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

描述（由申请人提供）：对致癌转化的基本、硬连线反应是增强的细胞应激（例如，氧化、复制、代谢、ER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，癌细胞生存需要适应压力，因此癌细胞可能依赖于通常在正常细胞中不执行这种重要功能的压力反应途径。因此，针对这些相关的脆弱性进行压力适应显然是至关重要的，并为可能引起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之窗。尽管癌细胞的应激表型非常重要，但我们对转化细胞中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反应来应对细胞应激。令人惊讶的是，我们的研究结果表明，主要帽结合蛋白eIF 4 E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者。 通过产生eIF 4 E的第一个遗传功能丧失小鼠模型，我们意外地发现eIF 4 E减少50%对正常发育或细胞功能没有影响，而是特异性地限制了致癌转化。利用无偏的全基因组翻译谱分析，我们发现eIF 4 E选择性地限制了参与细胞应激反应途径的特定mRNA亚群的表达，包括氧化应激（例如Fth 1，Gclc）和ER应激（例如Atf 6，XBP-1），至少部分是通过其5 'UTR中的一种新的顺式作用调节序列，该序列使这些mRNA对eIF 4 E剂量敏感。此外，我们的初步数据表明，这些应激反应途径的eIF 4 E依赖性控制是肿瘤细胞存活和致癌转化的关键。这些发现为这一提议奠定了基础，该提议旨在为我们理解维持癌细胞适应压力的翻译程序打开一个新的门户，并开发一种新的治疗方案来靶向转化细胞的这种脆弱性。在目的1中，我们将评估eIF 4 E依赖性控制氧化应激在体内非小细胞肺癌中的作用。在目标2中，我们将定义eIF 4 E通过一种新的顺式作用调控元件指导应激诱导的致癌翻译程序的分子机制。在目标3中，我们将确定eIF 4 E通过翻译对细胞转化的贡献。 未折叠蛋白反应（UPR）。

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).