elF4E-Dependent Translation Control in the Oncogenic Stress Response and Cancer

描述（由申请人提供）：对致癌转化的一个基本的、固有的反应是增强的细胞应激（例如，氧化、复制、代谢、内质网应激和DNA损伤），这是癌细胞的标志。这些常见的应激表型必须通过应激支持途径被癌细胞耐受。此外，对压力的适应是癌细胞生存所必需的，因此癌细胞可能依赖于正常细胞通常不执行如此重要功能的应激反应途径。因此，针对这些与压力适应相关的脆弱性显然是至关重要的，并为可能导致癌细胞选择性死亡的合成致命相互作用提供了巨大的机会。尽管癌细胞的应激表型非常重要，但我们对转化细胞如何维持应激耐受性的遗传基础的理解存在很大差距，从而限制了我们设计合理治疗剂的能力。细胞需要基因表达的适应性反应来应对细胞应激。引人注目的是，我们的研究结果揭示了主要的帽结合蛋白eIF4E出乎意料地是癌细胞适应致癌应激的翻译程序的中心整合子。

DESCRIPTION (provided by applicant): A fundamental, hard-wired response to oncogenic transformation is enhanced cellular stress (for example, oxidative, replicative, metabolic, ER stress, and DNA damage) that is a hallmark of cancer cells. These common stress phenotypes must be tolerated by cancer cells through stress support pathways. Moreover, adaptation to stress is required for cancer cell survival, and consequently cancer cells may become dependent on stress response pathways that do not ordinarily perform such a vital function in normal cells. Thus, targeting these associated vulnerabilities to stress adaptation are clearly paramount and offer a tremendous window of opportunity for a synthetic lethal interaction that may elicit selective death of cancer cells. Despite the tremendous importance of the stress phenotype of cancer cells, there is a large gap in our understanding of the genetic basis for how stress tolerance is maintained in transformed cells, thereby limiting our ability to design rationa therapeutic agents. Cells require adaptation responses in gene expression to respond to cellular stress. Strikingly, our findings reveal that the major cap binding protein eIF4E is unexpectedly a central integrator of the translation program for the adaption of cancer cells to oncogenic stress. By generating the first genetic loss-of-function mouse model for eIF4E, we have unexpectedly discovered that 50% reductions in eIF4E have no effect on normal development or cellular function but instead are specifically limiting for oncogenic transformation. Utilizing unbiased genome-wide translational profiling, we find that eIF4E is selectively limiting for the translationof specific subsets of mRNAs involved in cellular stress response pathways, including oxidative stress (e.g. Fth1, Gclc,) and ER stress (e.g. Atf6, XBP-1), at least in part, through a novel cis-acting regulatory sequence in their 5'UTRs that sensitizes these mRNAs to eIF4E dosage. Moreover, our preliminary data demonstrate that eIF4E-dependent control of these stress response pathways is critical for tumor cell survival and oncogenic transformation. These findings lay the foundation for this proposal, which seeks to open a new portal into our understanding of the translation program that maintains the adaptation of cancer cells to stress and develops a novel therapeutic regimen to target this vulnerability of transformed cells. In Aim 1, we will assess the role of eIF4E dependent control of oxidative stress in non-small cell lung carcinoma in vivo. In Aim 2, we will define the molecular mechanism by which eIF4E directs the stress-induced oncogenic translation program through a novel cis-acting regulatory element. In Aim 3, we will determine the contribution of eIF4E to cellular transformation through translational control of the unfolded protein response (UPR).