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The study of Abnormal Amplification of Centrosome in bladder cancer

膀胱癌中心体异常扩增的研究

基本信息

批准号：
15591720
负责人：
SHIBA Nobuyuki
金额：
$ 1.6万
依托单位：
KANAZAWA MEDICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591720/
关键词：
centrosome amplification chromosome instability cyclin E p53 中心体放射線照射 G2停止膀胱癌 P53

项目摘要

The centrosome, which is composed of a pair of centrioles and surrounding amorphous pericentriolar material, is a major microtubule organizing center in animal cells. Its most prominent function is observed during mitosis, in which the duplicated centrosomes form the spindle poles, which direct spindle microtubule assembly and establish bipolarity, both of which are required for accurate segregation of chromosomes into daughter cells.Centrosome amplification frequently occurs in human cancers and is a major cause of chromosome instability (CIN). In mouse cells, centrosome amplification can be readily induced by loss or mutational inactivation of p53. In human cells, however, silencing of endogenous p53 alone does not induce centrosome amplification or CIN, although high degrees of correlation between p53 mutation and CIN/centrosome amplification in human cancer can be detected, suggesting the presence of additional regulatory mechanism(s) in human cells that ensures the numeral integri … More ty of centrosomes and genomic integrity. Cyclin E, a regulatory subunit for CDK2 that plays a key role in centrosome duplication, frequently is overexpressed in human cancers. We found that cyclin E overexpression, together with loss of p53, efficiently induces centrosome amplification and CIN in human bladder cancer cells but not by either cyclin E overexpression or loss ofp53 alone. We extended these findings to bladder cancer specimens and found that centrosome amplification is strongly correlated with concomitant occurrence of cyclin E overexpression and p53 inactivation but not with either cyclin E overexpression or p53 inactivation alone. Because cyclin E expression is strictly controlled in human cells compared with mouse cells, our findings suggest that this stringent regulation of cyclin E expression plays an additional role underlying numeral homeostasis of centrosomes in human cells and that deregulation of cyclin E expression, together with inactivation of p53, results in centrosome amplification. Less

中心体由一对中心粒和周围无定形的中心粒周围物质组成，是动物细胞中主要的微管组织中心。它最突出的功能是在有丝分裂过程中观察到的，在有丝分裂过程中，复制的中心体形成纺锤体极，指导纺锤体微管组装并建立双极性，这两者都是染色体准确分离成子细胞所必需的。中心体扩增经常发生在人类癌症中，是染色体不稳定性（CIN）的主要原因。在小鼠细胞中，中心体扩增可以容易地由p53的缺失或突变失活诱导。然而，在人类细胞中，内源性p53的沉默单独不诱导中心体扩增或CIN，尽管在人类癌症中可以检测到p53突变和CIN/中心体扩增之间的高度相关性，提示在人类细胞中存在额外的调节机制，其确保了细胞的数量整合。 ...更多信息中心体和基因组的完整性。细胞周期蛋白E是CDK 2的调节亚基，在中心体复制中起关键作用，在人类癌症中经常过表达。我们发现，细胞周期蛋白E的过度表达，以及p53的丢失，有效地诱导中心体扩增和CIN在人膀胱癌细胞，但不是由细胞周期蛋白E过度表达或p53的丢失单独。我们将这些发现扩展到膀胱癌标本，发现中心体扩增与同时发生的细胞周期蛋白E过表达和p53失活密切相关，但与单独的细胞周期蛋白E过表达或p53失活无关。由于细胞周期蛋白E的表达是严格控制在人类细胞与小鼠细胞相比，我们的研究结果表明，这种严格的调节细胞周期蛋白E的表达起着额外的作用，潜在的数字稳态的中心体在人类细胞和细胞周期蛋白E的表达失调，连同失活的p53，结果在中心体扩增。少