Cellular Responses to Stress

细胞对压力的反应

• 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
• 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

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基础。最近发现的一种策略涉及到应力颗粒的形成。我们发现了应激颗粒和丝氨酸/苏氨酸激酶RSK2之间的一种新的、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株中，内源性RSK2与促凋亡蛋白TIA-1结合并共同定位，TIA-1是应激颗粒的基本成分。出乎意料的是，RSK2通过一条涉及eIF21的途径调控应激颗粒的形成。有丝分裂原的加入触发了应激颗粒的溶解，释放的RSK2积聚在细胞核中，在那里它诱导了细胞周期蛋白D1的表达，推动进入细胞周期。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可能是一个将应激反应与生存和增殖联系起来的关键因子。一个重要的目标是在分子水平上阐明这种联系的机制。具体目的是：(1)验证RSK2通过调节应激颗粒组装来控制应激反应的假说。我们将利用体外结合研究、基因沉默、免疫荧光和活细胞成像来研究RSK2在应激颗粒的启动和维持中的作用。(2)验证应激后恢复依赖RSK2核转位的假说。RSK2核输入的机制和RSK2在生存中的作用将使用与AIM 1中使用的类似方法进行研究。 这些研究将增加我们对RSK2在促进疾病，特别是癌症中的作用的机制的理解，并可能为治疗干预确定新的靶点。与公共健康相关：我们发现了一种新的机制，将蛋白激酶RSK2与应对压力的生存联系起来。应激反应的扰动是许多疾病的基础。我们的研究可能为癌症和炎症性疾病的治疗干预确定新的靶点。