SPONTANEOUS MELANOMA DEVELOPMENT IN TRANSGENIC MICE

描述：（改编自研究者摘要） 恶性黑色素瘤的发病率比其他任何恶性黑色素瘤的发病率都高。 人类癌症 导致肺结核发生的病因学因素 恶性肿瘤是多发性的;遗传因素可能被认为是原发性的。 重要性与致癌刺激的次要贡献。 几 癌基因和肿瘤抑制基因与黑色素瘤有关 然而，没有特定的扩增、突变或 已经发现这些基因的重排有助于转化。 为了暗示一个癌基因在恶性肿瘤的发生发展中起作用， 功能，最有可能通过现有基因的突变，是必需的。 相反，肿瘤抑制基因的失活可以通过以下方式实现： 许多不同的机制，包括突变，删除，或 重排 转基因小鼠提供了模型系统，可用于拓宽 了解人类疾病。 目前，很少有实验动物 存在黑色素瘤形成的模型，所有小鼠模型都需要 致癌物质和紫外线处理的组合。 相反，一个孤独的 在实验室中产生了转基因小鼠， 类似于黑色素瘤而没有暴露于任何已知刺激。 动物 在出生后10至14天， 随后在约2至3个月时出现升高的色素性病变， 年龄 大多数动物在一岁之前死亡。 他们提出 一组研究宿主基因的实验， 转基因的插入。 这种中断可能激活了一个“关闭” 癌基因的“上”状态，从而激活其表达，并导致 细胞的转化。 或者，它们的转基因可能具有 中断了一个肿瘤抑制基因，从而导致了不受限制的扩张， 的靶细胞。 第三种可能性是特定的相互作用 在转基因和中断的宿主序列之间发生， 相互作用导致肿瘤发展。 为了区分这些可能性，他们提出了一系列实验 分离和表征被破坏的宿主的基因产物 序列的 将对cDNA克隆的DNA序列进行分析 先看看这些序列是已知的还是新的 如果DNA序列 已知的“癌基因”或“肿瘤抑制基因”，其调控 将在系统中检查表达。 如果DNA序列没有 已经描述过，将进行体外生物测定以观察它是否是一种 一般或特异的“癌基因”或“肿瘤抑制基因”。 调控 将在正常和肿瘤细胞中进行该推定基因的表达。 这个假定的基因在人类黑色素瘤肿瘤的参与将被研究。 长期的目标是使用这一系列的转基因小鼠作为模型系统 的分子和遗传特征的发展， 黑素瘤

DESCRIPTION: (adapted from the investigator's abstract) The incidence of malignant melanoma is increasing at a rate greater than that of any other human cancer. The etiologic factors contributing to the development of malanoma are multiple; genetic factors may be considered to be of primary importance with secondary contributions from carcinogenic stimuli. Several oncogenes and tumor suppressor genes have been implicated in melanoma progression, however, no particular amplification, mutation, or rearrangement of these genes has been found to contribute to transformation. To implicate an oncogene in the onset of malanoma development, a gain of function, most likely through mutation of an existing gene, is required. Conversely, inactivation of a tumor suppressor gene can be achieved through a number of different mechanisms, including mutation, deletion, or rearrangement. Transgenic mice provide model systems that can be used to broaden the understanding of human diseases. Currently, very few experimental animal models exist for melanoma formation and all mouse models require a combination of carcinogen and UV treatments. In contrast, a lone of transgenic mice was generated in the laboratory that displays a phenotype similar to melanoma without exposure to any known stimuli. The animals showed areas of pigmented spots on the ear at 10 to 14 days after birth followed by appearance of raised pigmented lesions by about 2 to 3 months of age. The majority of the animals died before one year of age. They propose a set of experiments to study the host gene(s) which was interrupted by the insertion of the transgene. This interruption may have activated an "off" oncogene to the "on" state, thus activating its expression and resulting in the transformation of cells. Alternatively, their transgene may have interrupted a tumor suppressor gene, thus leading to unrestricted expansion of targeted cells. A third possibility is specific interaction(s) transpired between the transgene and the interrupted host sequences, such interaction(s) resulted in tumor development. To distinguish among these possibilities, they propose a set of experiments to isolate and characterize the gene product of the disrupted host sequences. Analysis of the DNA sequences from cDNA clones will be done first to see if the sequences is known or novel. If the DNA sequences are of a known "oncogene" or "tumor suppressor gene", regulation of its expression will be examined in the system. If the DNA sequences have not been described, in vitro biological assays will be done to see if it is a general or specific "oncogene" or "tumor suppressor gene". Regulation of expression of this putative gene in normal and tumor cells will be done. Involvement of this putative gene in human melanoma tumors will be studied. The long term goal is to use this line of transgenic mice as a model system for the molecular, and genetic characterization of the development of melanoma.