CENTROSOME-NUCLEAR LINKS AND CANCER

中心体-核链接与癌症

• 批准号: 7055028
• 负责人: STEPHEN J DOXSEY
• 金额: $ 13.26万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7055028
• 关键词: centrosome; dynein ATPase; human; neoplasm /cancer; proteins

Centrosomes are involved in mitotic spindle organization and an increasing number of other fundamental cellular processes. Defects in centrosomes contribute to spindle defects, chromosome missegregation and aneuploidy. Recent work initially from our labraotory and one other showed that centrosome defects are a characteristic feature of human tumors. The long-term goal of our laboratory is to gain insight into the function of centrosomes and centrosome proteins in fundamental cellular processes and human cancer, toward this goal, we recently discovered that the centrosome protein pericentrin interacts with proteins of the nucleosome remodeling and deacetylase (NuRD) complex. Our preliminary results show that NuRD complex components are at the centrosome and that alteration of their levels affects centrosome integrity, spindle organization and genetic stability. We unexpectedly found that pericentrin localizes to the nucleus and that functional abrogation of pericentrin has dramatic effects on nuclear structure. We have also shown that pericentrin induces the formation of multipolar spindles when elevated in cells and mislocalizes dynein from spindles. Other work confirms that loss of dynein from mitotic spindles induces multipolarity and shows that re-establishing dynein binding to spindles results in clustering of spindle poles and restoration of spindle bipority. Based on these observations we propose three specific aims: Aim 1. To determine the mechanism of centrosome disruption and spindle dysfunction in cells with abrogated NuRD components. Aim 2. To determine the mechanism of nuclear disruption and functional changes in nuclei following abrogation of pericentrin function. Aim 3. To restore spindle bipolarity in tumor cells that have multipolar spindles and elevated levels of pericentrin as was accomplished in tumor cells overexpressing another dynein-interacting protein, NuMA. If successful this work will increase our basic understanding of centrosomes and centrosome proteins. In addition, it will provide information on how cells develop genetic changes that accompany human tumorigenesis. This could prove useful in cancer diagnosis and prognosis, and provide new targets for designing cancer therapeutics.

中心体参与有丝分裂纺锤体的组织和越来越多的其他基本的 细胞过程中心体缺陷导致纺锤体缺陷、染色体错误分离， 非整倍性最近的工作最初来自我们的实验室和另一个实验室，表明中心体缺陷是一个重要的遗传因素。 人类肿瘤的特征。我们实验室的长期目标是深入了解 中心体和中心体蛋白在基本细胞过程和人类癌症中的功能， 为了实现这一目标，我们最近发现中心体蛋白pericentrin与 核小体重塑和脱乙酰酶（NuRD）复合物。我们的初步结果表明，NuRD 复杂成分位于中心体，它们水平的改变影响中心体的完整性， 纺锤体组织和遗传稳定性。我们意外地发现中心周蛋白定位于细胞核 并且中心周围蛋白的功能性废除对核结构具有显著影响。我们还表明 当在细胞中升高时，中心周蛋白诱导多极纺锤体的形成，并使动力蛋白错误定位， 从Spindles。其他的研究证实，有丝分裂纺锤体中动力蛋白的丢失诱导了多极化， 重新建立动力蛋白与纺锤体的结合导致纺锤体极的聚集和纺锤体的恢复， 双孔性根据这些意见，我们提出三个具体目标： 目标1.为了确定细胞中中心体破坏和纺锤体功能障碍的机制， 废除了NuRD组件。 目标2.为了确定核破裂的机制和核功能的变化， 去除中心周围蛋白的功能。 目标3。为了恢复具有多极纺锤体和高水平的 在过度表达另一种动力蛋白相互作用蛋白NuMA的肿瘤细胞中完成。 如果成功的话，这项工作将增加我们对中心体和中心体蛋白的基本了解。在 此外，它还将提供有关细胞如何发展伴随人类的遗传变化的信息。 肿瘤发生这可以证明在癌症诊断和预后中是有用的，并为癌症的治疗提供新的靶点。 设计癌症疗法