Characterization of GEFT AS a Novel Glioblastoma Oncogene

描述(申请人提供)：项目摘要：胶质母细胞瘤(GBM)是最常见和最致命的原发中枢神经系统肿瘤。采用最积极的治疗方法，中位生存期为14.6个月。到目前为止，还没有一种系统的方法来验证体细胞扩增的候选基因的功能，以确定它们在胶质瘤发病机制中的作用。这些基因可能直接驱动肿瘤的形成，或者肿瘤细胞可能依赖它们来生存和增殖，这一过程被称为“癌基因成瘾”。因此，这些通路是有吸引力的治疗靶点。我进行了针对GBM中常见扩增区域的RNA干扰筛选，发现Geft是一种鸟嘌呤核苷酸交换因子(Geft)，对GBM细胞的增殖和/或活力至关重要。使用遗传学和生物化学方法，我建议对GEFT及其蛋白质-蛋白质相互作用进行表征。我将测试GEFT抑制如何调节细胞生长和/或存活，并测试过度表达是否足以将基因定义明确的永生化星形胶质细胞转变为恶性胶质瘤状态。此外，我将确定GEFT对细胞增殖和/或生存的影响因素(S)。 公共卫生相关性：胶质母细胞瘤(GBM)是最常见和最致命的原发脑肿瘤。采用最积极的治疗方法，中位生存期为14.6个月。我建议描述一种名为geft的基因，它可能在这些肿瘤的形成和维持中发挥作用。

DESCRIPTION (provided by applicant): Project Summary: Glioblastomas (GBM) are the most common and lethal primary central nervous system tumors. With the most aggressive therapy, median survival is 14.6 months. To date, there has not been a systematic approach to validate the function of candidate genes that are somatically amplified, for their role in glioma pathogenesis. These genes might play direct roles driving tumorigenesis, or tumor cells might depend on them for their survival and proliferation, a process known as "oncogene addiction." Therefore, these pathways are attractive targets for therapy. I performed an RNA interference screen targeting genes on regions commonly amplified in GBM and identified GEFT, a guanine nucleotide exchange factor (GEF), as essential for GBM cell proliferation and/or viability. Using genetic and biochemical approaches, I propose to characterize GEFT and its protein- protein interactions. I will test how suppression of GEFT regulates cell growrth and/or survival, and test if over-expression is sufficient to transform genetically well defined, immortalized astrocytes into a malignant glioma state. Additionally, I will determine the effector(s) of GEFT for cell proliferation and/or survival. Public Health Relevance: Glioblastomas (GBM) are the most common and lethal primary brain tumors. With the most aggressive therapy, median survival is 14.6 months. I propose to characterize a gene, GEFT, which might play a role in formation and maintenance of these tumors.