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The Role of HuR in mutant SOD1 dysregulation of VEGF mRNA Processing

HuR 在突变 SOD1 VEGF mRNA 加工失调中的作用

基本信息

批准号：
8101403
负责人：
PETER H KING
金额：
$ 1.76万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101403
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Abbreviations Address Affect Amino Acid Sequence Amyotrophic Lateral Sclerosis Antibodies Antioxidants Appearance Area Attenuated BRF1 gene Binding Cell Survival Cellular Stress Cessation of life Clinical Code Complex Cultured Cells Cuprozinc Superoxide Dismutase Cytoplasm Cytoplasmic Granules Dactinomycin Degenerative Disorder Disease Doxycycline EMSA Electrophoretic Mobility Shift Assay Elements Embryo Enzyme-Linked Immunosorbent Assay Enzymes Familial Amyotrophic Lateral Sclerosis Funding Gene Expression Gene Expression Regulation Genes Genetic Grant Growth Factor Half-Life IL8 gene Immunoprecipitation In Vitro Indium Interleukin-8 Interleukins Investigation Lead Ligands Link Location Maintenance Messenger RNA Methylation Modification Molecular Motor Neuron Disease Motor Neurons Mus Muscle Mutant Strains Mice Mutation Nature Neuroblastoma Neurodegenerative Disorders PTGS2 gene Paralysed Phenotype Phosphorylation Play Polyribosomes Post-Translational Protein Processing Process Progressive Disease Property Proteins Publishing RNA RNA Binding RNA Degradation RNA Processing RNA Recognition Motif RNA Splicing RNA-Binding Proteins RNA-Protein Interaction Regulation Ribonucleoproteins Role Spinal Cord Stress Superoxide Dismutase Symptoms TIS11 protein Tetanus Helper Peptide Tetracyclines Time Toxic effect Transcript Transgenic Mice Transgenic Organisms Translations Tumor Necrosis Factor-alpha Ubiquitination Untranslated Regions Vascular Endothelial Growth Factors Visual Work alpha-tocopherol transfer protein base butyrate response factor 1 copper zinc superoxide dismutase crosslink cyclooxygenase 2 effective therapy end stage disease gain of function genetic regulatory protein in vivo in vivo Model mRNA Expression mRNA Stability motor neuron degeneration mutant novel nucleocytoplasmic transport preference protein expression protein protein interaction public health relevance response superoxide dismutase 1 tissue/cell culture ultraviolet

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a catastrophic degenerative disease of motor neurons that inexorably leads to progressive weakness and death. Genetic depletion of vascular endothelial growth factor (VEGF) leads to selective degeneration of motor neurons, providing a direct link between VEGF and ALS. Furthermore, VEGF attenuates the phenotype of ALS mice expressing the copper-zinc superoxide dismutase (SOD)-1 mutation. Posttranscriptional regulation plays a critical role in VEGF expression, particularly under conditions of cellular stress, allowing an adaptive response to promote cell survival. We recently showed that mutant SOD1 disrupts VEGF posttranscriptional regulation, leading to a significant decline in RNA and protein expression. This finding supports the toxic gain of function hypothesis for SOD1-associated ALS. These initial observations, funded by an exploratory R21 grant and recently published (Lu et al., 2007), have led to three important findings that begin to delineate the mechanism for this toxic effect. First, we discovered that mutant SOD1 is capable of directly binding AU-rich elements (ARE) in the 3' untranslated region (3'UTR) of VEGF. These cis elements are critical for posttranscriptional regulation of VEGF through interaction with cellular factors. Second, we have found that mutant but not wild-type SOD1 associates with HuR, a major regulator of VEGF mRNA stability via the ARE. Third, mutant SOD1 leads to cytoplasmic translocation and posttranslational modification of HuR. Based on these findings, we hypothesize in this proposal that mutant SOD1 exerts its negative effect on VEGF mRNA processing by disrupting the normal regulatory function of HuR. We propose three specific aims: 1) To investigate the novel RNA binding property of mutant SOD1 and its negative effect on HuR. 2) To investigate whether mutant SOD1, through its protein-protein or protein-RNA interaction, disrupts the RNA stabilizing function of HuR, or increases the association of VEGF mRNA with translational silencers or RNA destabilizers. 3) To investigate how mutant SOD1 induces HuR translocation to the cytoplasm and its post-translational modification. The long term objective of this proposal is: a) to determine how mutant SOD1 disrupts VEGF posttranscriptional regulation and b) the impact of this novel function on the ALS phenotype. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis is a relentless disease of motor neurons that leads to progressive paralysis of the muscles and ultimately death. There is no cure for this disease or any mitigating therapy. This proposal will address a novel area of growth factor regulation that may contribute to the cause of this disease, and thus may ultimately lead to novel therapies.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种运动神经元的灾难性退行性疾病，可无情地导致进行性虚弱和死亡。血管内皮生长因子（VEGF）的基因缺失导致运动神经元的选择性变性，提供了VEGF和ALS之间的直接联系。此外，VEGF减弱表达铜锌超氧化物歧化酶（SOD）-1突变的ALS小鼠的表型。转录后调节在VEGF表达中起关键作用，特别是在细胞应激条件下，允许适应性反应以促进细胞存活。我们最近发现突变的SOD 1破坏了VEGF的转录后调控，导致RNA和蛋白质表达的显著下降。这一发现支持SOD 1相关ALS的毒性功能获得假说。这些最初的观察，由探索性R21赠款资助，最近发表（Lu等人，2007），已经导致了三个重要的发现，开始描绘这种毒性作用的机制。首先，我们发现突变体SOD 1能够直接结合VEGF的3'非翻译区（3' UTR）中的富含AU的元件（ARE）。这些顺式元件通过与细胞因子相互作用对VEGF的转录后调节至关重要。其次，我们发现突变型而非野生型SOD 1与HuR相关，HuR是通过ARE调节VEGF mRNA稳定性的主要调节因子。第三，突变的SOD 1导致HuR的胞质易位和翻译后修饰。基于这些发现，我们假设突变的SOD 1通过破坏HuR的正常调节功能对VEGF mRNA的加工产生负面影响。我们提出了三个具体的目标：1）研究突变SOD 1的新的RNA结合特性及其对HuR的负面影响。2)研究突变体SOD 1是否通过其蛋白质-蛋白质或蛋白质-RNA相互作用破坏HuR的RNA稳定功能，或增加VEGF mRNA与翻译沉默因子或RNA不稳定因子的相关性。3)研究突变体SOD 1如何诱导HuR向细胞质转运及其翻译后修饰。该提议的长期目标是：a）确定突变SOD 1如何破坏VEGF转录后调节和B）这种新功能对ALS表型的影响。公共卫生相关性：肌萎缩侧索硬化症是一种无情的运动神经元疾病，导致肌肉进行性瘫痪，最终死亡。这种疾病无法治愈，也没有任何缓解疗法。这项提案将解决一个新的领域的生长因子调节，可能有助于这种疾病的原因，从而可能最终导致新的疗法。