Exploriing the role of oncogenic Ras in stress response mechanisms

描述(由申请人提供)：对压力的适应是癌症进展和对治疗的抵抗不可或缺的一部分。应激刺激诱导形成离散的细胞质焦点，称为应激颗粒(SGS)，它招募细胞内稳态和停滞的mRNA复合体的关键调节因子。新的证据表明，SG的形成是综合应激反应的关键组成部分。SGS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因子。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在应激条件下对细胞存活的影响。为此，我们将：1)研究致癌RAS对SG动力学的影响；2)定义RAS调控SG形成的分子框架；3)研究RAS调控SG形成如何有助于提高癌细胞的抗压能力和肿瘤的发生。总之，这些研究应该为致癌RAS在应激反应机制中的作用以及治疗干预的新靶点提供新的和重要的见解。公共卫生相关性：这项申请中提出的研究的相关性是因为已知癌症组织比正常组织对应激刺激更具抵抗力。这一特点可能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，对控制癌细胞抗应激的机制的了解有助于理解和开发更好的治疗这种致命疾病的方法。

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.