IDENTIFYING TARGETS OF E3 UBIQUITIN LIGASES:ROLE IN BRCA1-MEDIATED BREAST CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 乳腺癌是美国女性癌症死亡的第二大原因。据估计，5%-10%的乳腺癌具有遗传基础，而乳腺癌易感基因1(BRCA1)基因的突变在这些癌症的发生发展中起着重要作用。BRCA1是一种肿瘤抑制蛋白，部分通过促进E3泛素(Ub)连接酶对其他细胞蛋白的破坏来抑制细胞的不受控制的增殖。目前识别E3Ub连接酶靶标的方法取得了有限的成功。因此，在很大程度上还不清楚BRCA1分解或降解了哪些细胞蛋白。 我们研究的长期目标是了解蛋白质降解是如何导致细胞增殖和肿瘤发展的。这项建议的目的是开发一种创新的策略来分离E3Ub连接酶(包括BRCA1)的靶标，将BRCA1靶标的表达与其抗增殖活性联系起来。为了验证这一假设，我们将使用各种病毒学、生化和细胞生物学技术来开发这一系统并识别BRCA1靶标。这些研究的主要理论基础是表征乳腺癌发生的分子事件。我们的研究结果将具有重要意义，因为我们将利用我们的策略识别细胞蛋白，作为检测乳腺肿瘤发生的潜在诊断标记和治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Breast cancer is the second leading cause of cancers deaths in women in the United States. It is estimated that between 5-10% of breast cancers have a heritiable basis, and mutations in breast cancer susceptibility gene 1 (BRCA1) gene contribute significantly to the development of these cancers. BRCA1 is a tumor suppressor protein that inhibits the uncontrolled proliferation of cells, in part, by promoting the destruction of other cellular proteins as an E3 ubiquitin (Ub) ligase. Current methods for identifying targets of E3 Ub ligases have met with limited success. As a result, it is largely unclear which cellular proteins BRCA1 breaks down or degrades. The long-term goal of our research is to understand how protein degradation leads to cellular proliferation and tumor development. The objective of this proposal is to develop an innovative strategy to isolate targets of E3 Ub ligases (which includes BRCA1), relating the expression of BRCA1 targets to its anti-proliferative activity. To test this hypothesis, we will use a variety of virological, biochemical, and cell biology techniques to develop this system and identify BRCA1 targets. The primary rationale for these studies is to characterize the molecular events in the initiation of breast cancer. Results from our studies will be significant because the cellular proteins we will identify with our strategy can be used as potential diagnostic markers in the detection of and as therapeutic targets in breast tumorigenesis.