The steroid hormone progesterone (P) is essential for the proper functioning of the uterus due to its pleiotropic effects on proliferation, differentiation, and apoptosis. The physiological actions of P are mediated by interaction with specific progesterone receptor (PR) isoforms PR-A and PR-B. Defects in PR signaling have been associated with abnormal endometrial proliferation and differentiation, which can underlie the clinical conditions of sub-fertility, infertility, endometrial carcinoma, and endometriosis. In the previous funding period, we identified a novel PR-interacting protein termed Basic Transcription Element Binding Protein-1 (BTEB1), whose interaction with PR in vivo and in vitro elicited functional consequences on endometrial cells. We found that: a) BTEB1 enhances the P-sensitivity of uterine endometrial epithelial-associated genes to PR-B mediated transactivation; b) under low Estrogen (E) and/or P environments, BTEB1 functions as a serum-dependent growth stimulator of endometrial epithelial cells; and c) ablation of the BTEB1 gene in female mice, albeit non-embryo-lethal, results in uterine and reproductive phenotypes of diminished litter size, smaller uteri, and greater frequency of peri-natal death, relative to wild type (WT) littermates. Since BTEB1 likely constitutes an important determinant in optimal PR signaling, an intriguing question involves the physiologic context under which PR utilizes BTEB1 to elicit distinct biological activities that are important to normal uterine biology. This renewal proposal will test the hypothesis that specific functional associations of PR isoforms with BTEB1 in stromal vs. epithelial cells generate distinct transcriptional responses. We will address the consequence of Ioss-of-BTEB1-function on PR-mediated gene transcription, proliferation and differentiation in endometrial epithelial and stromal cells using BTEB1 knock-out mice in four Specific Aims: 1) Characterize the physiological role of BTEB1 on PR-mediated pregnancy events; 2) Evaluate PR-A-mediated endometrial stromal cell proliferation and PR gene expression with loss of BTEB1 function; 3) Evaluate functional association of PR-B and BTEB1 in endometrial glandular epithelial differentiation; and d) Examine E- and P-regulation of BTEB1 gene expression. This research will provide novel mechanistic insights into PR signaling involving PR coregulators that have relevance to human subfertility and hormone-dependent gynecological diseases.

R01HD021961

1986-07-01

2010-09-30