Centrosome biogenesis and copy number control

中心体生物发生和拷贝数控制

• 批准号: 10582649
• 负责人: Brendan Cormack
• 金额: $ 33.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582649
• 关键词: Animals; Binding; Biochemistry; Biogenesis; Biological; Cell Cycle Regulation; Cell Proliferation; Cell division; Cell physiology; Cells; Cellular Structures; Centrioles; Centrosome; Chromosomes; Cilia; Competence; Continuous Positive Airway Pressure; Creativeness; Cytoskeleton; Defect; Disease; Ensure; Functional disorder; G1 Phase; G2 Phase; Gene Expression; Genome; Goals; Growth; Health; Homeostasis; Human; Interphase; Liquid substance; Locomotion; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Microcephaly; Microtubules; Mitosis; Mitotic spindle; Molecular; Movement; Mus; Noise; Open Reading Frames; Organelles; PLK1 gene; Phosphorylation; Phosphorylation Site; Play; Procentriole; Proteins; Regulation; Research; Role; Signal Transduction; Structure; Testing; Translational Regulation; Translations; Variant; Work; daughter cell; gene replacement; genetic approach; human disease; imaging approach; insight; kinetosome; protein degradation; recruit; scaffold; tumorigenesis

Project Summary The long-term goal of our lab is to understand the molecular mechanisms that control centriole duplication and ensure the accurate distribution of the genome during cell division. Centrioles form the core of centrosomes, which organize the interphase microtubule cytoskeleton of most animal cells and form the poles of the mitotic spindle. Centrioles can also be modified to form basal bodies, which template the formation of cilia and play central roles in cellular signaling, fluid movement, and locomotion. To coordinate these diverse cellular processes, centriole copy number must be precisely controlled. Cells begin G1 phase with two centrioles, which are duplicated during S/G2 phase and are then carefully partitioned into both daughter cells during mitosis. We and others have shown that extra centrioles cause cell division errors that are sufficient to drive malignant transformation. Understanding the mechanism by which cells achieve the once per cycle duplication of the centrioles is, therefore, an important fundamental question of considerable relevance to human health. Although significant progress has been made in understanding the composition of centrioles, it remains unclear which specific steps in centriole formation are controlled by the enzymatic regulator Polo-like-kinase 4 (PLK4). Equally unclear is how a critical regulatory step, termed the ‘centriole-to-centrosome conversion’ (CCC), functions to maintain centriole homeostasis by enabling new centrioles to acquire competence for duplication. Our proposed research seeks to capitalize on our identification of key interactions and contributors to centriole formation to elucidate molecular mechanisms that control centriole assembly. We will examine three independent components of centriole biogenesis control: the translational regulation of PLK4 expression, the impact of PLK4 phosphorylation of specific substrates in centriole assembly, and the function of a new component required for the CCC. Aim 1 will define how a pair of conserved upstream open reading frames in the PLK4 mRNA regulate critical aspects of PLK4 expression. Aim 2 will mechanistically dissect how a critical PLK4 phosphorylation site we identified on STIL controls centriole assembly. Finally, Aim 3 will define how a new centriole protein, PPP1R35, functions to promote the CCC. Understanding how centriole assembly is regulated will reveal fundamental principles of organelle homeostasis and provide insight into the molecular basis of human diseases caused by centriole dysfunction.

项目摘要 我们实验室的长期目标是了解控制中心复制和的分子机制 确保细胞分裂过程中基因组的准确分布。中心形成中心体的核心， 它组织了大多数动物细胞的相间微管细胞骨架，并形成有丝分裂的杆子 主轴。也可以修改中心元素以形成基本物体，这些物体模板是纤毛的形成和播放 在细胞信号传导，流体运动和运动中的中心作用。协调这些潜水的细胞 过程，中心拷贝号必须精确控制。细胞从两个中心元素开始G1相， 在S/G2阶段重复的，然后在 有丝分裂。我们和其他人表明，额外的中心元素会导致细胞分裂错误，足以驱动 恶性转化。了解细胞实现每个周期重复一次的机制 因此，中心群是与人类健康相关的重要基本问题。 尽管在理解中心元素的组成方面取得了重大进展，但仍不清楚 中心形成中哪些特定步骤由酶调节剂Polo-like-kinase 4（PLK4）控制。 同样不清楚的是，关键的监管步骤是如何称为“中心到中心转换”（CCC）， 通过使新的Centrioles获得重复的能力来维持中心稳态的功能。 我们拟议的研究旨在利用我们对关键互动的识别和中心的贡献者 格式以阐明控制中心装配的分子机制。我们将检查三个 中心生物发生控制的独立成分：PLK4表达的翻译调节， Centriole组装中特定底物的PLK4辐射的影响，以及新的功能 CCC所需的组件。 AIM 1将定义一对构成上游的开放式阅读帧 PLK4 mRNA调节PLK4表达的临界方面。 AIM 2将机械地剖析如何关键 PLK4磷酸化位点我们在stil控制中心装配中鉴定出来。最后，AIM 3将定义如何 新的Centriole蛋白PPP1R35功能促进CCC。了解中心装配方式 受管制的人会揭示细胞器稳态的基本原理，并提供有关分子的洞察力 由中心功能障碍引起的人类疾病的基础。