MECHANISMS OF INDUCTION OF SKIN CANCERS BY UV LIGHT

已知存在于阳光中的紫外线（UV）辐射是导致 诱发大多数人类皮肤癌。 因为皮肤癌 是人类癌症最普遍的形式，紫外线辐射是一个重要的 环境致癌物这项建议的长远目标是 研究紫外线辐射诱导皮肤的分子机制 癌 已证明特定化学品可诱导啮齿类动物发生肿瘤 涉及特定致癌基因的激活。 但殊不知 紫外线辐射是否激活了致癌物质特异性 方式 由于紫外线辐射引起的DNA损伤是独特的， 从任何其他致癌物质引起的病变来看， 特定的紫外线诱导的癌基因结构的改变可以导致 诱发肿瘤。 我们之前的研究表明人类皮肤 发生在暴露于阳光的身体部位的癌症含有缺失，突变， 和ras癌基因的扩增。 在这项研究中，我们计划使用 UV诱导的小鼠肿瘤作为模型系统，以确定它们是否含有 特异性ras基因突变、扩增或缺失，如果是， 它们是否与发生在人类皮肤癌中的那些相似， 暴露在阳光下的身体部位 由于紫外线引起的小鼠皮肤病的病因 癌症比人类皮肤癌更确定，我们可以测试 假设紫外线辐射激活特定的癌基因， 致癌物特异性方式。 具体目标是：（1）确定 紫外线诱导的小鼠皮肤肿瘤是否含有ras特异性突变， 致癌基因(2)为了确定紫外线诱导的小鼠皮肤癌是否 表达放大的癌基因。(3)为了确定紫外线诱导的小鼠是否 皮肤癌显示癌基因的丢失或重排或p53肿瘤 抑制基因Ras基因突变将通过聚合酶链分析 反应后进行斑点杂交， 设计用于检测单碱基对突变的寡脱氧核苷酸探针。 选择的癌基因如ras、myc、myb、fos、erbA和 通过Southern和北方印迹杂交分析erbB。损失或 选定癌基因（ras、myc、myb、fos、erbA和erbB）重排 并通过限制性片段长度分析p53基因 多态 此外，还将分析紫外线诱导的小鼠皮肤癌 p53基因中可能的突变，因为已知在一些 在癌症中，一个p53等位基因丢失，而另一个突变。 从这些研究中获得的信息可能有助于了解 紫外线致癌的分子机制。

Ultraviolet (UV) radiation present in sunlight is known to be responsible for the induction of most human skin cancers. Since cancers of the skin are the most prevalent form of human cancer, UV radiation is an important environmental carcinogen. The long-term objective of this proposal is to investigate the molecular mechanisms by which UV radiation induces skin cancer. Induction of tumors in rodents by defined chemicals has been shown to involve activation of specific oncogenes. However, it is not known whether UV radiation activates proto-oncogenes in a carcinogen-specific manner. Since the DNA damage induced by UV radiation is unique and differs from the lesions induced by any other carcinogen, it is quite possible that specific UV-induced alterations in oncogene structure can lead to the induction of tumors. Our previous studies have shown that human skin cancers occurring on sun-exposed body sites contain deletions, mutations, and amplifications in ras oncogenes. In this study, we plan to use UV-induced mouse tumors as a model system to determine whether they contain specific ras gene mutations, amplifications or deletions, and if so, whether they are similar to those found in human skin cancers occurring on sun-exposed body sites. Since the etiology of UV-induced murine skin cancers is more certain than that of human skin cancers, we can test the hypothesis that UV radiation activates particular oncogenes in a carcinogen-specific manner. Our specific aims are: (1) To determine whether the UV-induced murine skin tumors contain specific mutations in ras oncogenes. (2) To determine whether the UV-induced murine skin cancers express amplified oncogenes. (3) To determine whether the UV-induced murine skin cancers display loss or rearrangement of oncogenes or the p53 tumor suppressor gene. Ras gene mutations will be analyzed by polymerase chain reaction followed by dot-blot hybridization to synthetic oligodeoxynucleotide probes designed to detect single base pair mutations. Amplification of selected oncogenes such as ras, myc, myb, fos, erbA, and erbB will be analyzed by Southern and Northern blot hybridization. Loss or rearrangement of selected oncogenes (ras, myc, myb, fos, erbA, and erbB) and the p53 gene will be analyzed by restriction fragment length polymorphism. In addition, UV-induced murine skin cancers will be analyzed for possible mutations in the p53 gene, because it is known that in some cancers, one of the p53 allele is lost, while the other is mutated. Information obtained from these studies may help to understand the molecular mechanisms of UV carcinogenesis.