ROLE OF TUMOR SUPPRESSOR GENES AND ONCOGENS IN CHEMICAL CARCINOGENESIS

抑癌基因和癌基因在化学致癌作用中的作用

• 批准号: 3876903
• 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/3876903
• 关键词: cell fusion; chemical carcinogenesis; chromosome aberrations; complementary DNA; embryo /fetus tissue /cell culture; fibroblasts; gene expression; genetic library; genetic manipulation; genetic mapping; hamsters; lung neoplasms; molecular cloning; neoplasm /cancer genetics; nephroblastoma; oncogenes; protooncogene; rhabdomyosarcoma; tissue /cell culture; tropomyosin; tumor suppressor genes; uterus neoplasms

Cancer development in humans and animals is a multistep process involving at least two classes of genes, proto-oncogenes and tumor suppressor genes. We have shown that neoplastic transformation of Syrian hamster embryo cells (SHE) in culture is a multistep process involving both activation of proto-oncogenes and inactivation of a tumor suppressor gene. The loss or inactivation of tumor suppressor genes is an essential step in the multistep neoplastic transformation of SHE cells. Non-tumorigenic variants have been isolated that have lost (sup-) or retained (sup+) the ability to suppress tumorigenicity of tumor cells in cell hybrids. Fusions of sup+ or sup- variants with different tumor cells show different patterns of suppression indicating that a family of tumor suppressor genes exists in these fibroblast cells. Currently, several strategies to clone tumor suppressor genes are in progress. cDNA libraries of sup+ hamster cells have been screened with RNA from sup+ or sup- cells and differentially expressed cDNAs have been cloned. Two-dimensional gel analyses of proteins showed that a reduction in the expression of tropomyosin I correlates with the loss of the tumor suppressor function. A cellular phenotype associated with the loss of tumor suppressor gene function has also been found. Sup- cells suspended in agar respond reversibly to transforming and normal growth factors by forming colonies in agar whereas sup+ cells fail to grow., Tumor suppressor genes can be mapped to specific chromosomes by introduction of normal chromosomes into tumor cells by microcell fusion. We have shown that normal human chromosome 11 suppresses cervical carcinoma cells, lung adenocarcinoma cells, rhabdomyosarcoma cells, and Wilms' tumor cells, whereas chromosome 3 suppresses renal carcinoma and lung adenocarcinoma cells. An uterine endometrial cancer cell was suppressed by three different chromosomes (Nos. 1, 6, and 9). In addition to the tumor suppressor genes described above that are expressed in some immortal cell lines, tumorigenicity also may be limited by cellular senescence. Our results indicate that a gene(s), possibly involved in the senescence phenotype, can be mapped to human chromosome 1.

人类和动物的癌症发展是一个多步骤的过程，涉及 至少两类基因，原癌基因和抑癌基因。 我们已经证明叙利亚仓鼠胚胎细胞的肿瘤转化 （SHE）在文化中是一个多步骤的过程，涉及激活 原癌基因和抑癌基因失活。损失或 抑癌基因失活是肿瘤抑制的重要一步 SHE 细胞的多步肿瘤转化。非致瘤性变异 已被隔离，失去（sup-）或保留（sup+）能力 抑制细胞杂交体中肿瘤细胞的致瘤性。 super+ 或 的融合 不同肿瘤细胞的超变体表现出不同的模式 抑制表明存在肿瘤抑制基因家族 这些成纤维细胞。目前克隆肿瘤的几种策略 抑制基因正在进行中。 super+ 仓鼠细胞的 cDNA 文库具有 用来自sup+或sup-细胞的RNA进行筛选并差异表达 cDNA 已被克隆。蛋白质的二维凝胶分析表明 原肌球蛋白 I 表达的减少与 肿瘤抑制功能丧失。与相关的细胞表型 还发现肿瘤抑制基因功能丧失。超级细胞 悬浮在琼脂中，对转化和正常生长产生可逆反应 通过在琼脂中形成集落而导致sup+细胞无法生长。, 肿瘤 通过引入抑制基因可以将其映射到特定染色体 通过微细胞融合将正常染色体引入肿瘤细胞。我们已经证明 正常人11号染色体抑制宫颈癌细胞、肺癌 腺癌细胞、横纹肌肉瘤细胞和肾母细胞瘤细胞， 而3号染色体则抑制肾癌和肺腺癌 细胞。三种不同的方法可抑制子宫内膜癌细胞 染色体（1、6 和 9 号）。除了抑癌基因 如上所述，在一些永生细胞系中表达， 致瘤性也可能受到细胞衰老的限制。我们的成果 表明可能与衰老表型有关的基因可以 被映射到人类1号染色体上。