Exploriing the role of oncogenic Ras in stress response mechanisms

描述（由申请人提供）：适应压力是癌症进展和对治疗耐药性的组成部分。 应激刺激诱导形成离散的细胞质灶，称为应激颗粒（SG），其募集细胞稳态和停滞的mRNA复合物的关键调节剂。 新出现的证据表明，SG的形成是一个关键组成部分的综合应激反应。 SG是动态结构;它们的形成受RNA结合蛋白的调节，其中几种是已知的癌基因效应物。 因此，SGs可能是癌基因调控的靶点。 本项目的目的是研究致癌Ras在SG形成中的作用以及随后对应激下细胞存活的影响。 为此，我们将：1）研究SG动力学如何响应致癌Ras而改变; 2）定义Ras调节的SG形成的分子框架; 3）研究Ras调节的SG形成如何有助于增强癌细胞和肿瘤发生的应激抗性。 总之，这些研究应该提供新的和重要的洞察致癌Ras在应激反应机制中的作用，以及治疗干预的新靶点。 公共卫生相关性：本申请中提出的研究的相关性通过已知癌组织比其正常对应物更能抵抗应激刺激的事实来强调。 这种特性会干扰放疗和化疗的疗效，而放疗和化疗依赖于应激诱导的细胞死亡才能有效。 因此，了解控制癌细胞抗应激性的机制有助于理解和开发这种致命疾病的更好治疗方法。

DESCRIPTION (provided by applicant): Adaptation to stress is an integral part of cancer progression and resistance to therapies. Stress stimuli induce the formation of discrete cytoplasmic foci known as stress granules (SGs), which recruit critical regulators of cellular homeostasis and stalled mRNA complexes. Emerging evidence indicates that SG formation is a critical component of the integrated stress response. SGs are dynamic structures; their formation is regulated by RNA binding proteins, several of which are known oncogene effectors. Accordingly, SGs may be targets of oncogene regulation. The aim of this project is to investigate the role of oncogenic Ras in SG formation and the subsequent effects on cell survival under stress. To accomplish this we will: 1) investigate how SG dynamics are altered in response to oncogenic Ras; 2) define the molecular framework for Ras-regulated SG formation; 3) examine how Ras-regulated SG formation contributes to the enhanced stress resistance of cancer cells and tumorigenesis. Altogether, these studies should provide new and significant insight into the role of oncogenic Ras in stress response mechanisms as well as new targets for therapeutic interventions. PUBLIC HEALTH RELEVANCE: The relevance of the research proposed in this application is emphasized by the fact that cancer tissues are known to be more resistant to stress stimuli than their normal counterparts. This characteristic can interfere with the efficacy of radiotherapy and chemotherapy, which relies on stress-induced cell death to be effective. Consequently, the understanding of the mechanisms that govern the stress resistance of cancer cells is instrumental to the comprehension and the development of better treatments for this lethal disease.