We propose to investigate the biochemical events that result in tumor specific elevated expression of the proto-oncogene MYC, which is found in the majority of adenocarcinomas of the large bowel. Our preliminary results demonstrate that COLON CANCER cells differ from other carcinomas in regulation of myc RNA abundance. Our investigation will lead to the definition of cellular regulatory mechanisms that differ between normal and neoplastic colonic epithelial cells. These studies will increase our understanding of GENETIC REGULATORY MECHANISMS in a cell type that has been relatively neglected in this regard. Also, in view of the fact that enhanced expression of c-myc has been shown to be a potentially oncogenic event, we may gain a deeper understanding of the regulatory alterations that underlie the neoplastic state. An increase in the abundance of a cellular macromolecule results from either increased BIOSYNTHESIS or decreased DEGRADATION. In order to determine the stage(s) of gene expression which is responsible for enhancing the level of myc RNA in malignant colon cells, we will analyze both synthesis (transcription) and stability of myc RNA in cell lines and patient samples, derived from normal colon and colorectal carcinoma. In further work on transcription of the myc gene, we will study chromatin structure, DNA binding proteins, and transcription factors. In further work on myc RNA stability, we will analyze RNA structure, RNA binding proteins, and factors involved in myc RNA degradation.
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