Role of PTEN in Mitosis and Chromosome Stability

PTEN 在有丝分裂和染色体稳定性中的作用

• 批准号: 9311230
• 负责人: WEN H. SHEN
• 金额: $ 33.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311230
• 关键词: Affect; Anaphase; Animal Model; Architecture; Behavior; Biochemical; Biological Models; Cancer Patient; Cells; Centromere; Chromatin; Chromosomal Instability; Chromosomal Stability; Chromosome Segregation; Chromosome abnormality; Chromosomes; Complex; Coupled; DNA; DNA biosynthesis; Data; Development; Elements; Ensure; Environment; Epigenetic Process; Evolution; Exhibits; Failure; Functional disorder; Gene Mutation; Genes; Genetic; Genetic Materials; Genetic Processes; Genetic Transcription; Genome; Genome Stability; Goals; Histones; Impairment; In Vitro; Kinetochores; Knowledge; Laboratories; Maintenance; Malignant Neoplasms; Mediating; Metaphase; Mitosis; Mitotic; Mitotic Activity; Mitotic Chromosome; Mitotic spindle; Modification; Molecular and Cellular Biology; Mouse Strains; Mus; Mutation; Numerical Chromosomal Abnormality; Outcome; PTEN gene; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Physical condensation; Play; Polyploidy; Preventive Intervention; Process; Publishing; Regulation; Regulatory Element; Research; Role; Shapes; Signal Pathway; Signal Transduction; Testing; Therapeutic Intervention; Transgenic Mice; Tumor Suppression; Tumor Suppressor Proteins; Tweens; Work; base; chromatin remodeling; design; driving force; effective therapy; epigenome; high resolution imaging; in vivo Model; innovation; knockin animal; novel; personalized cancer therapy; precision medicine; prevent; repaired; segregation; spatiotemporal; targeted treatment; transmission process; tumor

Role of PTEN in Mitosis and Chromosome Stability Project Summary The chromatin environment shapes DNA-based processes and recent studies reveal that the PTEN tumor suppressor con- trols both DNA duplication/segregation and chromatin remodeling. A fundamental question is how PTEN mediates the interplay between the genome and the epigenome to ensure faithful transmission of genetic materials. Our long-term goal is to illuminate the function of PTEN in maintaining mitotic chromosome stability and to understand why this function is a major driving force in tumor suppression. The overall objective of this project is to identify critical regulatory elements in both mitosis-intrinsic machinery and global chromatin architecture that work together under the control of PTEN to promote mitotic fidelity. In support of this goal, our recent studies show that depletion of PTEN results in spindle shorten- ing and pole fragmentation, accompanied by misalignment and non-disjunction of chromosomes, leading to catastrophic mitotic failure and polyploidy. These observations suggest that PTEN is directly involved in mediating the interaction be- tween chromosomes and the mitotic spindle. In addition, metaphase cells lacking PTEN exhibit prominent chromosome entanglement, centromere breakage, and acentric anaphase bridges, indicating structural chromosome instability likely due to impaired chromatin architecture. Interestingly, our published data demonstrate that PTEN regulates histone anchor- age and modification on chromatin and thereby affects the chromatin compaction status. These results collectively support our hypothesis that PTEN maintains structural and numerical chromosome stability by coordinating mitotic chromatin compaction and mitotic spindle assembly for proper chromosome alignment and segregation. We will test this hypothesis by pursuing two specific aims. In the first aim, we will demonstrate impairment of mitotic chromatin compaction and epi- genetic deregulation of kinetochore assembly as a prevailing phenotypic consequence of PTEN dysfunction. High- resolution imaging and biochemical approaches, in combination with knock-in animal models developed in our laborato- ry, will be used to analyze PTEN function in promoting mitotic chromatin condensation. In the second aim, we will delin- eate the mechanism underlying the functional interaction among interrelated PTEN pathways in governing spindle activity and chromosome behavior. Using a comprehensive set of cellular and molecular biology approaches, coupled with newly generated transgenic mouse strains, we will depict a PTEN-associated mitotic signaling network comprised of both struc- tural and functional regulatory elements that act in concert to guard the genome. Successful completion of these aims will fundamentally advance our mechanistic understanding of the multifaceted function of PTEN in mitosis and chromosome stability. Data from our studies will illustrate how PTEN deficiency triggers a deteriorative interaction between deregulat- ed mitotic machinery and unfavorable chromatin milieus, leading to structural and numerical chromosome aberrations. Newly discovered mitotic pathways and targets in this innovative project will contribute to precision medicine through tailoring targeted therapies based on the genetic and epigenetic signatures of each cancer patient.

PTEN在有丝分裂和染色体稳定性中的作用 项目摘要 染色质环境塑造了基于DNA的过程，最近的研究表明，PTEN肿瘤抑制因子抑制了DNA的表达。 拖拉DNA复制/分离和染色质重塑。一个根本的问题是PTEN是如何调节 基因组和表观基因组之间的相互作用，以确保遗传物质的忠实传递。我们的长期目标 目的是阐明PTEN在维持有丝分裂染色体稳定性中的作用，并了解为什么这一功能 是肿瘤抑制的主要驱动力。该项目的总体目标是确定关键的监管要素 在有丝分裂的内在机制和全球染色质结构中，它们在PTEN的控制下共同工作 促进有丝分裂的保真度。为了支持这一目标，我们最近的研究表明，PTEN的耗尽会导致纺锤体缩短- ING和极点断裂，伴随着染色体的错位和不分离，导致灾难性的 有丝分裂失败和多倍体。这些观察结果表明，PTEN直接参与了相互作用的调节。 在染色体和有丝分裂纺锤体之间。此外，缺乏PTEN的中期细胞显示出显著的染色体。 缠结、着丝粒断裂和无着丝粒后期桥，表明结构染色体可能不稳定 由于染色质结构受损。有趣的是，我们发表的数据表明，PTEN调节组蛋白锚- 老化和染色质的修饰，从而影响染色质的压缩状态。这些结果共同支持 我们的假设是PTEN通过协调有丝分裂染色质来维持染色体结构和数量的稳定性 紧凑和有丝分裂纺锤体组件，以实现适当的染色体排列和分离。我们将检验这一假设 通过追求两个具体目标。在第一个目标中，我们将展示有丝分裂染色质致密和表观损伤。 动粒组装的遗传去调控是PTEN功能障碍的主要表型结果。高- 分辨率成像和生化方法，结合我们实验室开发的敲打动物模型- RY，将用于分析PTEN在促进有丝分裂染色质凝聚中的作用。在第二个目标中，我们将删除- 研究相互关联的PTEN通路在调节纺锤体活动中的功能相互作用的机制 和染色体行为。使用一套全面的细胞和分子生物学方法，再加上新的 产生的转基因小鼠株系，我们将描绘一个与PTEN相关的有丝分裂信号网络，该网络由两个结构组成- 协同作用保护基因组的结构和功能调节元件。这些目标的成功实现将 从根本上促进我们对PTEN在有丝分裂和染色体中多方面功能的机制理解 稳定性。我们研究的数据将说明PTEN缺乏如何触发放松管制- ED有丝分裂机制和不利的染色质环境，导致染色体结构和数量上的异常。 在这个创新项目中新发现的有丝分裂途径和靶点将通过 根据每个癌症患者的基因和表观遗传特征量身定做靶向治疗。