During the last funding period, the applicant has made a number of published as well as preliminary observations that suggest: 1) c-Myc mediated anchorage independent growth of rat fibroblast is associated with the deregulated expression of genes including cyclin A, ornithine decarboxylase and several genes that he has cloned and are as yet undefined, 2) Deregulated cyclin A expression induces anchorage independent growth and apoptosis of rat fibroblasts, 3) Chromosomal localization of the MXI-1 gene and loss of heterozygosity studies suggest that MXI-1 is a tumor suppressor gene in human prostate cancer and glioblastomas, and 4) TNFb (lymphotoxin) selectively induces apoptosis in Myc- overexpressing fibroblasts. A unique, rapid and efficient model and systematic approach to identify c-Myc responsive genes has been established. Based on these observations and to reach the long term goal of delineating the mechanisms by which c-Myc transform cells, experiments are proposed to answer the following questions: 1) What are the genes that are upregulated by c-Myc, and how do they contribute to neoplasia? 2) What are the genes that are downregulated by c-Myc and how do they participate in neoplasia? 3) What are the effects of Mxi-1 on the expression of c-Myc target genes? and 4) Which c-Myc target genes predispose fibroblasts to lymphotoxin-mediated apoptosis, and is this pathway exploitable for therapeutic purposes?
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