MUC1 is a large mucin glycoprotein abundantly expressed at the apical surface of uterine epithelia and protects the uterus from enzymatic and microbial attack. In addition, MUC1 is removed at the time of blastocyst attachment in most species to create access to embryo binding sites at the apical surface of uterine epithelia. A possible exception is humans where MUC1 may serve as a selectin ligand for blastocysts. MUC1 expression varies considerably during the menstrual/estrous cycle in all species, although the molecular mechanisms underlying this regulation remain largely undefined. In addition to progesterone, proinflammatory cytokines and peroxisome proliferator-activated receptors (PPARs) modulate MUC1 expression in other contexts and have important roles in uterine physiology. Recent work, primarily derived from studies of tumor cells that highly overexpress MUC1, indicates a receptor function for MUC1 with the highly conserved cytoplasmic tail participating in multiple interactions with intracellular signal transducing molecules, including beta-catenin and Grb2. Nonetheless, it remains unclear if these interactions occur in non-tumorigenic cell lines or uterine epithelia. Moreover, in spite of the fact that the cytoplasmic tail is critical to these events and is released from the ectodomains as a result of ectodomain shedding, nothing is known about the subsequent processing and fate of the cytoplasmic tail following release. This proposal will examine basic aspects of MUC1 expression and function in uterine epithelia using a battery of MUC1 specific probes, MUC1 expressing human uterine epithelial cell lines and a novel transgenic mouse harboring the full length human MUC1 gene. Detailed information will be gained regarding the interplay among cytokines, progesterone and PPARs in the regulation of MUC1 gene expression. We will identify the intracellular pathways by which the highly active cytoplasmic domain released following ectodomain shedding is trafficked and degraded as well as determine what interactions take place between the cytoplasmic tail and signal transducing molecules in human uterine epithelial cell lines. Given MUC1's key roles in protecting the uterus from infection and modulating embryo implantation, these studies will provide new information on how we can therapeutically intervene to increase MUC1 expression to improve protection of the reproductive tract mucosa or reduce MUC1 expression to improve implantation success as well as reduce protection of tumors by MUC1. ? ? ?
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