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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD029963-15A1
Application #
7149941
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
1992-12-01
Project End
2011-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
15
Fiscal Year
2006
Total Cost
$281,993
Indirect Cost
Name
University of Delaware
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
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Neeraja Dharmaraj; Engel, Brian J; Carson, Daniel D (2013) Activated EGFR stimulates MUC1 expression in human uterine and pancreatic cancer cell lines. J Cell Biochem 114:2314-22
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Dharmaraj, Neeraja; Wang, Peng; Carson, Daniel D (2010) Cytokine and progesterone receptor interplay in the regulation of MUC1 gene expression. Mol Endocrinol 24:2253-66
Wang, Peng; Dharmaraj, Neeraja; Brayman, Melissa J et al. (2010) Peroxisome proliferator-activated receptor gamma activation inhibits progesterone-stimulated human MUC1 expression. Mol Endocrinol 24:1368-79
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Julian, JoAnne; Enders, Allen C; Fazleabas, Asgerally T et al. (2005) Compartmental distinctions in uterine Muc-1 expression during early pregnancy in cynomolgous macaque (Macaca fascicularis) and baboon (Papio anubis). Hum Reprod 20:1493-503
Brayman, Melissa; Thathiah, Amantha; Carson, Daniel D (2004) MUC1: a multifunctional cell surface component of reproductive tissue epithelia. Reprod Biol Endocrinol 2:4

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