Cellular Responses to Stress

描述（由申请人提供）：细胞已经进化出多种策略来科普各种不可避免的生存压力。应激反应的紊乱是许多疾病的基础。最近发现的一种策略涉及压力颗粒的形成。我们已经发现了一种新的，意想不到的联系之间的压力颗粒和丝氨酸/苏氨酸激酶，RSK 2。我们发现，在乳腺癌细胞系受到氧化应激或血清饥饿，内源性RSK 2协会和共定位与促凋亡蛋白，TIA-1，一个重要组成部分的压力颗粒。出乎意料的是，RSK 2通过涉及eIF 21的途径调节应激颗粒形成。添加有丝分裂原触发应激颗粒的溶解，释放的RSK 2在细胞核中积累，在那里它诱导细胞周期蛋白D1表达，驱动进入细胞周期。我们提出了一种双向调节机制，其中应激颗粒隔离RSK 2以防止不适当的细胞周期进入，RSK 2促进应激颗粒组装以抑制翻译。因此，RSK 2可能是连接应激反应与存活和增殖的关键因子。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RSK 2通过调节应激颗粒的组装来控制应激反应的假说。RSK 2在应激颗粒的启动和维持中的功能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。(2)检验应激后恢复依赖于RSK 2核转位的假设。将使用与Aim 1中使用的方法类似的方法研究RSK 2核输入的机制和RSK 2在存活中的功能。 这些研究将增加我们对RSK 2在促进疾病，特别是癌症中的功能的机械理解，并可能确定治疗干预的新靶点。公共卫生相关性：我们发现了一种新的机制，将蛋白激酶RSK 2与应对压力的生存联系起来。应激反应的紊乱是许多疾病的基础。我们的研究可能会发现新的癌症和炎症性疾病的治疗干预的目标。

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.