Exploriing the role of oncogenic Ras in stress response mechanisms

探索致癌 Ras 在应激反应机制中的作用

• 批准号: 7936093
• 负责人: Elda Grabocka
• 金额: $ 4.35万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936093
• 关键词: Cell Death; Cell Survival; Cells; Characteristics; Complex; Comprehension; Cytoplasmic Granules; Defense Mechanisms; Development; Disease; Exhibits; Homeostasis; Immunofluorescence Microscopy; Lead; Life; Link; Malignant Neoplasms; Mediator of activation protein; Messenger RNA; Molecular; Oncogenes; Oncogenic; RNA-Binding Proteins; Radiation therapy; Recruitment Activity; Regulation; Research; Resistance; Role; Signal Pathway; Stimulus; Stress; Structure; Testing; Therapeutic; Therapeutic Intervention; Tissues; biological adaptation to stress; cancer cell; cellular imaging; chemotherapy; defense response; design; insight; public health relevance; research study; response; therapy resistant; tumor progression; tumorigenesis

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.

描述（由申请人提供）：适应压力是癌症进展和抗疗法耐药性的组成部分。 应力刺激诱导被称为应激颗粒（SGS）的离散细胞质灶的形成，后者募集了细胞稳态的关键调节剂和停滞的mRNA复合物。 新兴证据表明，SG的形成是综合应力反应的关键组成部分。 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子。 因此，SGS可能是癌基因调节的靶标。 该项目的目的是研究致癌性RA在SG形成中的作用，以及在应激下对细胞存活的后续影响。 为此，我们将：1）研究如何响应于致癌性RA的SG动力学； 2）定义RAS调节的SG形成的分子框架； 3）检查RAS调节的SG形成如何有助于癌细胞的增强胁迫抗性和肿瘤发生。 总的来说，这些研究应为致癌性RA在压力反应机制以及治疗干预措施的新目标中的作用提供新的重大见解。 公共卫生相关性：已知癌症组织对压力刺激的抵抗力比其正常对应物更具抵抗力来强调本应用中提出的研究的相关性。 这种特征会干扰放疗和化学疗法的功效，这依赖于应激诱导的细胞死亡是有效的。 因此，对控制癌细胞压力抗性的机制的理解有助于对这种致命疾病的更好治疗方法的理解和发展。