ISOLATION OF TUMOR SUPPRESSOR GENE ON CHROMOSOME 3P

人类3号染色体3p21.3区域的短臂在 许多癌症，包括导致40,000人死亡的肺癌 每年在美国。来自该区域的3号染色体的片段 抑制A9小鼠纤维肉瘤裸鼠成瘤的实验研究 小鼠试验。此外，3号染色体的这个相同片段也发生了变化 A9细胞对化疗药物的反应 增长停滞。这项研究的目的是确定诱导基因 A9对肿瘤的抑制作用并确定其是否为同一基因 赋予化疗药物不同的反应。CDNA3 其中抑制肿瘤生长的小鼠A9纤维肉瘤细胞将 使用可诱导表达系统进行鉴定。候选基因cDNA 将进行测试以确定它是否是相同的基因 对化疗药物的不同反应。诱导出的c DNA 小鼠A9细胞的肿瘤抑制和药物差异性反应 在包括Small Call在内的人类肿瘤细胞中测试这些效应 肺癌。该基因在人类肿瘤中的失活将是 通过突变分析和甲基化分析进行了探索。这个 抑癌基因的作用机制及其作用基础 从细胞凋亡到生长停滞的转变将与此相关 基因与其他基因在细胞凋亡途径中的相互作用。这项研究将定义一个 该基因已经被认为与许多癌症有关 删除并确定其在正常细胞中和在 肿瘤发生学。该基因在肿瘤中的状态可能提供关于 肿瘤对化疗药物的反应。

The short arm of human chromosome 3 in the region 3p21.3 is deleted in many cancers including lung cancer which is the cause of 40,000 deaths in the U.S. each year. A fragment of chromosome 3 from this region suppresses tumor formation of A9 mouse fibrosarcoma cells in a nude mouse assay. Furthermore, this same fragment of chromosome 3 changes the response of A9 cells to chemotherapeutic drugs from apoptosis to growth arrest. This study is designed to identify the gene inducing tumor suppression in A9 and to determine whether it is the same gene imparting the differential response to chemotherapeutic drugs. The cDNA which suppresses tumor growth of mouse A9 fibrosarcoma cells will be identified using an inducible expression system. The candidate cDNA will be tested to determine if it is the same gene which gives a differential response to chemotherapeutic drugs. The cDNA which induces tumor suppression and differential drug response in mouse A9 cells will be tested for these effects in human tumor cells including small call lung cancer. The inactivation of this gene in human tumors will be explored by both mutation analysis and by methylation assays. The mechanism of action of the tumor suppressor gene and the basis of the switch from apoptosis to growth arrest will be determined relating this gene to other genes in apoptotic pathways. This study will define a gene which already has been implicated in a number of cancers by deletion and define its functioning in normal cells and during tumorigenesis. Status of this gene in a tumor may provide clues about that tumor's response to chemotherapeutic drugs.