BRCAL AND P21 IN CELL CYCLING

描述：（改编自研究者摘要）生殖系 BRCA 1是一种功能未知的肿瘤抑制基因， 与85-90%的女性乳腺癌终生风险相关。 来自我们实验室和其他实验室的数据表明，BRCA 1是一种核蛋白， 一种磷蛋白，当在细胞中过度表达时产生生长抑制作用， 培养的细胞系。 还有其他数据表明BRCA 1 在G1/S边界表达达到峰值，在其他区域几乎检测不到表达。 BRCA 1 G1/S的表达是由 有丝分裂原暴露。 我们小组最近的数据表明，BRCA 1激活 细胞生长抑制剂p21的转录，并且p21是 BRCA 1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BRCA 1与p53结合， 肿瘤抑制因子已知在G1/S起检查点的作用。 基于这些 数据，我们假设BRCA 1是一个G1/S检查点分子，至少 它的一些作用是由p21介导的。 本提案中概述的工作 将通过解决以下具体目标来检验这一假设：1） 明确BRCA 1在p21表达和细胞周期中的作用 调节，2）证明BRCA 1和p53之间的相互作用， 确定这种相互作用在p21依赖性和非依赖性 BRCA 1功能，以及3）使用BRCA 1，p21和p53之间的关联， 定义对DNA损伤的反应和细胞凋亡的调节。 这些 实验将确定肿瘤“预防”基因的终点， 通过p21依赖性途径维持基因组稳定性。 他们将延长 在细胞培养中对一系列150个档案乳房进行观察， 我们从BRCA 1突变携带者中收集的癌症样本， 研究结果的潜在临床意义。 作为一个指数 越来越多的文献表明细胞周期的改变 调节可能是恶性转化的一个统一特征， 我们提出的研究应该能够深入了解BRCA 1在以下方面所起的作用： 肿瘤抑制 鉴别生长中的特定病变 BRCA 1相关乳腺癌中改变的调节途径也 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.