CENTROSOME FUNCTION IN TUMOR CELLS

这项工作的长期目标是了解中心体如何 有助于肿瘤发生。对中心体的了解很少 有丝分裂纺锤体的组织所需的细胞器和准确的 细胞分裂时染色体的分离。因此， 基因组重新分配和重组的关键参与者， 在有丝分裂后组装成新生核。没有其他 对数量有较大影响的单个细胞事件， 细胞核内染色质的组成和组织。我们 最近有一个惊人的观察， 中心体蛋白pericentrin水平升高，异常 中心体、异常的有丝分裂纺锤体和错误分离的染色体。 此外，人工升高正常细胞中的中心周蛋白诱导 几乎相同的特征，包括非整倍体， 肿瘤恶性度、转移和死亡率。Pericentrin过表达 也似乎废除了有丝分裂检查点， 在未附着的染色体存在下的有丝分裂停滞。在- 表达的中心周蛋白结合和错误定位的细胞质动力蛋白， 已知分子马达在纺锤体组织中起作用， 检查点控制基于这些观察，我们提出了一个模型， 哪些中心体缺陷通过引起 基因组分离不当并产生非整倍体细胞。的 发现中心粒与恶性肿瘤的关系 进展为我们提供了一个独特的机会来阐释一部小说 肿瘤发生的机制。这项建议的具体目标是： 1.为了确定中心体和细胞核的蛋白质是否 在肿瘤中改变。 2.以测试是否pericentrin具有致癌潜力。 3.确定围中心蛋白水平升高如何导致非整倍体。

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.