Biological function of the MUC1 cytoplasmic tail in human pancreatic cancer

MUC1, a membrane-associated mucin, consists of an extracellular domain and a membrane-associated subunit including a transmembrane domain and intracellular cytoplasmic tail. Overexpression and aberrant post-translational processing of MUC1 molecules by tumor cells affect cell adhesion and cellular morphogenetic signaling. Downstream effects of MUC1-mediated signaling are predicted to influence gene expression and to affect cellular differentiation, motility, and transformation.; In studies conducted in this dissertation, we investigated the subcellular distribution of MUC1 cytoplasmic tail (CT) in human pancreatic cancer cells and found that fragments of MUC1 CT were distributed on the inside of the membrane, in the cytoplasm, and in the nucleus in cells expressing high-levels of MUC1. This finding raised the possibility that fragments of MUC1 CT interact with other signaling factors in the cytosol and nucleus. In addition, a number of post-translational modifications including phosphorylation of serine, threonine and tyrosine were detected on cytoplasmic and nuclear fragments of MUC1 CT by Q-TOF proteomics analysis, which implies that there are interactions between the MUC1 CT and kinases responsible for these modifications.; Our results further suggested that MUC1 CT modulates the canonical Wnt/beta-catenin signal transduction and the transcriptional regulation of downstream gene expression. Under conditions of MUC1 CT overexpression, the steady state levels of nuclear beta-catenin were significantly enhanced as compared to cells expressing low-levels of MUC1. The association between nuclear beta-catenin and nuclear fragments of MUC1 CT was not affected by elimination of cadherin-catenin complexes. Furthermore, overexpression of MUC1 CT contributes to the transactivation of cyclin D1 (CCND1) gene, a downstream gene regulated by Wnt/beta-catenin signal pathway, and to the elevation of cyclin D1 protein. This contribution was affected by cellular differentiation level since the transactivation of cyclin D1 gene only presented in some but not all human pancreatic cancer lines of different differentiation states. In addition, the interactions between the MUC1 CT and p120 catenin, another molecule with dual functions in cell-adhesion and gene regulation, were determined in human pancreatic cancer cells.