The human mucin MUC1 is being investigated to determine its function and potential for use as a target antigen for different immunodiagnostic and immunotherapeutic protocols for diagnosing and treating pancreatic, breast, ovarian, and lung adenocarcinomas. Many of the tumor associated epitopes found on MUC1, which can include both carbohydrate and protein epitopes, are distinct among adenocarcinomas from different organ sites. These tumor antigens result from differential glycosylation of the core protein in different normal tissues and tumors derived from them. The types of complex oligosaccharides that can be added to MUC1 include those that are found on the family of cell surface adhesion molecules known as selectins and selectin ligands. MUC1 has several structural features deduced from primary amino acid sequence that are similar to selectin ligands. It is possible that some of these have biological functions as cell surface adhesion molecules for the tumor cells, or that secreted, soluble, glycoforms of MUC1 produced by some adenocarcinomas affect the cell trafficking patterns of lymphoid and inflammatory cells in patients with these malignancies. An epitope tagged MUC1 construct has have been developed and presents a unique opportunity to use MUC1 as a paradigm to study the relationship between its primary amino acid sequence its post- translational processing. The hypothesis being tested is that elements in the primary amino acid sequence of MUC1 contribute to its unique post- translational processing by secretory epithelial cells. The biological effects (molecular, morphological, and functional) of introducing mutations in the MUC1 sequence will also be evaluated. The proposed studies are designed to investigate: the types of oligosaccharides attached to MUC1 and their positions of attachment; the processes whereby the secreted and membrane bound forms of MUC1 are produced; the relative contribution of primary amino acid sequence to trafficking patterns, glycosylation, recycling secretion, and function; whether MUC1 plays a functional role in the metastatic properties of human adenocarcinomas.
Showing the most recent 10 out of 59 publications
