BRCAL AND P21 IN CELL CYCLING

描述：(改编自研究人员的摘要)生殖系 BRCA1是一种功能未知的肿瘤抑制基因，它的变化是 与患女性乳腺癌的终生风险85%-90%有关。 来自我们实验室和其他实验室的数据表明，BRCA1是一种核 过表达时会产生生长抑制的磷蛋白 培养的细胞系。还有更多的数据表明BRCA1 表达高峰在G1/S交界处，在其他部位几乎检测不到 细胞周期各时相，BRCA1 G1/S的表达是由 有丝分裂原暴露。我们小组的最新数据表明，BRCA1激活 转录细胞生长抑制因子p21，而该p21是 BRCA1在细胞培养模型中的生长抑制作用。 此外，他们有初步证据表明，BRCA1与P53、a 已知的肿瘤抑制因子在G1/S起检查点的作用。 数据，我们假设BRCA1是一个G1/S检查点分子，至少 它的一些作用是通过p21介导的。这项提案中概述的工作 我将通过解决以下具体目标来验证这一假设：1) 明确BRCA1在细胞周期中p21表达和功能中的作用 调控，2)证明BRCA1和P53之间的相互作用 确定这种相互作用在p21依赖和非依赖中的作用 BRCA1功能，以及3)使用BRCA1、p21和p53之间的关联来 定义对DNA损伤的反应和对细胞凋亡的调节。这些 实验将确定肿瘤“防御者”基因的终点 通过依赖p21的途径维持基因组的稳定性。他们将延长 150例档案乳房的细胞培养观察 我们从BRCA1突变携带者身上收集的癌症 这些发现的潜在临床相关性。作为一个指数级的 越来越多的文献表明，细胞周期的变化 监管可能是恶性转化的统一特征， 我们提出的研究应该能深入了解BRCA1在 肿瘤抑制。生长过程中特定病变的鉴定 BRCA1相关乳腺癌中的调节通路也发生了变化 将确定潜在的预防和治疗目标。

DESCRIPTION: (adapted from the investigator's abstract) Germline alterations in BRCA1, a tumor suppressor gene of unknown function, are associated with an 85-90% lifetime risk of developing female breast cancer. Data from our laboratory and others suggest that BRCA1 is a nuclear phosphoprotein that produces growth inhibition when overexpressed in cultured cell lines. There are additional data that suggest that BRCA1 expression peaks at the G1/S boundary and is barely detectable at other phases of the cell cycle, and that BRCA1 G1/S expression is induced by mitogen exposure. Recent data for our group suggests that BRCA1 activates transcription of the cell growth inhibitor p21, and that p21 is required for the growth inhibitory effects of BRCA1 in a cell culture model. Additionally, they have preliminary evidence that BRCA1 binds to p53, a tumor suppressor known to function as a checkpoint at G1/S. Based on these data, we hypothesize that BRCA1 is a G1/S checkpoint molecule, and at least some of its effects are mediated by p21. The work outlined in this proposal will test this hypothesis by addressing the following specific aims: 1) to define the role of BRCA1 in p21 expression and function in cell cycle regulation, 2) to demonstrate interaction between BRCA1 and p53 and to determine the role of this interaction in p21-dependent and -independent BRCA1 function, and 3) to use the association between BRCA1, p21, and p53 to define the response to DNA damage and regulation of apoptosis. These experiments will define the endpoints of tumor "preventor" gene that helps maintain genome stability through a p21-dependent pathway. They will extend the observations made in cell culture to a series of 150 archival breast cancers we have collected from BRCA1 mutation carriers to determine the potential clinical relevance of the findings. As an exponentially increasing body of literature suggests that alterations in cell cycle regulation may be a unifying feature of malignant transformation, the studies we propose should provide insight into the role played by BRCA1 in tumor suppression. Identification of the specific lesions in growth regulatory pathways that are altered in BRCA1-associated breast cancer also will define potential preventative and therapeutic targets.