Regulation of Centromere Protein Stability and Impact on Cancer Progression

着丝粒蛋白稳定性的调节及其对癌症进展的影响

基本信息

批准号：
9095795
负责人：
Gary H KARPEN
金额：
$ 52.09万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9095795
关键词：
Affect Aneuploidy Animals Binding Biochemical Biological Biological Process Cancer Diagnostics Cell Culture Techniques Cell Cycle Regulation Cell Death Cell division Cells Centromere ChIP-seq Chromatin Chromosome Segregation Chromosome abnormality Chromosomes Colonic Neoplasms Congenital Abnormality Cultured Cells DNA Sequence Defect Development Diagnosis Drosophila genus Drosophila melanogaster Ensure Epidermal Growth Factor Epidermal Growth Factor Receptor Etiology Euchromatin Eukaryota Foundations Functional disorder Gene Expression Generations Genetic Genome Genome Stability Genomic Instability Glioblastoma Glioma Goals Growth Heterochromatin Histone H3 Histones Human Hyperplasia In Vitro Individual Investigation Kinetochores Lead Link Liver neoplasms Malignant - descriptor Malignant Neoplasms Mammals Mammary Neoplasms Mediating Meiosis Mitosis Modeling Molecular Chaperones Molecular Genetics Mono-S Neoplasm Metastasis Neoplasms Nucleosomes Organism Pathway interactions Phenotype Phosphatidylinositols Phosphotransferases Play Positioning Attribute Process Protein Overexpression Proteins Proteolysis Publishing Receptor Activation Regulation Reproduction Role Signal Transduction Pathway Site Specific qualifier value Staging Structure System Tissues Ubiquitin-mediated Proteolysis Pathway Ubiquitination Work animal tissue base cancer diagnosis cancer initiation cancer therapy centromere protein A chromatin protein chromosome replication fly human disease imaginal disc insight overexpression public health relevance research study segregation tool tool development trait transcriptome transcriptome sequencing transmission process tumor progression ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Chromosome replication and transmission are essential for the inheritance of genetic traits, but the mechanisms responsible for these processes remain poorly understood in multicellular eukaryotes. The centromere is required for kinetochore formation, which serves as the key attachment site to the spindle during mitosis and meiosis. Defects in centromere or kinetochore function result in aneuploidy, which is a hallmark of human cancers and is responsible for many birth defects. A pressing question in the centromere field today is how centromere identity is propagated from one generation to the next in multicellular eukaryotes. Our published and unpublished results demonstrate that the levels of centromeric chromatin proteins and their regulators are tightly regulated by gene expression and proteolytic mechanisms to ensure faithful centromere and chromosome propagation. This proposal integrates genetic, molecular, cell biological and biochemical approaches to identify the molecules and mechanisms that regulate the levels of centromeric chromatin proteins, and promote the assembly and propagation of centromeric chromatin, using Drosophila cell culture and animal tissues. The entry point into centromeric chromatin is a conserved histone H3-like protein (CENP-A, CID in flies) that localizes exclusively to functional centromeres. We previously identified key regulators of CENP-localization and assembly, as well as a link between cell cycle regulation and centromere formation, which provide an intellectual and technical foundation for the proposed aims. The specific focus of this proposal is to elucidate the cell cycle regulation of centromeric protein stability and the consequences of misregulation by investigating: 1) how mutual protection and other mechanisms regulate the stability of CID and its chaperone CAL1, 2) the impact of centromere protein misregulation on cells, tissues and the organism, and 3) how centromere protein misregulation contributes to cancer initiation and progression in Drosophila model of glioblastoma. The deeper understanding of the normal regulation of centromere assembly generated by these studies will provide basic information about this essential biological process, insights into mechanisms responsible for the etiology of aneuploidy associated with cancer and birth defects, and ultimately will lead to the development of tools for diagnosis and treatment of human diseases associated with centromere defects, such as cancer.

描述（由申请人提供）：染色体复制和传递对于遗传性状的遗传至关重要，但在多细胞真核生物中，对这些过程的机制仍知之甚少。着丝粒是着丝粒形成所必需的，着丝粒是着丝粒的关键附着位点。有丝分裂和减数分裂过程中的纺锤体的着丝粒或着丝粒功能缺陷会导致非整倍性，这是人类癌症的一个标志，也是造成这种现象的原因。当今着丝粒领域的一个紧迫问题是，着丝粒身份如何在多细胞真核生物中从一代传播到下一代。我们已发表和未发表的结果表明，着丝粒染色质蛋白及其调节因子的水平受到基因的严格调控。该提案整合了遗传、分子、细胞生物学和生化方法来识别调节着丝粒和染色体水平的分子和机制。着丝粒染色质蛋白，并使用果蝇细胞培养物和动物组织促进着丝粒染色质的组装和增殖。着丝粒染色质的入口点是一种保守的组蛋白 H3 样蛋白（CENP-A，果蝇中的 CID），该蛋白专门定位于功能性。我们之前确定了 CENP 定位和组装的关键调节因子，以及细胞周期调节和着丝粒形成之间的联系，这提供了一个智力模型。该提案的具体重点是阐明拟议目标的技术基础。着丝粒蛋白稳定性的细胞周期调节以及失调的后果，通过研究：1) 相互保护和其他机制如何调节 CID 及其分子伴侣 CAL1 的稳定性，2) 着丝粒蛋白失调对细胞、组织和生物体的影响，以及3）着丝粒蛋白的失调如何导致胶质母细胞瘤果蝇模型中癌症的发生和进展。这些研究产生的对着丝粒组装正常调节的更深入了解将提供有关这些研究的基本信息。这一重要的生物学过程，对与癌症和出生缺陷相关的非整倍体病因学机制的深入了解，最终将导致开发出用于诊断和治疗与着丝粒缺陷相关的人类疾病（例如癌症）的工具。