ROLE OF TUMOR SUPPRESSOR GENES AND ONCOGENES IN CHEMICAL CARCINOGENESIS

越来越多的证据表明，存在一个肿瘤超家族-- 参与不同癌症的升压基因。使用一种技术 被称为微细胞介导的染色体转移，我们绘制了肿瘤 人类和啮齿类肿瘤与1号染色体相关的抑制基因 (子宫内膜癌、纤维肉瘤)，染色体3(肾和肺 6号染色体(子宫内膜癌)，7号染色体 (绒毛膜癌)、9号染色体(子宫内膜癌)和染色体 宫颈癌、肾母细胞瘤、横纹肌肉瘤、肺癌 纤维肉瘤)和18号染色体(子宫内膜癌)。的变种 化学永生化的叙利亚仓鼠胚胎细胞被亚克隆 保留了(supB+)丢失的(supB-)抑制能力 与纤维肉瘤细胞株杂交后的致瘤性。两个SuB细胞 类型是非致癌的；然而，supB-，而不是supB+细胞表现出 有条件的锚地独立增长潜力。审查 这些细胞的各种细胞骨架成分显示出 肿瘤特有的SuB细胞中肌动蛋白微丝的组织 细胞，而supB+细胞表现出典型的正常微丝 培养中的成纤维细胞。来研究这一现象的分子基础 细胞骨架修饰，细胞总蛋白来源于两个细胞 用双向聚丙烯酰胺凝胶进行类型比较 电泳法。最显著的区别是减少了 超B细胞中的肌动蛋白结合蛋白原肌球蛋白。要检查 TM-1表达与肿瘤的发生有直接关系的可能性 SupB-表型，将表达载体导入supB+细胞 含有反义方向的TM-1基因。反义诱导 SuB+克隆中TM-1水平的降低导致微丝 重组和授予独立于锚地的增长潜力 与suB-细胞的特征无明显区别。这些 数据提供了TM-1可以调节微丝的直接证据 组织和锚定--独立成长。

There is increasing evidence for the existence of a family of tumor sup- pressor genes that are involved in different cancers. Using a technique known as microcell-mediated chromosome transfer, we mapped tumor suppressor genes involved in human and rodent cancers to chromosome 1 (endometrial cancer, fibrosarcomas), chromosome 3 (renal and lung cancer), chromosome 6 (endometrial cancer), chromosome 7 (choriocarcinoma), chromosome 9 (endo- metrial cancer), and chromosome 11 (cervical cancer, Wilms' tumor, rhab- domyosarcoma, lung cancer, fibrosarcoma) and chromosome 18 (endometrial cancer). Variants of chemically-immortalized Syrian hamster embryo cells were subcloned that had either retained (supB+) of lost (supB-) the ability to suppress tumorigenicity when hyridized with fibrosarcoma cell line. Both supB cell types are nontumorigenic; however, the supB-, but not supB+ cells exhibit conditional anchorage-independent growth potential. Examination of various cytoskeletal components of these cells revealed alterations of actin microfilament organization in supB- cells characteristic of tumor cells, while the supB+ cells exhibited microfilaments typical of normal fibroblasts in culture. To investigate the molecular basis for this cytoskeletal modification, total cellular proteins from the two cell types were compared by two-dimensional polyacrylamide gel electrophoresis. The most significant difference was reduction of the actin-binding protein tropomyosin in supB- cells. To examine the possibility of a direct relationship between TM-1 expression and the supB- phenotype, supB+ cells were transfected with an expression vector containing the TM-1 cDNA in an antisense orientation. Antisense-induced reduction of TM-1 levels in supB+ clones caused a microfilament reorganization and conferred anchorage- independent growth potential that was indistinguishable from those charact- eristic of supB- cells. These data provide direct evidence that TM-1 can regulate microfilament organization and anchorage-independent growth.