Linking Breast Cancer to Chromatin Remodeling

将乳腺癌与染色质重塑联系起来

• 批准号: 6515004
• 负责人: RAMIN SHIEKHATTAR
• 金额: $ 28.71万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515004
• 关键词: DNA repair; MCF7 cell; brca gene; breast neoplasms; chromatin; estrogen receptors; estrogens; gene mutation; genetic promoter element; genetic transcription; hormone regulation /control mechanism; immunoprecipitation; neoplasm /cancer genetics; protein protein interaction; protein structure function; recombinant proteins; reporter genes; tumor suppressor proteins

APPLICANT'S DESCRIPTION: Germ line mutations in the BRCA1 gene predispose individuals to breast and ovarian cancer. Although, BRCA1 has been implicated in transcriptional control and DNA strand break repair, its precise function is unknown. Our laboratory is focused on the function of nuclear multiprotein complexes. We hypothesize that purification of the BRCA 1 complex(es) and determination of their composition and normal functions will allow us to understand their roles in malignant transformation. We have purified a BRCA1-containing complex from HeLa cells and identified a number of its components as subunits of the chromatin remodeling complex SWI/SNF. We hypothesize that the BRCA1 protein exerts its biological functions through the SWI/SNF complex. The three Aims are designed to provide a thorough physical and functional characterization of the BRCA1-SWI/SNF complex. Aim 1 will identify the remaining components of the BRCA1 complex, and describes experiments that will begin to define the function of the individual proteins in the BRCA1 complex. Aim 2 describes a detailed functional analysis of the BRCA1 -SWI/SNF complex in estrogen signaling. Aim 3 extends the work by analyzing the role of the BRCA1-SWI/SNF complex in tumor suppression and the complex's involvement in DNA repair.

申请人的描述：BRCA1 基因的种系突变使个体易患乳腺癌和卵巢癌。尽管 BRCA1 与转录控制和 DNA 链断裂修复有关，但其确切功能尚不清楚。我们的实验室专注于核多蛋白复合物的功能。我们假设，BRCA 1 复合物的纯化以及其组成和正常功能的测定将使我们能够了解它们在恶性转化中的作用。我们从 HeLa 细胞中纯化了含有 BRCA1 的复合物，并鉴定了其许多成分作为染色质重塑复合物 SWI/SNF 的亚基。我们假设 BRCA1 蛋白通过 SWI/SNF 复合物发挥其生物学功能。这三个目标旨在提供 BRCA1-SWI/SNF 复合物的全面物理和功能表征。目标 1 将鉴定 BRCA1 复合物的其余成分，并描述将开始定义 BRCA1 复合物中各个蛋白质的功能的实验。目标 2 描述了 BRCA1 -SWI/SNF 复合物在雌激素信号传导中的详细功能分析。目标 3 通过分析 BRCA1-SWI/SNF 复合物在肿瘤抑制中的作用以及该复合物参与 DNA 修复来扩展工作。