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.
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