ROLE OF TUMOR SUPPRESSOR GENES AND ONCOGENES IN CHEMICAL CARCINOGENESIS

抑癌基因和癌基因在化学致癌中的作用

• 批准号: 5202169
• 负责人: J C BARRETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5202169
• 关键词: SDS polyacrylamide gel electrophoresis; actins; antisense nucleic acid; carcinogen testing; cell line; chemical carcinogen; chemical carcinogenesis; chromosomes; complementary DNA; embryo /fetus tissue /cell culture; fibrosarcoma; gene expression; genetic mapping; hamsters; microfilaments; mutagen testing; neoplasm /cancer genetics; oncogenes; transfection /expression vector; tropomyosin; tumor suppressor genes

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.

越来越多的证据表明存在一个肿瘤超家族， 与不同癌症有关的升压基因。使用一种技术 称为微细胞介导的染色体转移， 与人类和啮齿类动物1号染色体癌症有关的抑制基因 （子宫内膜癌，纤维肉瘤），3号染色体（肾和肺 癌症），染色体6（子宫内膜癌），染色体7 （绒毛膜癌）、9号染色体（子宫内膜癌）和9号染色体（子宫内膜癌）。 11例（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）。的变体 将化学永生化的叙利亚仓鼠胚胎细胞亚克隆， 保留（supB+）或丧失（supB-）抑制 当与纤维肉瘤细胞系杂交时，两种supB细胞 类型是非致瘤性的;然而，supB-，而不是supB+细胞表现出 条件锚定独立的生长潜力。审查 这些细胞的各种细胞骨架成分揭示了 肿瘤特征性supB细胞肌动蛋白微丝结构 细胞，而supB+细胞表现出典型的正常微丝 培养的成纤维细胞。为了研究这种现象的分子基础 细胞骨架修饰，来自两个细胞的总细胞蛋白 采用双向凝胶电泳技术， 电泳最显著的差异是减少了 supB细胞中肌动蛋白结合蛋白原肌球蛋白。审查 TM-1的表达与肿瘤的发生有直接关系。 supB-表型，用表达载体转染supB+细胞 含有反义方向的TM-1 cDNA。反义诱导 在supB+克隆中TM-1水平的降低导致微丝 重组和赋予锚定独立的增长潜力， 与supB细胞的特征难以区分。这些 数据提供了TM-1可以调节微丝的直接证据 组织和锚定独立增长。