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（通过应用程序提供）：染色体复制和传播对于遗传性状的遗传至关重要，但是在多细胞真核生物中，负责这些过程的机制仍然很少理解。动孔形成需要丝粒，这是有丝分裂和减数分裂过程中纺锤体的关键附着位点。 Centromere或Kinetochore功能的缺陷导致非整倍性，这是人类癌症的标志，并且负责许多先天缺陷。当今Centromere领域的一个紧迫性问题是，在多细胞真核生物中，Centromere身份如何在一代中传播到另一代。我们发表的未发表的结果表明，丝粒染色质蛋白及其调节剂的水平受到基因表达和蛋白水解机制的严格调节，以确保忠实的centromere和染色体传播。该建议将遗传，分子，细胞生物学和生化方法整合在一起，以鉴定调节丝粒染色质蛋白水平的分子和机制，并使用果蝇细胞培养和动物组织促进室染色质的组装和传播。进入丝粒染色质的入口点是组成的组蛋白H3样蛋白（CENP-A，CID，FLIES中的CID），该蛋白仅本地定位在功能性centromeres中。我们先前鉴定了CENP平局和组装的关键调节剂，以及细胞周期调节与丝粒形成之间的联系，这为所提出的目标提供了智力和技术基础。该提案的具体重点是阐明通过研究：1）相互保护和其他机制如何调节CID及其伴侣CAL1的稳定性如何调节中心蛋白稳定性的细胞周期调节以及不调节的后果，2）丝粒蛋白质错误调节对细胞，组织和生物体的影响，以及3）在癌症中的中性蛋白质造成癌症造成癌症的疾病和进展的影响。对这些研究产生的丝粒组件的正常调节的更深入了解将提供有关这种基本生物学过程的基本信息，对负责与癌症相关的非整倍性病因的机制的见解和与癌症相关的方法，并最终将导致开发与Centromere Defects诊断和治疗的工具，以开发与Centromere Defects相关的工具。