Localization of RNA binding proteins in the control of cell survival

RNA结合蛋白在细胞存活控制中的定位。***我实验室的研究项目主要是了解不同的RNA结合蛋白是如何调节细胞应激反应的。在过去的10年里，我们将注意力集中在hnRNP A1蛋白上，它在RNA代谢中起着多种作用，包括端粒修复、mRNA剪接、mRNA输出、应激颗粒形成以及病毒和细胞mRNA的选择性mRNA翻译。我们已经证明，在不同的细胞胁迫下，如紫外线照射、渗透休克或病毒感染，hnRNP A1在受影响细胞的细胞质中积累，并调节mRNA的稳定性或编码关键凋亡调节蛋白cIAP1、XIAP、Bcl-xL和Apaf-1的mRNA的选择性翻译。此外，hnRNP A1的细胞质积累是肠病毒（如脊髓灰质炎病毒、肠病毒和鼻病毒）生命周期进展的关键步骤，这些病毒都是重要的人类病原体。然而，令人惊讶的是，哪些信号通路调节hnRNP A1的细胞质积累，以及这种调节是如何发挥作用的，人们知之甚少。***最近，siRNA技术和自动化高通量成像技术的进步使复杂生物网络的系统询问成为可能。我们已经应用这些技术研究了hnRNP A1在渗透应激或人鼻病毒感染下的亚细胞定位。我们的初步数据确定了几种调节hnRNP A1在细胞中的定位的新激酶。我们的工作假设是不同的激酶和信号通路控制着hnRNP A1的亚细胞定位，以响应明确的生理和病理刺激。该项目的长期目标是详细了解细胞信号通路如何与离散的RNA顺式调节元件相交，从而在不同的生理条件下选择性地调节基因表达。为了实现这一愿景，本提案的具体短期研究目标是：***1。确定hnRNPA1激酶如何控制hnRNPA1的定位。研究调节这些信号通路对细胞存活和病毒生命周期的作用机制和生物学后果。* * * 3。鉴定和表征在病毒感染反应中调节hnRNP A1细胞质积累的激酶。***虽然我们最初的重点是hnRNP A1，但我们将确定的激酶可能具有其他可能对细胞应激反应很重要的靶标。我们的长期计划是利用我们的资源和专业知识，利用这些激酶来研究其他rbp及其在细胞存活和病毒感染中的作用。* * * * *

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.*** **