NEUROFIBROMATOSIS-1 MUTATIONS AND NEUROBLASTOMA

1型神经纤维瘤病（NF 1）是最常见的常染色体 男性显性疾病。NF 1患者往往发展为良性 神经纤维瘤，并在增加的风险，几个恶性神经 系统肿瘤负责NF 1的基因最近已被克隆， 显示编码一种能够激活p2 lras的GT3的蛋白。我们有 发现NF 1突变在神经嵴来源的肿瘤中很常见， 神经母细胞瘤，这与NF 1无关。频繁的检测 神经母细胞瘤中的NF 1突变表明这些突变有助于 与肿瘤的发展有关NF 1缺陷型神经母细胞瘤不同于 NF 1肿瘤细胞系显示ras-GTP几乎没有增加，如果有的话， 程度.为了跟进这些发现，我们提出了几个实验。 我们要解决的一个重要问题是，NF 1是否是一种 神经母细胞瘤肿瘤抑制因子。为了确定NF 1突变是否发生在 我们将检测患者的血液和肿瘤样本， 神经母细胞瘤分析NF 1基因是否为神经母细胞瘤 肿瘤抑制因子，我们将在缺陷细胞中重建表达 系，并测试其体外和体内生长潜力。 NF 1缺陷细胞系将用于解决两个问题。第一、 我们将继续我们的发现，与NF 1恶性肿瘤细胞不同， NF 1缺乏的神经母细胞瘤只有低水平的ras-GTP。其次我们 将分析NF 1中是否有任何ras介导的过程异常 缺陷细胞在这些实验中，我们将分析配体刺激 c-raf-1和MAP蛋白激酶以及c-fos mRNA的激活 诱导我们认为，这两种方法都具有重要意义。 可能有助于确定NF 1的功能，这是下一个 这个领域的挑战。

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders of man. Patients with NF1 often develop benign neurofibromas and are at increased risk for several malignant nervous system tumors. The gene responsible for NF1 has recently been cloned and shown to encode a protein that can activate the GTPase of p2lras. We have found that NF1 mutations are frequent in a neural crest derived tumor, neuroblastoma, which is not associated with NF1. The detection of frequent NF1 mutations in neuroblastomas suggests that these mutations contribute to the development of this tumor. NF1 deficient neuroblastomas differ from NF1 tumor cell lines in showing little, if any, increase in ras-GTP levels. To follow up on these findings we propose several experiments. An important question that we will address is whether NF1 is a neuroblastoma tumor suppressor. To determine if NF1 mutations occur in primary neuroblastomas we will test blood and tumor samples from patients with neuroblastoma. To analyze whether the NF1 gene is a neuroblastoma tumor suppressor, we will reestablish expression in the deficient cell lines and test their in vitro and in vivo growth potential. The NF1 deficient cell lines will be used to address two questions. First, we will follow up on our finding that, unlike NF1 malignant tumor cells, NF1 deficient neuroblastomas have only low levels of ras-GTP. Secondly, we will analyze whether any ras-mediated processes are abnormal in NF1 deficient cells. In these experiments we shall analyze ligand stimulated activation of the c-raf-1 and MAP protein kinases, as well as c-fos mRNA induction. We believe that both these approaches have significant potential to help determine the function of NF1, which is the next challenge in this field.