Cellular Responses to Stress

细胞对压力的反应

基本信息

批准号：
7596226
负责人：
Deborah Lannigan
金额：
$ 24万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7596226
关键词：
Animals Automobile Driving Binding Biological Assay Cell Cycle Cell Cycle Arrest Cell Nucleus Cell Survival Cells Cellular Stress Complex Cyclin D1 Cytoplasm Cytoplasmic Granules Data Disease Eukaryotic Initiation Factor-2 Gene Silencing Goals Growth Factor Immunofluorescence Immunologic In Vitro Inflammation Inflammatory Life Link Maintenance Malignant Neoplasms Mass Spectrum Analysis Mediating Mitogens Mitosis Molecular Nuclear Nuclear Import Nuclear Pore Nuclear Translocation Oxidative Stress Pathway interactions Phosphorylation Phosphotransferases Physiological Poly(A)+ RNA Polyribosomes Process Protein Kinase Proteins Proteomics Radiation therapy Recovery Recruitment Activity Regulation Serum Signal Pathway Signal Transduction Site Starvation Stress Testing Therapeutic Intervention Time Tissues Translational Repression Translations Triage abstracting base biological adaptation to stress cellular imaging coping environmental stressor link protein malignant breast neoplasm mutant novel pressure prevent pro-apoptotic protein response ribosomal protein S6 kinase 2

项目摘要

DESCRIPTION (provided by applicant): Cells have evolved multiple strategies to cope with the varied and inevitable stresses of existence. Perturbation of stress responses underlies numerous diseases. One recently discovered strategy involves the formation of stress granules. We have discovered a novel, unanticipated link between stress granules and the Ser/Thr kinase, RSK2. We found that in breast cancer lines subjected to oxidative stress or serum starvation, endogenous RSK2 associates with and co-localizes with the pro-apoptotic protein, TIA-1, an essential component of stress granules. Unexpectedly, RSK2 regulates stress granule formation through a pathway involving eIF21. Addition of mitogens triggers the dissolution of stress granules, and the released RSK2 accumulates in the nucleus where it induces cyclin D1 expression, driving entry into the cell cycle. We propose a bidirectional regulatory mechanism in which stress granules sequester RSK2 to prevent inappropriate cell cycle entry, and RSK2 facilitates stress granule assembly to repress translation. Thus, RSK2 may be a pivotal factor linking the stress response to survival and proliferation. An essential goal is to elucidate, at a molecular level, the mechanism of this linkage. The specific aims are: (1) Test the hypothesis that RSK2 controls the stress response through regulation of stress granule assembly. The function of RSK2 in initiation and maintenance of stress granules will be investigated using in vitro binding studies, gene silencing, immunofluorescence and live cell imaging. (2) Test the hypothesis that post-stress recovery depends on RSK2 nuclear translocation. The mechanism of RSK2 nuclear import and the function of RSK2 in survival will be investigated using similar approaches to those used in Aim 1. These studies will increase our mechanistic understanding of the function of RSK2 in promoting disease, in particular cancer, and may identify new targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: We have discovered a novel mechanism that links the protein kinase RSK2 with survival in response to stress. Perturbation of stress responses underlies numerous diseases. Our studies may identify new targets for therapeutic intervention in cancer and inflammatory diseases.

描述（由申请人提供）：细胞已经进化出多种策略来应对各种不可避免的生存压力。应激反应的扰动是许多疾病的根源。最近发现的一种策略涉及应力颗粒的形成。我们发现应激颗粒和 Ser/Thr 激酶 RSK2 之间存在一种新颖的、意想不到的联系。我们发现，在遭受氧化应激或血清饥饿的乳腺癌细胞系中，内源性 RSK2 与促凋亡蛋白 TIA-1 结合并共定位，TIA-1 是应激颗粒的重要组成部分。出乎意料的是，RSK2 通过涉及 eIF21 的途径调节应激颗粒的形成。添加有丝分裂原会触发应激颗粒的溶解，释放的 RSK2 会在细胞核中积累，并在细胞核中诱导细胞周期蛋白 D1 的表达，从而驱动细胞进入细胞周期。我们提出了一种双向调节机制，其中应激颗粒隔离 RSK2 以防止不适当的细胞周期进入，而 RSK2 促进应激颗粒组装以抑制翻译。因此，RSK2可能是将应激反应与生存和增殖联系起来的关键因素。一个基本目标是在分子水平上阐明这种联系的机制。具体目标是： (1) 检验 RSK2 通过调节应激颗粒组装来控制应激反应的假设。将使用体外结合研究、基因沉默、免疫荧光和活细胞成像来研究 RSK2 在应激颗粒启动和维持中的功能。 (2) 检验应激后恢复依赖于RSK2核转位的假设。将使用与目标 1 中使用的类似方法来研究 RSK2 核输入机制和 RSK2 在生存中的功能。这些研究将增加我们对 RSK2 在促进疾病（特别是癌症）中的功能的机制理解，并可能确定治疗干预的新靶点。公共健康相关性：我们发现了一种新机制，将蛋白激酶 RSK2 与应激反应中的生存联系起来。应激反应的扰动是许多疾病的根源。我们的研究可能会确定癌症和炎症性疾病治疗干预的新目标。