SPONTANEOUS MELANOMA DEVELOPMENT IN TRANSGENIC MICE

描述：(改编自调查员的摘要) 恶性黑色素瘤的增长速度比其他任何疾病都要快。 人类癌症。慢性阻塞性肺疾病发生发展的病因 恶性瘤是多发性的；遗传因素可被认为是主要的。 重要的是致癌刺激的次要贡献。几个 癌基因和肿瘤抑制基因与黑色素瘤有关 进展，然而，没有特定的扩增、突变或 这些基因的重排已被发现有助于转化。 为了将癌基因与恶性肿瘤的发生联系起来，我们获得了 功能，最有可能是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 许多不同的机制，包括突变、缺失或 重新编排。 转基因小鼠提供的模型系统可以用来扩大 对人类疾病的理解。目前，很少有实验动物 黑色素瘤形成的模型已经存在，所有的小鼠模型都需要 致癌物质和紫外线治疗的组合。相比之下，一个孤独的人 在实验室中产生了表现出表型的转基因小鼠 类似于黑色素瘤，没有暴露在任何已知刺激下。动物们 出生后10至14天，耳朵上有色素斑点。 随后约2至3个月出现隆起的色素性皮损 年龄。大多数动物在一岁前死亡。他们提议 研究寄主基因的一系列实验(S)被 转基因的插入。这一中断可能已经激活了一个“关” 致癌基因进入“开”状态，从而激活其表达并导致 细胞的转化。或者，他们的转基因可能已经 阻断了肿瘤抑制基因，从而导致了不受限制的扩张 目标细胞的数量。第三种可能性是特定的互动(S) 在转基因和中断的宿主序列之间，例如 相互作用(S)导致了肿瘤的发展。 为了区分这些可能性，他们提出了一系列实验 分离和鉴定被破坏的宿主的基因产物 序列。将对来自cdna克隆的DNA序列进行分析 首先看看这些序列是已知的还是新颖的。如果DNA序列是 已知的“癌基因”或“肿瘤抑制基因”，其调控 表达将在系统中进行检查。如果DNA序列没有 将进行体外生物检测，以确定它是否是一种 一般或特定的“癌基因”或“肿瘤抑制基因”。规管 这个假定的基因在正常细胞和肿瘤细胞中的表达将完成。 这个假定的基因与人类黑色素瘤肿瘤的关系将被研究。 长期目标是利用这一转基因小鼠作为模型系统。 对于分子和基因特征的发展 黑色素瘤。

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.