Characterization of GEFT AS a Novel Glioblastoma Oncogene

描述（由申请人提供）：项目概述：胶质母细胞瘤（GBM）是最常见和致命的原发性中枢神经系统肿瘤。采用最积极的治疗，中位生存期为14.6个月。到目前为止，还没有一个系统的方法来验证候选基因的功能，体细胞扩增，其在胶质瘤发病机制中的作用。这些基因可能在肿瘤发生中起直接作用，或者肿瘤细胞可能依赖它们生存和增殖，这一过程被称为“癌基因成瘾”。“因此，这些途径是有吸引力的治疗靶点。我进行了RNA干扰筛选，靶向GBM中常见扩增区域的基因，并确定GEFT（一种鸟嘌呤核苷酸交换因子（GEF））对GBM细胞增殖和/或活力至关重要。使用遗传和生化方法，我建议描述GEFT及其蛋白质-蛋白质相互作用的特征。我将测试GEFT的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遗传上明确定义的永生化星形胶质细胞转化为恶性胶质瘤状态。此外，我将确定GEFT对细胞增殖和/或存活的效应物。 公共卫生相关性：胶质母细胞瘤（GBM）是最常见和致命的原发性脑肿瘤。采用最积极的治疗，中位生存期为14.6个月。我建议描述一个基因，GEFT，这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.