Elucidating the Regulation and Function of the NF1 tumor suppressor

 描述（由申请人提供）：Ras途径是癌症中最常见的失调途径之一。RAS基因、上游调节因子或下游效应因子的突变发生在大多数人类肿瘤中。参与癌症的一个重要Ras调节基因是NF 1肿瘤抑制基因，其编码Ras GTP酶激活蛋白（RasGAP）。NF 1催化Ras-GTP水解为Ras-GDP，并通常终止Ras信号传导。因此，NF 1的功能丧失突变导致Ras过度活化。NF 1突变是一种常见的家族性癌症综合征I型神经纤维瘤病（NF 1）的基础。最近，NF 1已被证明在包括黑色素瘤、胶质母细胞瘤和肺癌在内的多种散发性肿瘤中发挥作用。然而，尽管该基因在1990年被克隆，但令人惊讶的是，人们对NF 1蛋白如何正常调节或发挥功能知之甚少。此外，对于NF 1突变型肿瘤没有有效的治疗方法。在这个应用程序中，我们的目标是解决这两个重要的问题。具体来说，我们将1）确定NF 1蛋白是如何正常调节和终止Ras信号传导的，2）解构下游和会聚信号传导途径，3）确定在NF 1突变型肿瘤中失调的广泛信号传导网络。总的来说，这些研究不仅应该揭示NF 1和Ras信号转导的新见解，而且将确定NF 1突变肿瘤中的关键调节因子和效应因子，这些因子最终可能成为治疗靶点。

 DESCRIPTION (provided by applicant): The Ras pathway is one of the most commonly deregulated pathways in cancer. Mutations in RAS genes, upstream regulators, or downstream effectors occur in the majority of human tumors. One important Ras regulatory gene involved in cancer is the NF1 tumor suppressor, which encodes a Ras GTPase-activating protein (RasGAP). NF1 catalyzes the hydrolysis of Ras-GTP to Ras-GDP and normally terminates Ras signaling. Accordingly, loss-of-function mutations in NF1 result in hyperactivated Ras. NF1 mutations underlie a common familial cancer syndrome neurofibromatosis type I (NF1). More recently, NF1 has been shown to play a role in a variety of sporadic tumors including melanoma, glioblastoma, and lung cancer. However, while the gene was cloned in 1990, surprisingly little is known about how the NF1 protein is normally regulated or functions. In addition, there are no effective therapies for NF1-mutant tumors. In this application we aim to tackle both of these important problems. Specifically, we will 1) determine how the NF1 protein is normally regulated and terminates Ras signaling, 2) deconstruct downstream and converging signaling pathways, and 3) identify broad signaling networks that are deregulated in NF1-mutant tumors. Collectively, these studies should not only reveal novel insight into NF1 and Ras signaling, but will identify key regulators and effectors in NF1-mutant tumors that may ultimately serve as therapeutic targets.