GENES INVOLVED IN PRENEOPLASTIC PROGRESSION

这项研究的目的是识别和表征两类 参与多阶段致癌的基因。第一个类包括 与肿瘤启动子诱导肿瘤易感性相关的基因 转型。第二类包括指定表达的基因 肿瘤细胞表型。小鼠JB6启动子抵抗(P-)，促进- 敏感(P+)和致瘤(TX)JB6来源的表皮细胞系 中描述的几个基因的表达有所不同 伴随项目Z01CP05383-09 LVC，“膜信号转导在 这些基因在肿瘤发生过程中表达的变化。 从P-到P+再到Tx表型的进展似乎是遗传的 在这些稳定的变异细胞系中进行控制。我们最近做了 发现JB6对肿瘤促进剂的反应发生稳定变化- 衍生的致瘤细胞系。这一变化涉及到获取一个细胞- 对蛋白激酶C激活剂的杀伤反应 显示以细胞凋亡为特征的非随机DNA损伤(程序化 细胞死亡)，这一发现对癌症治疗具有重要意义。一本小说 与任何已知癌基因无关的转化相关序列具有 用人ALU从人鼻咽癌细胞中克隆 鼻咽癌/JB6转基因细胞基因组文库的筛选一个最近被孤立的 同源鼻咽癌基因克隆部分编码免疫球蛋白kappa。在……里面 此外，鼻咽癌细胞株和活检组织显示相同的表达突变 肿瘤抑制基因P53的“热点”之一。新证据 表明新突变的P53具有致癌活性。新增全国人大 来自阿拉斯加患者的样本正被提供给我们用于检查 新克隆的鼻咽癌转化相关基因和p53基因 与转化相关的突变。最后，我们了解到JB6 P+细胞过度表达可转化为肿瘤表型 激活v-H-ras、v-raf或src，但不是由其他任何一种激活 致癌基因。这些JB6/癌基因的基因表达谱 正在对转基因细胞系进行检查，以增加我们对 JB6模型中的转换路径。

The aim of this research is to identify and characterize two classes of genes involved in multistage carcinogenesis. The first class includes genes associated with susceptibility to tumor promoter-induced neoplastic transformation. The second class includes genes that specify expression of tumor cell phenotype. Mouse JB6 promotion-resistant (P-), promotion- sensitive (P+), and tumorigenic (Tx) JB6-derived epidermal cell lines have been found to differ in the expression of several genes described in the accompanying project Z01CP05383-09 LVC, "Membrane Signal Transduction in Tumor Promotion." The changes in expression of these genes during the progression from P- to P+ to Tx phenotypes appear to be genetically controlled in these stable variant cell lines. We have recently discovered a stable change in a response to tumor promoters by a JB6- derived tumorigenic cell line. The change involves acquisition of a cell- killing response to activators of protein kinase C. The treated cells show the non-random DNA damage that characterizes apoptosis (programmed cell death), a finding of significance for cancer treatment. A novel transformation-associated sequence unrelated to any known oncogene has been cloned from human nasopharyngeal carcinoma (NPC) cells by human Alu screening of an NPC/JB6 transfectant genomic library. A recently isolated homologous NPC cDNA clone encodes, in part, immunoglobulin kappa. In addition, NPC cell lines and a biopsy show the same expressed mutation in one of the "hot spots" of the tumor suppressor gene p53. New evidence shows that the novel mutated p53 has oncogenic activity. Additional NPC samples from Alaskan patients are being provided to us for examination of both the newly cloned NPC transformation-associated gene and the p53 gene for transformation-relevant mutations. Finally, we have learned that JB6 P+ cells can be transformed to a tumor phenotype by overexpression of activated v-H-ras, v-raf, or src, but not by any of several other oncogenes. The profiles of gene expression in these JB6/oncogene transfectant cell lines are being examined to increase our understanding of transformation pathways in the JB6 model.