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Tumor Necrosis Factor Stimulates MUC1 Synthesis and Ectodomain Release in a Human Uterine Epithelial Cell Line

Department of Biological Sciences, University of Delaware, Newark, Delaware 19716

Address all correspondence and requests for reprints to: Daniel D. Carson, Department of Biological Sciences, University of Delaware, Newark, Delaware 19716. E-mail: dcarson{at}udel.edu.

Regulation of MUC1 expression and removal is a salient feature of embryo implantation, bacterial clearance, and tumor progression. In some species, embryo implantation is accompanied by a transcriptional decline in uterine epithelial expression of MUC1. In other species, MUC1 is locally removed at blastocyst attachment sites, suggesting a proteolytic activity. Previously, we demonstrated that MUC1 is proteolytically released from the surface of a human uterine epithelial cell line, HES, and identified TNF converting enzyme/a disintegrin and metalloprotease 17 as a constitutive and phorbol ester-stimulated MUC1 sheddase. The aims of the current study were to test the ability of soluble factors elevated during the periimplantation interval in vivo to stimulate ectodomain shedding of MUC1 from HES uterine epithelial cells and to characterize the nature of this proteolytic activity(ies). We identified TNF as a prospective endogenous stimulus of MUC1 ectodomain release and of MUC1 and TNF converting enzyme/a disintegrin and metalloprotease 17 expression. Moreover, we established that TNF-stimulated MUC1 shedding occurs independently of increased de novo protein synthesis and demonstrated that the TNF-induced increase in MUC1 gene expression is mediated through the B site in the MUC1 promoter. Finally, we determined that the TNF-sensitive MUC1 sheddase is inhibited by the metalloprotease inhibitor, TNF protease inhibitor (TAPI), and the endogenous tissue inhibitor of metalloprotease-3. Collectively, these studies provide the initial in vitro characterization of a putative physiological stimulus of MUC1 ectodomain release and establish the nature of the metalloproteolytic activity(ies) involved.

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