GENES INVOLVED IN PRENEOPLASTIC PROGRESSION

这项研究的目的是识别和表征基因， 对肿瘤促进剂诱导肿瘤特异性易感性 在小鼠和人类中的转化。 证据显示 这些基因在动物和人类系统中的参与已经 从观察到动物可以通过对 肿瘤促进 两个指定对促进敏感性的基因 小鼠肿瘤转化的研究 表皮JB 6细胞先前已被克隆。 这些推定 被称为pro-1和pro-2的基因已经被测序， 以激活和调节方式为特征的 的表达。 独特的pro-1杂交转录本已经被发现， 在小鼠细胞质和poly（A）+ RNA中鉴定。 P细胞 与P+或细胞相比， 转化的肿瘤促进剂，12-0-十四酰基佛波醇- 13-醋酸盐（TPA），这表明过度表达是一种可能的模式， activation. 一例中国人鼻咽癌的基因组DNA 细胞系CNE 2赋予促进敏感性（P+）活性， 抗性小鼠细胞。 这项活动，至少在一定程度上， 可归因于小鼠pro-1的活化同源物，如 用小鼠pro-1探针筛选CNE 2基因组文库， 在转染到pH1.5细胞中后测试同源物的P+活性， 抗性小鼠细胞。从一种分离的无活性pro-1同系物 正常人类图书馆和CNE 2图书馆正在 与活化的CNE 2 pro-1进行比较，以确定 activation. 异源双链分析正在进行， 非同源序列 嵌合构建体的测定 P+活性或非活性的人pro-1序列， 有望阐明生物活性的关键序列。 两个cDNA文库，一个来自启动促进诱导的皮肤 乳头状瘤和其他鳞状细胞癌， 得到与pro-2同源的克隆，含有cDNA片段 2.1和0.9 kb。 这一发现意义重大，因为它不仅 促进基因组克隆中的内含子-外显子分配，而且 开启了对pro-2表达在 体内致癌作用

The aim of this research is to identify and characterize genes that specify susceptibility to tumor promoter-induced neoplastic transformation in mice and humans. Evidence suggesting the involvement of such genes in animal and human systems has come from the observation that animals can be bred for sensitivity to tumor promotion. Two genes that specify sensitivity to promotion of neoplastic transformation by tumor promoters in mouse epidermal JB6 cells have been previously cloned. These putative genes, termed pro-1 and pro-2, have been sequenced and are being characterized with respect to mode of activation and regulation of expression. Unique pro-1-hybridizing transcripts have been identified in mouse cytoplasmic and poly(A)+ RNA. P- cells express lower levels of this transcript than do P+ or cells transformed by the tumor promoter, 12-0-tetradecanoylphorbol- 13-acetate (TPA), suggesting overexpression as a possible mode of activation. Genomic DNA of a Chinese nasopharyngeal carcinoma cell line, CNE2, confers promotion sensitivity (P+) activity on resistant mouse cells. This activity is, at least in part, attributable to activated homologs of mouse pro-1, as shown by screening a CNE2 genomic library with a mouse pro-1 probe and testing the homologs for P+ activity after transfection into resistant mouse cells. Inactive pro-1 homologs isolated from a normal human library and from the CNE2 library are being compared with activated CNE2 pro-1 to ascertain the mode of activation. Heteroduplex analysis is being carried out to pinpoint nonhomologous sequences. Assay of chimeric constructs of sequence from human pro-1 that is P+ active or inactive is expected to elucidate sequences critical to biological activity. Two cDNA libraries, one from initiation-promotion induced skin papillomas and the other from a squamous carcinoma, have yielded clones homologous to pro-2, containing cDNA fragments of 2.1 and 0.9 kb. This finding is significant in that it not only facilitates intron-exon assignment in the genomic clone, but also opens up investigation of the role of pro-2 expression in carcinogenesis in vivo.