Using Zebrafish to Identify and Analyze Cancer Genes

斑马鱼正成为一个越来越有吸引力的癌症模型，因为几个癌基因和肿瘤 抑制基因在鱼类和哺乳动物中似乎具有相似的特性。一个插入 突变筛选以鉴定斑马鱼胚胎发育所需的基因， 数百种突变的集合，其中突变基因已被鉴定。迄今为止， 确定了18个基因，它们的突变使鱼对其他疾病的发展非常敏感。 肿瘤类型罕见，恶性周围神经鞘瘤。这些基因之一是斑马鱼的直系同源基因， 哺乳动物肿瘤抑制型神经纤维瘤病2型（NF 2），其突变也可导致 神经源性肿瘤的发展。令人惊讶的是，其他17个基因都编码核糖体蛋白 (RPs)分子生物学研究表明，rp基因具有单倍不足的抑癌基因功能 基因.对rp突变体的初步分析以及哺乳动物rp的已知作用表明， 两种可能的模型来解释RPS的肿瘤抑制功能，翻译能力的缺陷， 和/或p53信号传导。该提案中的实验将测试这些模型。首先，斑马鱼将被雇用 以更好地理解RP杂合突变如何促进肿瘤的发展。第二、 rp杂合突变体的翻译特性与肿瘤的关系 将建立抑制活性。最后，对斑马鱼的突变体进行了小组分析，并在 哺乳动物细胞，将被用来建立如何RP有助于调节p53，并确定 这条通路对肿瘤发生过程的影响。

The zebrafish is becoming an increasingly attractive cancer model as several oncogenes and tumor suppressor genes appear to have similar properties in fish as they do in mammals. An insertional mutagenesis screen to identify genes required for embryonic development in the zebrafish has led to a collection of hundreds of mutations for which the mutated genes have been identified. To date we have identified 18 genes whose mutation renders the fish highly susceptible to the development of an otherwise rare tumor type, malignant peripheral nerve sheath tumor. One of these genes is a zebrafish ortholog of the mammalian tumor suppressor neurofibromatosis type 2 (NF2), whose mutation can also lead to the development of tumors of neuronal origin. Surprisingly, the other 17 genes all encode ribosomal proteins (RPs), and molecular studies indicate that the rp genes function as haploinsufficient tumor suppressor genes. Preliminary analysis of the rp mutants, and also the known roles of the mammalian RPs, suggests two possible models to account for the rps' tumor suppressor function, defects in translational capacity and/or p53 signaling. Experiments in the proposal will test these models. First, zebrafish will be employed to better understand how the rp heterozygous mutations contribute to the development of tumors. Second, the relationship between the translation properties of the rp heterozygous mutants and their tumor suppressive activity will be established. Finally, the panel of zebrafish mutants, and parallel analysis in mammalian cells, will be used to establish how the RPs contribute to the regulation of p53 and, to determine the impact of this pathway on the tumorigenic process.