Spinocerebellar ataxia 7 protein function

脊髓小脑共济失调7蛋白功能

• 批准号: 7617227
• 负责人: PATRICK A GRANT
• 金额: $ 32.94万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617227
• 关键词: Acetylation; Acetyltransferase; Address; Affect; Alleles; Ataxia; Biochemical; Biological Assay; Biological Models; CAG repeat; Cancer Etiology; Cell Line; Cell Nucleus; Cerebellum; Chromatin; Clinical; Code; Complement; Complex; Coupling; Defect; Deletion Mutation; Disease; Disease Progression; Enzymes; Epitopes; Eukaryota; Eukaryotic Cell; Family; Functional disorder; Gene Expression Regulation; Genes; Goals; Grant; Growth; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Homologous Gene; Human; Huntington Disease; Immunoblotting; Investigation; Knockout Mice; Mammalian Cell; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neurons; Nuclear Hormone Receptors; Nucleosomes; Oncogene Proteins; Orthologous Gene; Pathogenesis; Pathology; Phenotype; Physiological; Play; Proteins; Purkinje Cells; RNA Polymerase II; Regulation; Research; Research Personnel; Research Project Grants; Retina; Retinal Defect; Role; SCA7 protein; Saccharomyces cerevisiae; Silver Staining; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Trinucleotide Repeats; Tumor Suppressor Proteins; Type 7 Spinocerebellar Ataxia; Virus Diseases; Yeasts; base; cell type; chromatin immunoprecipitation; chromatin modification; dosage; effective therapy; expression vector; histone acetyltransferase; histone modification; human disease; immunoaffinity chromatography; insight; leukemia; mouse model; mutant; nervous system disorder; polyglutamine; programs; promoter; protein complex; protein function

DESCRIPTION (provided by applicant): In the eukaryotic cell nucleus, DMA is packaged by histones into nucleosomes, the repeating subunits of chromatin. The regulation of gene expression from chromatin involves the action of chromatin modifying activities including histone acetlytransferases (HATs). HAT enzymes are frequently associated with large multiprotein coactivator complexes that contain other transcriptional regulators. These observations have provided a direct molecular basis for the coupling of histone acetylation and the regulation of transcription. HAT proteins are known to associate with cellular oncoproteins and tumor suppressor proteins and have been described in certain translocations associated with leukemias and thus have been postulated to play a central role in the etiology cancer as well as viral infection and nuclear hormone receptor action. SAGA (Spt- Ada-Gcn5 Acetyltransferase) and SLIK (SAGA-Like) are 2 homologous and highly conserved multi-subunit HAT complexes that were originally identified in Saccharomyces cerevisiae. We have identified the protein Sgf73/ySca7, a homologue of the human protein ataxin-7, as a component of SAGA and SLIK. In its pathological form, this protein is responsible for the neurodegenerative disease spinocerebellar ataxia 7 (SCA7). Yeast Sca7 is necessary for the integrity and function of both SAGA and SLIK and a polyglutamine expanded version of human Sca7 assembles a SAGA complex that is specifically deficient in nucleosome acetylation. These observations have significant implications for the function of the human Sca7 protein in disease pathogenesis. The goals of this proposal are to use yeast, mammalian cell lines and mice as models to elucidate the mechanism behind the pathology of the SCA7 disorder. The Specific Aims are to determine the function of Sca7 protein, to examine the biochemical consequences of polyglutamine expansion on function of the SAGA family of complexes in histone modification and transcriptional regulation and test the hypothesis that depletion of GCN5 function in the CMS and retina contributes to SCA7 pathology in a mouse model. By identifying the physiological roles of these proteins it may be possible to gain insight as to how pathological alleles coding for proteins with polyglutamine tracts promote disease progression. Furthermore we aim to investigate the use of histone deacetylase inhibitors for the treatement of cellular dysfunction as a consequence SCA7 expansion. This, in turn, may suggest possible therapeutic treatments for this and other trinucleotide repeat diseases, such as Huntington's disease.

描述（由申请人提供）：在真核细胞核中，DMA被组蛋白包装到核小体（染色质的重复亚基）中。从染色质的基因表达的调节涉及染色质修饰活性的作用，包括组蛋白乙酰转移酶（HAT）。HAT酶通常与含有其他转录调节因子的大的多蛋白共激活因子复合物相关。这些结果为组蛋白乙酰化与转录调控的偶联提供了直接的分子基础。已知HAT蛋白与细胞癌蛋白和肿瘤抑制蛋白相关，并且已经在与白血病相关的某些易位中进行了描述，因此已经假定HAT蛋白在癌症的病因学以及病毒感染和核激素受体作用中起中心作用。佐贺（Spt-Ada-Gcn 5 Acetyltransferase）和SLIK（SAGA样）是最初在酿酒酵母（Saccharomycescerevisiae）中鉴定的两种同源且高度保守的多亚基HAT复合物。我们已经确定了蛋白Sgf 73/ySca 7，人类蛋白共济失调蛋白-7的同源物，作为佐贺和SLIK的组成部分。在其病理形式中，这种蛋白质负责神经退行性疾病脊髓小脑共济失调7（SCA 7）。酵母Sca 7对于佐贺和SLIK两者的完整性和功能是必需的，并且人Sca 7的多聚谷氨酰胺扩增形式组装核小体乙酰化特异性缺陷的佐贺复合物。这些观察结果对人类Sca 7蛋白在疾病发病机制中的功能具有重要意义。该提案的目标是使用酵母，哺乳动物细胞系和小鼠作为模型来阐明SCA 7疾病病理学背后的机制。具体目的是确定Sca 7蛋白的功能，检查多聚谷氨酰胺扩增对佐贺家族复合物在组蛋白修饰和转录调节中的功能的生化后果，并测试CMS和视网膜中GCN 5功能缺失导致小鼠模型中的SCA 7病理的假设。通过鉴定这些蛋白质的生理作用，有可能深入了解编码具有多聚谷氨酰胺束的蛋白质的病理等位基因如何促进疾病进展。此外，我们的目的是研究使用组蛋白去乙酰化酶抑制剂来缓解SCA 7扩增导致的细胞功能障碍。反过来，这可能表明这种疾病和其他三核苷酸重复疾病，如亨廷顿氏病的可能治疗方法。