Translational Control of Radiation-Induced Apoptosis

辐射诱导细胞凋亡的转化控制

• 批准号: 8018134
• 负责人: ALEXEY G. RYAZANOV
• 金额: $ 5.4万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018134
• 关键词: Academy; Apoptosis; Apoptotic; BIRC4 gene; Cell-Free System; Cells; Collaborations; Complex; Down-Regulation; Gamma Rays; Gastrointestinal tract structure; Goals; Grant; Gray unit of radiation dose; Hair; Institutes; Intestines; Knock-out; Lead; Life; Mammals; Mediating; Methodology; Methods; Molecular; Monitor; Mus; Parents; Pathway interactions; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Polyribosomes; Protein Biosynthesis; Proteins; Radiation; Radiation Tolerance; Regulation; Research; Resistance; Role; Russia; Science; Signal Transduction Pathway; Staging; System; Time; Tissues; Translation Initiation; Translation Process; Translations; United States National Institutes of Health; calmodulin-dependent protein kinase III; inhibitor/antagonist; novel; novel strategies; parent grant; prevent; professor; public health relevance; radiation resistance; research study

DESCRIPTION (provided by applicant): This research will be done primarily at the Institute of Protein Research, Russian Academy of Sciences, Puschino, Russia, in collaboration with professor A. S. Spirin as an extension of NIH grant No. RC1 AI078513. We have recently discovered a novel intracellular signal transduction pathway involved in the regulation of radiation sensitivity in mammals. This pathway is mediated by the elongation factor 2 kinase (eEF2K), a key regulator of global protein synthesis. We found that inactivation of this pathway in mice can confer resistance to the lethal effects of gamma radiation and also protects against radiation-induced hair graying and radiation- induced apoptosis in intestinal cells. The goal of the parent proposal is to characterize this novel signal transduction pathway and to develop new approaches that can be used to protect tissues particularly of gastrointestinal tract from radiation damage. In our preliminary experiments we found that downregulation of anti-apoptotic proteins FLIP and XIAP is blocked in cells lacking eEF2K, suggesting that phosphorylation of eEF2 by eEF2K stimulates radiation-induced apoptosis by inhibiting synthesis of short-lived anti-apoptotic proteins. We further provided evidence that eEF2K regulates expression of anti-apoptotic proteins at the level of translation. The goal of this proposal is to determine the molecular mechanism by which eEF2 phosphorylation controls translation of short-lived anti-apoptotic proteins. This will be achieved by using various cell-free translation systems and methods developed at the Institute of Protein Research by A. S. Spirin and his colleagues. PUBLIC HEALTH RELEVANCE: Translational control of radiation-induced apoptosis. We have recently found that inactivation of a protein synthesis regulator eEF2 kinase in mice can confer resistance to the lethal effects of gamma radiation and also protects against radiation-induced hair graying and radiation-induced apoptosis in intestinal cells. In our preliminary experiments we found that knockout of eEF2 kinase protects cells from radiation-induced apoptosis by preventing down-regulation of short-lived anti- apoptotic proteins. The goal of this proposal is to determine the molecular mechanism by which eEF2 kinase controls translation of short-lived anti-apoptotic proteins and therefore modulates radiation resistance. This research will be done in collaboration with the Institute of Protein Research, Russian Academy of Sciences, Puschino, Russia, in collaboration with professor A. S. Spirin as an extension of NIH grant No. RC1 AI078513.

描述（由申请人提供）：这项研究将主要在俄罗斯俄罗斯俄罗斯科学院的蛋白质研究所，俄罗斯与A. S. Spirin教授合作，作为NIH赠款编号RC1 AI078513的扩展。我们最近发现了一种新型的细胞内信号转导途径，涉及哺乳动物辐射敏感性的调节。该途径是由伸长因子2激酶（EEF2K）介导的，这是全球蛋白质合成的关键调节剂。我们发现，这种途径在小鼠中的失活可以赋予对伽马辐射的致命作用的抗性，还可以防止辐射引起的头发灰色和辐射诱导的肠细胞中的凋亡。父母建议的目的是表征这种新型的信号转导途径，并开发可用于保护组织，特别是胃肠道免受辐射损伤的新方法。在我们的初步实验中，我们发现抗凋亡蛋白的下调在缺乏EEF2K的细胞中被阻断，表明EEF2通过EEF2K磷酸化刺激了辐射诱导的凋亡，从而抑制短暂的抗蛋白质蛋白的合成。我们进一步提供了证据，表明EEF2K在翻译水平上调节抗凋亡蛋白的表达。该建议的目的是确定EEF2磷酸化控制短寿命抗凋亡蛋白的翻译的分子机制。这将通过使用A. S. Spirin及其同事在蛋白质研究所开发的各种无细胞翻译系统和方法来实现。 公共卫生相关性：辐射引起的凋亡的翻译控制。 我们最近发现，小鼠中蛋白质合成调节剂EEF2激酶的灭活可以赋予对伽马辐射的致命作用的抗性，并且还可以防止辐射诱导的头发灰色和辐射诱导的肠细胞凋亡。在我们的初步实验中，我们发现EEF2激酶的基因敲除通过防止短暂寿命抗凋亡蛋白的下调来保护细胞免受辐射诱导的凋亡。该建议的目的是确定EEF2激酶控制短寿命抗凋亡蛋白的翻译，从而调节辐射抗性的分子机制。这项研究将与俄罗斯俄罗斯俄罗斯科学院蛋白研究所合作，俄罗斯与A. S. Spirin教授合作，作为NIH Grant No. RC1 AI078513的扩展。