Metabolic stress responses and eIF2 kinase GCN2

代谢应激反应和 eIF2 激酶 GCN2

• 批准号: 7414098
• 负责人: RONALD C WEK
• 金额: $ 33.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414098
• 关键词: Address; Amino Acids; Apoptosis; Binding; Caspase; Cell physiology; Cells; Cellular Stress; Condition; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Eating Behavior; Eating Disorders; Enzymes; Eukaryotic Initiation Factor-2; Family; Feedback; Gene Expression; Genes; Genetic; Genome; Histidine-tRNA Ligase; Human; In Vitro; Induction of Apoptosis; Luciferases; Malignant Neoplasms; Malnutrition; Mammals; Messenger RNA; Metabolic stress; Metabolism; Mitogen-Activated Protein Kinases; Multiple Myeloma; Mus; Neurologic Dysfunctions; Nucleic Acid Regulatory Sequences; Nutritional; Open Reading Frames; Oxidation-Reduction; Pathway interactions; Phosphorylation; Phosphotransferases; Prevention; Proteasome Inhibition; Proteasome Inhibitor; Protein Biosynthesis; Protein Kinase; Protein phosphatase; Regulation; Reporter; Resources; Role; Starvation; Stress; System; Transcript; Transfer RNA; Translations; Yeasts; biological adaptation to stress; cancer therapy; cell injury; deprivation; design; genetic regulatory protein; human disease; inhibitor/antagonist; insight; prevent; programs; repaired; response; transcription factor; ultraviolet irradiation

DESCRIPTION (provided by applicant): Environmental stresses elicit programs of gene expression designed to remedy cellular injury, or alternatively induce apoptosis. An important contributor to stress adaptation is a family of protein kinases that phosphorylate eukaryotic initiation factor -2 (elF2). This proposal is centered on the elF2 kinase GCN2 (EIF2AK4) that is activated in response to amino acid starvation, UV irradiation and proteasome inhibition. GCN2 phosphorylation of elF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress. Accompanying this general protein synthesis control, elF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP transcriptional regulator ATF4. ATF4 also induces the expression of additional transcription factors, ATF3 and CHOP/GADD153, that assist in expression of stress responsive genes. Reduced translation by elF2 phosphorylation can also activate NF-nB by lowering the steady state-levels of the labile IDB regulatory protein. While many of the genes induced by elF2 phosphorylation are shared between different environmental stresses, GCN2 functions in conjunction with other stress pathways, such as those regulated by MAP kinases, to elicit gene expression programs that are tailored for the specific stress condition. Our hypothesis is that GCN2 recognizes different stresses and facilitates gene expression that is important for ameliorating cellular damage and treating and preventing disease. Consistent with this idea, mice deleted for GCN2 show sensitivity to nutritional deficiencies and aberrant eating behaviors. In this proposal, we will characterize the mechanisms regulating GCN2 and its role in cellular repair and detoxification in response to environmental stress. We propose four aims. Aim 1 Characterize mechanisms activating GCN2 in response to diverse cellular stresses. Aim 2 Characterize the mechanisms regulating ATF4 translation in response to elF2 phosphorylation. Aim 3 Characterize the role of ATF3 in the elF2 kinase stress response. Aim 4 Characterize the role of GCN2 in anti-cancer treatment. Addressing these major questions will increase our understanding of the process of cellular adaptation to environmental stress and its role in the treatment and prevention of human diseases such as diabetes, neurological dysfunctions, eating disorders, and cancer.

描述（由申请人提供）：环境应力引起的基因表达程序旨在弥补细胞损伤或诱导凋亡。压力适应的一个重要因素是磷酸化真核起始因子-2（ELF2）的蛋白激酶家族。该提案以ELF2激酶GCN2（EIF2AK4）为中心，该提案因响应氨基酸饥饿，紫外线照射和蛋白酶体抑制而激活。 ELF2的GCN2磷酸化减少了全局翻译，使细胞能够保存资源并启动基因表达的重新配置以有效地管理压力。伴随着这种一般蛋白质合成控制的ELF2磷酸化诱导特定mRNA的翻译，例如编码BZIP转录调节剂ATF4的MRNA。 ATF4还诱导了其他转录因子ATF3和CHOP/GADD153的表达，从而有助于表达压力响应基因。 ELF2磷酸化减少的翻译还可以通过降低不稳定IDB调节蛋白的稳态水平来激活NF-NB。尽管不同的环境应力之间共享了许多由ELF2磷酸化诱导的基因，但GCN2的功能与其他应力途径（例如由MAP激酶调节的途径）结合使用，以引起针对特定应力条件量身定制的基因表达程序。我们的假设是，GCN2识别出不同的应力并促进基因表达，这对于改善细胞损伤以及治疗和预防疾病很重要。与这个想法一致，删除了GCN2的小鼠对营养缺乏症和异常饮食行为表现出敏感性。在此提案中，我们将表征调节GCN2的机制及其在响应环境压力时在细胞修复和排毒中的作用。我们提出了四个目标。 AIM 1表征了激活GCN2的机制，以响应各种细胞应激。 AIM 2表征调节ATF4翻译的机制，以响应ELF2磷酸化。 AIM 3表征了ATF3在ELF2激酶应力反应中的作用。 AIM 4表征GCN2在抗癌治疗中的作用。解决这些主要问题将增加我们对细胞适应环境压力的过程的理解及其在治疗和预防人类疾病（例如糖尿病，神经功能障碍，饮食失调和癌症）中的作用。