RIG: MK-STYX and PTEN Role(s) in Stress Granule Assembly and/or Disassembly

RIG：MK-STYX 和 PTEN 在应力颗粒组装和/或拆卸中的作用

• 批准号: 0919651
• 负责人: Shanta Hinton
• 金额: $ 19.94万
• 依托单位: Hampton University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0919651&HistoricalAwards=false
• 关键词: RIG; MK; STYX; PTEN; Role

Intellectual MeritWhen cells are exposed to environmental stresses, such as heat shock, UV irradiation, or hypoxia, they initiate protective responses to ensure survival. A reversible block of mRNA translation, triggered by phosphorylation of the eukaryotic translation initiation factor elF2a under the action of several stress-activated kinases is one of the most rapid responses. These translationally-stalled mRNAs are sequestered in cytoplasmic structures called stress granules. Triage within stress granules recycles mRNA molecules for translation or directs them for degradation in processing bodies, which contain the mRNA decay machinery. Stress granules themselves contain a collection of molecules that regulate or initiate mRNA translation as well as proteins implicated in RNA remodeling or degradation. Ras-GTPase activating protein (G3BP) is a stress granule endoribonuclease implicated in RNA remodeling or degradation that is also implicated in the regulation of stress granule formation. Recently the PI showed that the dual specificity phosphatase MK-STYX interacts with G3BP and possibly affects stress granule formation. In addition, a second dual specificity phosphatase, PTEN, has been linked to G3BP expression. This linkage between G3BP and phosphatases suggests the intriguing possibility that phosphatases play an important role in the dynamic assembly and/or disassembly of stress granules in response to environmental signals. The concept is novel as stress sensing kinases are known to correlate stress granule formation but there is no known similar function for specific phosphatases. The overall goal of this project is to test the hypothesis that dual specific phosphatases supplement the role of stress sensing kinases in regulating stress granule dynamics by controlling the phosphorylation state of G3BP. The study will clarify the role(s) of dual specific phosphatases as regulators of the cellular stress response. Broader ImpactsThis project broadens the curriculum at Hampton University, a HBCU, by integrating science education and basic research in molecular and cellular biosciences. Hampton has a long history as an excellent teaching institution but is now expanding its program to include undergraduate research. However, currently there are limited resources for students to participate in research in the Department of Biological Sciences. Students who obtain research experiences traditionally do so at other schools. However, the goal of this project is to allow Hampton students to continue the traditional off-campus plan for research experiences but to also provide the opportunity for some students to have their first research experience at their home institution. This project will also extend into the Cell Biology teaching laboratory and replace some of the repetitive teaching laboratory experiences with original research associated with the project described here. As an outreach activity students in the Cell Biology course will apply their learning by assisting science teachers at Hampton City Schools in providing laboratory experiences for their students and in assisting students and teachers with the annual science fair. The idea is to introduce middle school and high school students to research early in their training with an ultimate goal of informing students of the research that supports the text and the figures in the textbooks that they use.

当细胞受到环境压力，如热休克、紫外线照射或缺氧时，它们会启动保护反应以确保生存。在几种应激激活激酶的作用下，真核翻译起始因子elF2a的磷酸化触发了mRNA翻译的可逆阻滞，这是最快速的反应之一。这些翻译停滞的mrna被隔离在称为应激颗粒的细胞质结构中。应力颗粒内的分选循环mRNA分子进行翻译或指导它们在含有mRNA衰变机制的加工体中降解。应激颗粒本身包含一系列调节或启动mRNA翻译的分子，以及与RNA重塑或降解有关的蛋白质。Ras-GTPase激活蛋白（G3BP）是一种与RNA重塑或降解有关的应激颗粒核糖核酸内酶，也与应激颗粒形成的调节有关。最近的PI研究表明，双特异性磷酸酶MK-STYX与G3BP相互作用，可能影响应激颗粒的形成。此外，第二种双特异性磷酸酶PTEN与G3BP表达有关。G3BP和磷酸酶之间的这种联系提示了一种有趣的可能性，即磷酸酶在响应环境信号的应激颗粒的动态组装和/或拆卸中发挥重要作用。这个概念是新颖的，因为已知应激感应激酶与应激颗粒形成有关，但对于特定的磷酸酶没有已知的类似功能。本项目的总体目标是验证双特异性磷酸酶通过控制G3BP的磷酸化状态来补充应激感应激酶调节应激颗粒动力学的假设。该研究将阐明双重特异性磷酸酶作为细胞应激反应调节因子的作用。更广泛的影响该项目将科学教育与分子和细胞生物科学的基础研究相结合，拓宽了汉普顿大学（HBCU）的课程。汉普顿作为一个优秀的教学机构有着悠久的历史，但现在正在扩大其项目，包括本科生研究。然而，目前生物科学系的学生参与研究的资源有限。传统上，获得研究经验的学生是在其他学校获得的。然而，这个项目的目标是让汉普顿的学生继续传统的校外研究经验计划，但也为一些学生提供机会，在他们的家乡机构有他们的第一次研究经验。这个项目还将扩展到细胞生物学教学实验室，用与这里描述的项目相关的原始研究取代一些重复的教学实验室经验。作为一项拓展活动，细胞生物学课程的学生将通过协助汉普顿市学校的科学教师为学生提供实验室体验，并协助学生和教师举办年度科学博览会来应用他们的学习。这个想法是让初中生和高中生在他们的早期训练中进行研究，最终目的是让学生了解支持他们使用的教科书中的文本和数字的研究。