CENTROSOME FUNCTION IN TUMOR CELLS

肿瘤细胞的中心体功能

• 批准号: 6580358
• 负责人: STEPHEN J DOXSEY
• 金额: $ 10.37万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580358
• 关键词: aneuploidy; breast neoplasms; centrosome; dynein ATPase; enzyme activity; gene targeting; genetically modified animals; immunofluorescence technique; laboratory mouse; microtubule associated protein; neoplasm /cancer genetics; p53 gene /protein; tubulin

The long term objective of this work is to understand how centrosomes contribute to tumorigenesis. Centrosomes are poorly understood organelles required for organization of mitotic spindles and accurate segregation of chromosomes during cell division. Thus, centrosomes are critical players in the redistribution and reorganization of the genome as it is assembled into nascent nuclei following mitosis. There is no other single cellular event that has a greater impact on the quantity, composition and organization of chromatin within the nucleus. We recently made the striking observation that malignant tumors had increased levels of the centrosome protein pericentrin, abnormal centrosomes, aberrant mitotic spindles and missegregated chromosomes. Moreover, artificial elevation of pericentrin in normal cells induced nearly identical features including aneuploidy, a condition linked to tumor malignancy, metastasis and fatality. Pericentrin over-expression also appeared to abrogate the mitotic checkpoint that normally induces mitotic arrest in the presence of unattached chromosomes. Over- expressed pericentrin bound and mislocalized cytoplasmic dynein, a molecular motor known to function in spindle organization and possibly checkpoint control. Based on these observations, we propose a model in which centrosome defects contribute to tumorigenesis by causing improper segregation of the genome and creating aneuploid cells. The discovery of centromsomes as potential contributors to malignant tumor progression provides us with a unique opportunity to elucidate a novel mechanism for tumorigenesis. The specific aims of this proposal are: 1. To determine whether proteins of the centrosome and nucleus are altered in tumors. 2. To test whether pericentrin has oncogenic potential. 3. To determine how elevated levels of pericentrin cause aneuploidy.

这项工作的长期目标是了解中心体是如何