MUCIN GENES--COLON CELL DIFFERENTIATION & TRANSFORMATION

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This proposal focuses on the cloning, physical characterization and regulatory studies of genes which encode human colonic mucin. Mucins are complex glycoconjugates which constitute the principal glycoprotein components of mucus gels. Mucins have often been implicated as tumor-associated antigens of adenocarcinoma from a variety of organs and tissues. Besides determining the carbohydrate determinants in mucins, which may become altered in tumor cells, it is important to characterize the molecular structure of mucin polypeptides and evaluate their relationship to transformation and differentiation. Our overall aim is to dissect biochemically and genetically the regulation of genes which encode peptides of human mucin during the differentiation of goblet cells, the colon epithelial cell lineage which synthesizes and produces mucins. Understanding the regulation of mucin gene expression will be instrumental to investigate whether and how this process is altered in tumor cells. Towards these goals we will specifically: 1. Clone cDNA and genomic sequences which encode a mucin backbone and link peptides (the proposed model of mucin peptide structure will be described below). a. determine the physical map of the genes and whether the genes for the core and link peptides are members of the same gene family. b. determine the promoter region of the gene. 2. Identify cis-acting elements and trans-acting factors required for accurate and efficient transcription of the mucin genes. 3. Determine whether the link and core peptide genes are coordinately regulated in goblets cells during differentiation or whether they respond to distinct regulatory circuits.