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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD021961-17
Application #
6860123
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Ilekis, John V
Project Start
1986-07-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
17
Fiscal Year
2005
Total Cost
$293,612
Indirect Cost
Name
Arkansas Children's Hospital Research Institute
Department
Type
DUNS #
002593692
City
Little Rock
State
AR
Country
United States
Zip Code
72202
Heard, Melissa E; Melnyk, Stepan B; Simmen, Frank A et al. (2016) High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status. Endocrinology 157:2870-82
Simmen, Rosalia C M; Heard, Melissa E; Simmen, Angela M et al. (2015) The Krüppel-like factors in female reproductive system pathologies. J Mol Endocrinol 54:R89-R101
Pabona, John Mark P; Zhang, Daying; Ginsburg, David S et al. (2015) Prolonged pregnancy in women is associated with attenuated myometrial expression of progesterone receptor co-regulator Krüppel-like Factor 9. J Clin Endocrinol Metab 100:166-74
Heard, Melissa E; Velarde, Michael C; Giudice, Linda C et al. (2015) Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis. Biol Reprod 92:140
Heard, Melissa E; Simmons, Christian D; Simmen, Frank A et al. (2014) Krüppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis. Endocrinology 155:1532-46
Pabona, John Mark P; Simmen, Frank A; Nikiforov, Mikhail A et al. (2012) Krüppel-like factor 9 and progesterone receptor coregulation of decidualizing endometrial stromal cells: implications for the pathogenesis of endometriosis. J Clin Endocrinol Metab 97:E376-92
Heard, Melissa E; Pabona, John Mark P; Clayberger, Carol et al. (2012) The reproductive phenotype of mice null for transcription factor Krüppel-like factor 13 suggests compensatory function of family member Krüppel-like factor 9 in the peri-implantation uterus. Biol Reprod 87:115
Simmen, Frank A; Simmen, Rosalia C M (2011) The maternal womb: a novel target for cancer prevention in the era of the obesity pandemic? Eur J Cancer Prev 20:539-48
Simmons, Christian D; Pabona, John Mark P; Heard, Melissa E et al. (2011) Krüppel-like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen. Biol Reprod 85:378-85
Pabona, John Mark P; Zeng, Zhaoyang; Simmen, Frank A et al. (2010) Functional differentiation of uterine stromal cells involves cross-regulation between bone morphogenetic protein 2 and Kruppel-like factor (KLF) family members KLF9 and KLF13. Endocrinology 151:3396-406

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