MUCIN GENES--COLON CELL DIFFERENTIATION &TRASFORMATION

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.