BRCA1 FUNCTION IN BREAST CANCER

描述：（逐字改编自研究者摘要） 提出BRCA 1基因通过促进肿瘤的生长抑制肿瘤的形成。 细胞对DNA损伤的反应BRCA 1编码的主要多肽具有两个 BRCT蛋白基序的串联拷贝，以及肿瘤相关的 突变表明，这些序列是BRCA 1介导的肿瘤所必需的。 镇压此外，最近的研究表明，BRCA 1是一种有效的 调节RNA转录，BRCT结构域也是必不可少的 为了这个活动。因此，Sos招聘系统（SRS），一种新的招聘形式， 酵母双杂交分析，被用来筛选蛋白质结合这一点， BRCA 1的关键区域初步数据显示，BRCT结构域 在体内与CtIP相互作用，CtIP是一种最初根据其 与CtBP转录辅阻遏物的关联。这一发现表明 BRCA 1至少部分通过调节基因表达， CtBP介导的转录抑制。此外，体内相互作用 BRCA 1和CtIP之间的相互作用被三种独立的 影响BRCT基序的肿瘤相关突变，表明 BRCA/1/CtIP相互作用也可能是BRCA 1抑制肿瘤所必需的。在 为了检验这些假设，我们将追求三个具体目标。一是 BRCA 1和CtIP的表达和体内相关性将通过以下定义： 在细胞周期进程和细胞对DNA损伤的反应方面。 第二，将使用CtIP缺陷型小鼠研究CtIP在以下中的作用： 在生物体水平的肿瘤抑制和在DNA损伤反应中， 细胞水平。第三，CtIP对CtBP依赖的转录的影响， 抑制和BRCA 1调节的转录激活将被探索。 这些研究将对BRCT结构域的功能产生新的认识 关于BRCA 1介导的肿瘤抑制。

DESCRIPTION: (adapted verbatim from the investigator's abstract) It has been proposed that the BRCA1 gene suppresses tumor formation by facilitating the cellular response to DNA damage. The major polypeptide encoded by BRCA1 has two tandem copies of the BRCT protein motif, and studies of tumor-associated mutations indicate that these sequences are required for BRCA1-mediated tumor suppression. In addition, recent work has shown that BRCA1 is a potent regulator of RNA transcription, and that the BRCT domains are also essential for this activity. Therefore, the Sos-recruitment system (SRS), a novel form of yeast two-hybrid analysis, was used to screen for proteins that bind this critical region of BRCA1. The preliminary data show that the BRCT domains interact in vivo with CtIP, a protein originally identified on the basis of its association with the CtBP transcriptional co-repressor. This finding suggests that BRCA1 regulates gene expression, at least in part, by modulating CtBP-mediated transcriptional repression. Moreover, the in vivo interaction between BRCA1 and CtIP is completely ablated by each of three independent tumor-associated mutations affecting the BRCT motifs, indicating that the BRCA/1/CtIP interaction may also be required for tumor suppression by BRCA1. In order to test these hypotheses, three Specific Aims will be pursued. First, the expression and in vivo association of BRCA1 and CtIP will be defined with respect to cell cycle progression and the cellular response to DNA damage. Second, CtIP-deficient mice will be used to investigate the role of CtIP in tumor suppression at the organismal level and in the DNA damage response at the cellular level. Third, the effects of CtIP on CtBP-dependent transcriptional repression and BRCA1-modulated transcriptional activation will be explored. These studies should yield new insights into the function of the BRCT domains with respect to BRCA1-mediated tumor suppression.