Characterization of GEFT AS a Novel Glioblastoma Oncogene

胶质母细胞瘤(GBM)是最常见、最致命的原发性中枢神经系统肿瘤。拥有最多的 积极治疗，中位生存期14.6个月。到目前为止，还没有一个系统的方法来 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发生，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，这些路径是有吸引力的 治疗的目标。我进行了一次针对基因的RNA干扰筛选，这些基因通常在 GEFT是一种鸟嘌呤核苷酸交换因子，对GBM细胞的增殖至关重要。 和/或生存能力。利用遗传学和生物化学方法，我建议对Geft及其蛋白质进行表征-- 蛋白质的相互作用。我将测试抑制Geft如何调节细胞生长和/或存活，并测试是否过度- 表达足以将基因定义明确的永生化星形胶质细胞转化为恶性胶质瘤 州政府。此外，我将确定GEFT对细胞增殖和/或生存的影响因素(S)。 相关性(请参阅说明)： 胶质母细胞瘤(GBM)是最常见、最致命的原发脑肿瘤。最具攻击性的 治疗后，中位生存期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。

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. RELEVANCE (See instructions): 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, that might play a role in formation and maintenance of these tumors.