CYCLIN GENES AND MULTISTAGE CARCINOGENESIS

说明：本提案的目的是审查 cyclin D1基因及相关基因在多阶段癌变中的作用， 强调食道癌。 这些研究的基本原理 包含该基因的染色体位点11q13， 在食管和某些其他类型的人类中经常扩增 癌 此外，在最近的研究中，我们发现大约30%的人 食管肿瘤不仅表现出细胞周期蛋白D1的扩增， 增加了这个基因的表达。 第二个理论基础是突变 在细胞周期蛋白D1和其他细胞周期蛋白或细胞周期蛋白相关基因中， 通过扰乱细胞周期控制在致癌作用中起关键作用， 从而增强细胞增殖和基因组不稳定性。 到 确定细胞周期蛋白D1过表达对表型的影响， 细胞，一系列过表达细胞周期蛋白D1的细胞培养系将被 与对照细胞系相比，可能存在的生长差异 性质，细胞周期进程，转化，基因表达， 对化学致癌物反应的差异，以及对 基因扩增 为了确定细胞周期蛋白D1是否发挥其作用， 通过与p110 Rb蛋白或其他特异性细胞因子相互作用， 蛋白质，我们将利用酵母双杂交系统，并进行 蛋白磷酸化测定。 这些研究将 提供了深入了解细胞周期蛋白基因的作用，在多阶段 致癌作用，并可能提出新的癌症治疗策略 化学预防和治疗。

DESCRIPTION: The purpose of this proposal is to examine the role of the cyclin D1 gene, and related genes, in multistage carcinogenesis, emphasizing cancers of the esophagus. The rationale for these studies is that the chromosome locus 11q13 which contains this gene is frequently amplified in esophageal and certain other types of human cancer. Furthermore, in recent studies we found that about 30% of human esophageal tumors display not only amplification of cyclin D1 but also increased expression of this gene. A second rationale is that mutations in cyclin D1, and in other cyclins or cyclin-related genes, could play a critical role in carcinogenesis by perturbing cell cycle control, and thereby enhancing cell proliferation and genomic instability. To determine the effects of cyclin D1 overexpression on the phenotype of cells a series of cell culture lines that overexpress cyclin D1 will be compared to control cell lines for possible differences in growth properties, cell cycle progression, transformation, gene expression, differences in responses to chemical carcinogens, and susceptibility to gene amplification. To determine whether cyclin D1 exerts its effects by interacting with the p110 Rb protein, or other specific cellular proteins, we will utilize the yeast two-hybrid system and also carry out protein phosphorylation assays. Taken together, these studies will provide insights into the role of cyclin genes in multistage carcinogenesis and may suggest novel strategies for cancer chemoprevention and treatment.