Centrosomes and BRCA1

中心体和 BRCA1

• 批准号: 7088395
• 负责人: JEFFREY D PARVIN
• 金额: $ 29.73万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088395
• 关键词: centrosome; mammary gland; proteins

DESCRIPTION (provided by applicant): Why mutations in the BRCA1 gene result in breast and ovarian cancer is unknown. Recent data from this laboratory suggest that the ubiquitination activity of the BRCA1 tumor suppressor regulates the duplication and function of centrosomes specifically in mammary epithelial cells in tissue culture. Using a transient assay to inhibit BRCA1 function, we have not observed centrosome amplification in cell lines derived from non- breast tissue. Centrosome amplification has been observed in the earliest and most aggressive breast cancer lesions, and it is likely that this function of BRCA1 is critical in the etiology of these tumors. Our data has revealed a new biological pathway, which controls centrosome number and function and which depends on the function of BRCA1 in breast cells. This project will dissect the BRCA1 function via three aims. 1.) Polypeptide targets of BRCA1 ubiquitination will be identified from centrosomes purified from breast cell lines. Proteins modified by the BRCA1-dependent ubiquitination activity will be assayed for effects on centrosome duplication. 2.) The effects of BRCA1-dependent ubiquitination on centrosome microtubule nucleation function will be assayed in vitro and in vivo, and the proteins and ubiquitinated substrates identified in aim 1 will also be tested for modulating the function of BRCA1 on this organelle. 3.) We will identify the factors in non-breast cells which render the BRCA1 ubiquitination activity redundant, and test whether the newly identified factor plus BRCA1 regulate centrosome amplification in these cell types. This project will identify the mechanism by which BRCA1 regulates centrosome duplication and centrosome function in breast cells. One of the earliest changes in the cells in an incipient breast cancer is a problem with the cellular machine that segregates the DNA when the breast cell divides. Research in this laboratory has found that the function of this machine, called a centrosome, is controlled in breast cells by the BRCA1 protein. This project will dissect the workings of the centrosome and determine how BRCA1 controls its function in normal cells, and we will learn how this process is changed when BRCA1 function is lost by mutation as happens in breast cancer.

描述（由申请人提供）：为什么 BRCA1 基因突变会导致乳腺癌和卵巢癌尚不清楚。该实验室的最新数据表明，BRCA1 肿瘤抑制因子的泛素化活性可调节中心体的复制和功能，特别是在组织培养的乳腺上皮细胞中。使用瞬时测定来抑制 BRCA1 功能，我们没有在非乳腺组织来源的细胞系中观察到中心体扩增。在最早和最具侵袭性的乳腺癌病变中已经观察到中心体扩增，并且 BRCA1 的这种功能很可能在这些肿瘤的病因学中至关重要。我们的数据揭示了一种新的生物途径，该途径控制中心体的数量和功能，并且取决于乳腺细胞中 BRCA1 的功能。该项目将通过三个目标剖析 BRCA1 功能。 1.)将从乳腺细胞系纯化的中心体中鉴定出 BRCA1 泛素化的多肽靶标。将检测由 BRCA1 依赖性泛素化活性修饰的蛋白质对中心体复制的影响。 2.) 将在体外和体内检测 BRCA1 依赖性泛素化对中心体微管成核功能的影响，并且还将测试目标 1 中鉴定的蛋白质和泛素化底物是否调节 BRCA1 在该细胞器上的功能。 3.) 我们将鉴定非乳腺细胞中导致 BRCA1 泛素化活性冗余的因子，并测试新鉴定的因子加上 BRCA1 是否调节这些细胞类型中的中心体扩增。该项目将确定 BRCA1 调节乳腺细胞中心体复制和中心体功能的机制。早期乳腺癌细胞中最早的变化之一是乳腺细胞分裂时分离 DNA 的细胞机器出现问题。该实验室的研究发现，乳腺细胞中这台称为中心体的机器的功能由 BRCA1 蛋白控制。该项目将剖析中心体的运作，并确定 BRCA1 如何控制其在正常细胞中的功能，并且我们将了解当 BRCA1 功能因乳腺癌中发生的突变而丧失时，该过程如何改变。