Chromosome Movement in Prometaphase

前中期染色体运动

• 批准号: 7926951
• 负责人: GARY J. GORBSKY
• 金额: $ 40.34万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926951
• 关键词: Algorithms; Anaphase; Antibodies; Antineoplastic Agents; Area; Binding Proteins; Cell Cycle; Cell Cycle Regulation; Cell Extracts; Cell Nucleus; Cell division; Cells; Chromosome Segregation; Chromosomes; Code; Complex; Congenital Abnormality; Cyclins; Cytoplasm; Cytoplasmic Organelle; Data; Disease; Ensure; Enzymes; Equilibrium; Event; Funding; Genes; Goals; Human Genome; Intervention; Investigation; Kinetochores; Life; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Meta-Analysis; Metaphase; Microtubules; Mitosis; Mitotic; Mitotic spindle; Mitotic/Spindle Checkpoint; Movement; Mutate; Names; Normal Cell; Normal Statistical Distribution; Nuclear; Nuclear Envelope; Open Reading Frames; Paclitaxel; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Prometaphase; Prophase; Proteins; Publishing; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Time; Troglodytinae; Ubiquitin; aurora-A kinase; cancer cell; cancer therapy; chromosome movement; enzyme activity; human disease; improved; interest; molecular mechanics; novel; overexpression; public health relevance; response; segregation; text searching

DESCRIPTION (provided by applicant): The long term objectives of this project are to understand the mechanisms that regulate chromosome movement and cell cycle control in mitosis. Balanced chromosome segregation in mitosis occurs through complex spatial and temporal regulation of enzyme activities, particularly kinases, phosphatases and enzymes of the ubiquitin cascade. Mitosis also involves highly dynamic and structural reorganization of nuclear and cytoplasmic organelles. Of particular interest in this project are the molecular mechanics of chromosome attachment to and movement on the microtubules of the mitotic spindle. The other main focus is cell cycle control of enzyme activities and their consequences for regulating mitotic progression and the mitotic spindle checkpoint. The mitotic spindle checkpoint is essential in ensuring the normal distribution of chromosomes. It is often defective in cancer cells and it plays a key role in the response of cells to therapeutic anti-cancer drugs such as paclitaxel. The current proposal consists of three aims. Two of the aims are focused on characterization of an entirely novel protein called Kinetochore Protein 1 (Kinp1). Preliminary data indicate that Kinp1 plays an essential role in normal microtubule-kinetochore attachment and/or in regulation of the mitotic spindle checkpoint. The other aim is focused on the general role of nuclear envelope integrity in controlling early events in mitosis. Accomplishing the goals proposed will add significantly to our understanding of cell cycle control of cell division in normal cells and contribute toward understanding how these controls become aberrant in chromosomal imbalances that contribute to human disease such as birth defects and cancer. PUBLIC HEALTH RELEVANCE: This project seeks to define novel aspects of the regulation of cell division in normal and cancer cells. Many of the control mechanisms in cancer cells are abnormal in cancer and these differences provide opportunities to target cancer cells specifically with new therapies. This project will also help us to understand how many current cancer therapies target cells and thus how these therapies can be improved. The results from this study will also enlighten the mechanisms that contribute to chromosome imbalances that are the cause of many birth defects.

描述（由申请人提供）：本项目的长期目标是了解有丝分裂中调节染色体运动和细胞周期控制的机制。有丝分裂中的平衡染色体分离通过酶活性的复杂空间和时间调节而发生，特别是激酶、磷酸酶和泛素级联的酶。有丝分裂还涉及核和细胞质细胞器的高度动态和结构重组。在这个项目中特别感兴趣的是染色体附着和有丝分裂纺锤体微管上的运动的分子力学。另一个主要焦点是酶活性的细胞周期控制及其调节有丝分裂进程和有丝分裂纺锤体检查点的后果。有丝分裂纺锤体检查点是确保染色体正常分布的关键。它通常在癌细胞中有缺陷，并且在细胞对治疗性抗癌药物（如紫杉醇）的反应中起关键作用。目前的建议包括三个目标。其中两个目标是集中在一个全新的蛋白质称为动粒蛋白1（Kinp 1）的表征。初步数据表明，Kinp 1在正常的微管-动粒附着和/或有丝分裂纺锤体检查点的调节中起着至关重要的作用。另一个目的是集中在核膜完整性在控制有丝分裂早期事件的一般作用。实现所提出的目标将大大增加我们对正常细胞中细胞分裂的细胞周期控制的理解，并有助于理解这些控制如何在染色体不平衡中变得异常，从而导致人类疾病，如出生缺陷和癌症。公共卫生相关性：该项目旨在定义正常细胞和癌细胞中细胞分裂调节的新方面。癌细胞中的许多控制机制在癌症中是异常的，这些差异为用新疗法特异性靶向癌细胞提供了机会。该项目还将帮助我们了解目前有多少癌症疗法靶向细胞，从而如何改进这些疗法。这项研究的结果也将启发染色体不平衡的机制，这是许多出生缺陷的原因。