TUMOR SUPPRESSOR GENES IN HERITABLE MELANOMA MODELS

最近发现了三种动物黑色素瘤模型 剑鱼属的有生命的鱼，包括贝类和 剑尾物种。其中两种是自发性黑色素瘤 不同种间的鸭嘴鱼回交杂交；另一种黑色素瘤是 LTV诱导的扇贝-剑尾回交杂交种。很可能是 这两种自发性黑色素瘤在肿瘤进展中都有调节作用 以前没有表征过的易感基因； 紫外线诱导的黑色素瘤最近才被研究，它的遗传学 监管还是个未知数。剑尾鱼的遗传连锁图谱是 在为数不多的鱼类中建立的最完整的，有75种色素，DNA， 蛋白质标记分布在24条染色体中的20条上 成对的。因此，通过等位酶与RFLP的多点连锁分析 回交杂交种中与黑色素瘤表型相关的标记， 调节恶性进展的遗传因素很容易被 在这些肿瘤模型中进行了鉴定和表征。既然有 人类黑色素瘤易感性的遗传异质性的证据 黑色素瘤动物模型研究结果的综合 多种遗传因素将促进更好地理解 黑色素瘤形成和进展的潜在遗传因素 人类的恶性。为了实现这个总目标，我们的具体目标 主要有：(1)分析了最近描述的两个基因的调控 剑鱼种间自发性杂交性黑色素瘤的多点治疗 连锁分析，以识别和定位遗传调控元件，与 确定肿瘤易感基因座的目标；(2)研究 剑尾鱼杂交黑色素瘤动物模型的遗传学基础 通过分析紫外线诱导的恶性进展的遗传因素 可能有助于LTV诱发黑色素瘤；(3)克隆和测序 剑尾鱼可能参与肿瘤发生的cDNA 黑色素瘤，包括剑尾藻erbB和RB同源物；以及(4)至 利用分子标记技术克隆一个已知抑癌基因的方法探讨 饱和使用匿名DNA RFLP。

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.