Localization of RNA binding proteins in the control of cell survival

点击翻译按钮获取中文摘要

Localization of RNA binding proteins in the control of cell survival. (5000 char maximum)***The research program in my laboratory is focused on understanding how distinct RNA binding proteins regulate cellular stress response. Over the past 10 years we focused our attention on one such protein, hnRNP A1, which plays diverse roles in RNA metabolism, including telomere repair, mRNA splicing, mRNA export, stress granule formation and selective mRNA translation of viral and cellular mRNAs. We have shown that in response to diverse cellular stresses, such as UV irradiation, osmotic shock or viral infection, hnRNP A1 accumulates in the cytoplasm of affected cells and regulates either mRNA stability or selective translation of mRNAs encoding key apoptosis-regulating proteins cIAP1, XIAP, Bcl-xL and Apaf-1. In addition, cytoplasmic accumulation of hnRNP A1 is a critical step in the life cycle progression of Enteroviruses , such as poliovirus, enterovirus, and rhinovirus, all important human pathogens. Yet surprisingly, which signaling pathways regulate cytoplasmic accumulation of hnRNP A1, and how is this regulation exerted is very poorly understood. ***Recently, advances in siRNA technologies and automated high throughput imaging technologies allowed for systematic interrogations of complex biological networks. We have applied these technologies to study subcellular localization of hnRNP A1 in response to osmotic stress or human rhinovirus infection. Our preliminary data identified several novel kinases that modulate hnRNP A1 localization in cells. Our working hypothesis is that distinct kinases and signaling pathways control subcellular localization of hnRNP A1 in response to defined physiological and pathological stimuli. The long-term goal of the program is to gain a detailed understanding of how cellular signaling pathways intersect with discrete RNA cis-regulatory elements to selectively regulate gene expression under distinct physiological conditions. To achieve this vision the specific short term research objectives of this proposal are:***1. To define how hnRNPA1 kinases control hnRNP A1 localization.***2. To investigate the mechanism and biological consequences of modulating these signaling pathways on cell survival and viral life cycle. ***3. To identify and characterize kinases that regulate cytoplasmic accumulation of hnRNP A1 in response to viral infection.***Although our initial focus is on hnRNP A1, the kinases that we will identify may have other targets that could be important for cellular stress response. Our long term plan is to use our resources and expertise and use these kinases to study other RBPs and their role in cell survival and viral infection.*** **