TUMOR SUPPRESSOR GENES IN HERITABLE MELANOMA MODELS

最近已经鉴定了三种动物黑色素瘤模型， 剑尾鱼属的一种活产鱼，包括比目鱼和 剑尾鱼 其中两个是自发性黑色素瘤， 不同的比目鱼种间回交杂交;其他黑色素瘤是 LTV诱导的鸭嘴鱼-剑尾鱼回交杂种。 很可能 两种自发性黑色素瘤在肿瘤进展中均受肿瘤 以前没有被描述的易感基因; 紫外线诱导的黑色素瘤最近才被研究，其遗传 监管尚不清楚。 剑尾鱼的遗传连锁图是 最完整的少数建立在鱼类，有75个色素，DNA， 蛋白质标记分布在24条染色体中的20条上 对. 因此，通过等位酶和RFLP的多点连锁分析， 在回交杂种中与黑色素瘤表型共分离的标记， 调节恶性进展的遗传因素很容易 在这些肿瘤模型中鉴定和表征。 由于 人类黑色素瘤易感性遗传异质性的证据， 研究动物黑色素瘤模型的结果的综合， 多个基因元件将促进对 黑色素瘤形成和进展的潜在遗传因素 人类的恶性肿瘤 为实现这一总体目标，我们的具体目标 （1）分析了两个新发现的基因型的遗传调控 剑尾鱼种间自发性杂交黑色素瘤多点 连锁分析，以确定和定位遗传调控元件， 目的：（1）研究肿瘤易感基因的表达;（2）研究肿瘤易感基因的表达。 剑尾鱼杂交黑色素瘤动物模型的遗传学基础 通过分析遗传因素， LTV可能参与黑色素瘤的诱导;（3）克隆和测序 剑尾鱼肿瘤发生相关的cDNA 黑色素瘤，包括剑尾鱼erbB和RB同源物;和（4） 利用标记技术克隆已知抑癌基因 使用匿名DNA RFLP饱和。

Three animal melanoma models have recently been identified in livebearing fishes of the genus Xiphophorus, comprising platyfish and swordtail species. Two of these are spontaneous melanomas occurring in different platyfish interspecies backcross hybrids; the other melanoma is LTV-induced in platyfish-swordtail backcross hybrids. It is likely that both spontaneous melanomas are regulated in tumor progression by tumor susceptibility genes that have not been previously characterized; the UV-induced melanoma has only been recently studied and its genetic regulation is as yet unknown. The genetic linkage map of Xiphophorus is the most complete of the few established in fishes, with 75 pigment, DNA, and protein markers distributed on as many as 20 of the 24 chromosome pairs. Therefore, by multipoint linkage analysis of allozyme and RFLP markers cosegregating with melanoma phenotype in backcross hybrids, genetic factors regulating progression to malignancy can readily be identified and characterized in these tumor models. Since there is evidence of genetic heterogeneity in human melanoma susceptibility, a synthesis of the results of investigating animal melanoma models with multiple genetic elements will promote a better understanding of the underlying genetic factors in melanoma formation and progression to malignancy in humans. To realize this overall goal, our specific aims are: (1) To analyze the genetic regulation of two recently described Xiphophorus interspecies spontaneous hybrid melanomas using multipoint linkage analysis to identify and map genetic regulatory elements, with the goal of identifying tumor susceptibility loci; (2) To investigate the genetic basis of a Xiphophorus hybrid melanoma useful as an animal model for UV-induced malignant progression by analyzing genetic factors that may contribute to LTV induction of melanomas; (3) To clone and sequence cDNAs that may be involved in tumorigenesis in Xiphophorus hybrid melanomas, including Xiphophorus erbB and RB homologues; and (4) To approach the molecular cloning of a known tumor suppressor gene by marker saturation using anonymous DNA RFLPs.