Integration of Ras, Myc and E2F Signaling Pathways

描述：(申请人提供)三条主要的细胞信号通路 已被发现在控制细胞生长和细胞生长方面发挥关键作用 命运决定。这些途径包括c-Myc转录因子，即 RAS信号分子，以及G1期细胞周期蛋白激酶/视网膜母细胞瘤/E2F通路。 综上所述，这些途径中的损伤可以解释 到目前为止，几乎所有描述的人类肿瘤。分析这些问题是如何 分子途径的相互作用和协同作用对控制细胞生长至关重要 为了我们对癌症发展的理解，以及为了建立 成功的治疗。我们实验室最近的工作已经确定 这三个细胞调控通路之间的重要联系。我们有 证明RAS的激活导致稳定和积累 转录活性Myc蛋白，我们已经鉴定出E2F 转录因子作为重要的下游效应因子介导c-Myc 功能。这项拨款提案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。我们建议 以下是具体目标。1)研究调解的分子机制 RAS对c-Myc的稳定作用及其对Myc功能的影响。 2)确定与c-Myc靶向有关的F-box蛋白 多泛素化和降解并研究其功能。3)研究 下游效应子在调节c-Myc功能中发挥作用。这些实验 为解决这些目标而提出的建议最初将在 指导内文斯博士，以开发几个新的系统来帮助 我们的分析。这一阶段的提案将需要一年时间。这之后， 提案的其余部分将在完全独立的 环境。我最初会在杜克大学获得实验室空间，但我打算 尽快在另一所大学找工作。我的职业生涯 目标是运营一个独立的实验室，致力于增加我们的 了解如何在多步骤中发生多个致癌病变 癌症的发展可以在分子水平上进行协作和协同。

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.