Translational Control by elF2 Kinase during ER Stress

ER 应激期间 eF2 激酶的翻译控制

• 批准号: 7476368
• 负责人: RONALD C WEK
• 金额: $ 26.55万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476368
• 关键词: Address; Antineoplastic Agents; Apoptosis; Biological Assay; Biological Models; Bypass; Caucasians; Caucasoid Race; Cell Survival; Cell physiology; Cellular Stress; Cellular Stress Response; Collection; Condition; Cultured Cells; Cytoprotection; DNA Damage; Diabetes Mellitus; Dimerization; Disease; Dysplasia; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Family; France; Gene Expression; Gene Targeting; Genes; Genetic Polymorphism; Genetic Transcription; Human; In Vitro; Indium; Insulin; Integral Membrane Protein; Kidney Diseases; Link; Liver; Liver diseases; MDM2 gene; MDM2 gene; Malignant Neoplasms; Mental Retardation; Messenger RNA; Metabolism; Missense Mutation; Molecular; Molecular Chaperones; Monitor; Mutation; Neonatal; Neurologic; Neurologic Dysfunctions; Nutrient; Open Reading Frames; Organelles; Oxidation-Reduction; PERK kinase; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Population; Process; Protein Biosynthesis; Protein Kinase; Range; Regulation; Research; Research Personnel; Resistance; Ribosomes; Role; Scanning; Stress; Stroke; TP53 gene; Transcription Coactivator; Translations; Wolcott-Rallison syndrome; Yeasts; biological adaptation to stress; bone; cell injury; cisplatin/etoposide protocol; deprivation; design; gene induction; genetic regulatory protein; human disease; mutant; neurological pathology; prevent; programs; protein misfolding; remediation; response; transcription factor; translation factor; ultraviolet irradiation

DESCRIPTION (provided by applicant): Cellular stresses such as accumulation of misfolded protein in the endoplasmic reticulum (ER stress), nutrient deprivation, UV irradiation, and oxidative damage induce a program of gene expression designed to alleviate cellular injury. An important contributor to stress gene expression is a family of protein kinases that phosphorylate eukaryotic initiation factor -2 (eIF2). Phosphorylation of eIF2 reduces the activity of this translation factor, leading to regulation of general protein synthesis and induced translation of mRNAs important for stress remediation. This proposal focuses on the eIF2 kinase, PEK (PERK, EIF2AK3), that is activated in response ER stress. PEK phosphorylation of eIF2 enhances cell viability in response to ER stress via activation of multiple transcription factors, including ATF4 and NF-KB, that direct expression of genes involved in stress remediation or apoptosis. An aberrant ER stress response is associated with a range of human diseases, including diabetes, bone and liver disorders, and circulatory and neurological pathologies. This proposal addresses the mechanisms regulating the program of stress-related gene expression in response to ER stress, and its role in disease. We propose four specific aims. Aim 1 Characterize PEK control of gene-specific translation in response to ER stress. We will determine whether translation reinitiation or alternative translation mechanisms are important for synthesis of regulatory proteins in the PEK response pathway. Aim 2 Characterize the role of eIF2 phosphorylation in the regulation of NF-KB activity. We will characterize the molecular mechanisms by which PEK activates NF-KB during ER stress and compare it to alternative NF-KB regulatory processes. Aim 3 Determine the role of eIF2 phosphorylation in cytoprotection against anti-cancer drugs. In this aim, we will explore the link between the eIF2 kinase and p53 stress pathways, and determine whether eIF2 phosphorylation contributes to resistance to anti-cancer drugs. Aim 4. Determine the functional consequences of PEK mutations identified in the human population. We will characterize the functional consequence of PEK missense changes derived from WRS patients or polymorphisms using mammalian cultured cells. Together, addressing these aims will increase our understanding of the process of cellular adaptation to environmental stresses and its impact in human disease.

描述（由申请人提供）：细胞应激，例如内质网中错误折叠蛋白的积累（ER应激），营养剥夺，紫外线照射和氧化损伤会导致旨在减轻细胞损伤的基因表达程序。胁迫基因表达的一个重要因素是磷酸化真核起始因子-2（EIF2）的蛋白激酶家族。 EIF2的磷酸化降低了该翻译因子的活性，从而导致一般蛋白质合成的调节和诱导的mRNA对压力修复重要的翻译。该提案着重于EIF2激酶PEK（PERK，EIF2AK3），该酶是在响应急剧应力中激活的。 EIF2的PEK磷酸化通过激活多种转录因子（包括ATF4和NF-KB）的激活来增强细胞活力，从而直接表达涉及应激修复或凋亡的基因。异常的ER应激反应与一系列人类疾病有关，包括糖尿病，骨骼和肝脏疾病以及循环系统和神经病理学。该提案探讨了调节应力相关基因表达程序的机制，以响应于ER应激及其在疾病中的作用。我们提出了四个具体目标。 AIM 1表征了PEK对基因特异性翻译的控制，以响应ER应激。我们将确定翻译重新引起或替代翻译机制对于佩克响应途径中调节蛋白的合成是否重要。 AIM 2表征了EIF2磷酸化在NF-KB活性调节中的作用。我们将表征PEK在ER应力期间激活NF-KB的分子机制，并将其与替代性NF-KB调节过程进行比较。 AIM 3确定EIF2磷酸化在针对抗癌药物的细胞保护中的作用。在此目标中，我们将探索EIF2激酶与p53应力途径之间的联系，并确定EIF2磷酸化是否有助于对抗癌药物的抗性。目标4。确定人口中鉴定出的PEK突变的功能后果。我们将表征使用哺乳动物培养的细胞从WRS患者或多态性产生的PEK错义变化的功能后果。共同解决这些目标将增加我们对细胞适应环境压力的过程及其对人类疾病的影响的理解。