， 多泛素化和降解，并研究其功能。 3)检查 下游效应子在调节c-Myc功能中的作用。 实验 为实现这些目标而提出的建议最初将在 内文斯博士的指导，以开发几个新的系统，以帮助 我们的分析。 该提案的这一阶段将需要一年时间。 在此之后， 其余的建议将在一个完全独立的 环境 我最初会在杜克大学获得实验室空间，但我打算 尽快去另一所大学找工作 我的职业生涯 我们的目标是运营一个独立的实验室，致力于提高我们的 了解在多个步骤中发生的多个致癌病变 癌症的发展可以在分子水平上协作和协同。

DESCRIPTION: (provided by Applicant) Three major cell signaling pathways have been identified that play key roles in controlling cell growth and cell fate decisions. These pathways include the c-Myc transcription factor, the Ras signaling molecule, and the G1 Cyclin kinase/retinoblastoma/E2F pathway. Taken together, lesions in these pathways can account for the development of virtually all human tumors described to date. An analysis of how these molecular pathways interact and synergize to control cell growth is essential for our understanding of cancer development, and for the establishment of successful treatments. Recent work in our laboratory has established important links between these three cell regulatory pathways. We have demonstrated that Ras activation leads to stabilization and accumulation of transcriptionally active Myc protein, and we have identified the E2F transcription factors as important downstream effectors that mediate c-Myc function. The research outlined in this grant proposal is intended to further our understanding of how these cell signaling pathways interact. We propose the following specific aims. 1) Investigate molecular mechanisms that mediate Ras-induced stabilization of c-Myc and determine its effects on Myc function. 2) Identify an F-box protein specifically involved in targeting c-Myc for multiubiquitination and degradation and study its function. 3) Examine the roles downstream effectors play in regulating c-Myc function. The experiments proposed to address these aims will initially be conducted under the mentorship of Dr. Nevins in order to develop several new systems to help with our analyses. This phase of the proposal will require one year. After this, the remainder of the proposal will be conducted in a completely independent environment. I will initially be given laboratory space at Duke, but I intend to look for a position at another university as soon as possible. My career goal is to operate an independent laboratory dedicated to increasing our understanding of how multiple oncogenic lesions that occur in the multi-step development of cancer can collaborate and synergize at the molecular level.