Chromosome Movement in Prometaphase

描述(申请人提供)：这个项目的长期目标是了解有丝分裂中染色体运动和细胞周期控制的调节机制。有丝分裂中平衡的染色体分离是通过对酶活性的复杂的时空调节来实现的，特别是泛素级联的激酶、磷酸酶和酶。有丝分裂还涉及核质细胞器的高度动态和结构重组。这个项目特别感兴趣的是染色体附着在有丝分裂纺锤体微管上和在微管上运动的分子力学。另一个主要焦点是细胞周期对酶活性的控制及其对有丝分裂进程和有丝分裂纺锤体检查点的影响。有丝分裂纺锤体检查点对于确保染色体的正常分布是必不可少的。它在癌细胞中通常是有缺陷的，在细胞对紫杉醇等治疗抗癌药物的反应中发挥着关键作用。目前的建议包括三个目标。其中两个目标集中在一种全新的名为Kinetochore Protein 1(Kinp1)的蛋白质的特征上。初步数据表明，Kinp1在正常的微管-动粒连接和/或有丝分裂纺锤体检查点的调节中起着重要的作用。另一个目标集中在核膜完整性在控制有丝分裂早期事件中的一般作用。完成所提出的目标将大大增加我们对正常细胞细胞分裂的细胞周期控制的理解，并有助于理解这些控制是如何在导致人类疾病(如出生缺陷和癌症)的染色体失衡中变得异常的。公共卫生相关性：该项目寻求定义正常细胞和癌细胞中细胞分裂调控的新方面。癌细胞中的许多控制机制在癌症中是异常的，这些差异为针对癌细胞的新疗法提供了机会。该项目还将帮助我们了解目前有多少癌症疗法针对细胞，从而了解如何改进这些疗法。这项研究的结果还将揭示导致染色体失衡的机制，而染色体失衡是许多出生缺陷的原因。

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.