The long-term goal of this study is to determine the function of transcription factors expressed during endometrial cell decidualization. We hypothesize that a handful of transcription factors regulate the downstream target gene activation to develop deciduoma receptive to the embryo and to maintain diversified biological functions during pregnancy. To pursue the proposed study, human endometrial cell culture which recapitulates the process of decidualization in vivo has been established. Using this system we have elucidated the progestin-induced production of insulin-like growth factor binding protein-1 (IGFBP-1), the major secretory protein of decidual cells. We have also identified the essential cis-elements in the promoter of the, IGFBP-1 gene. These cis-elements provide molecular tool to analyze the functions of decidual cell transcription factors. The proposed study has four specific aims:
Aim 1 will identify and characterize the transcription factors that regulate the activation of the IGFBP-1 gene. The study will focus on the modes of action of the binding proteins of C/TCAAT, CRE , Sp1 and GATA motifs and progesterone receptor (PR) of PRE motif.
Aim 2 will determine the functions of the transcription factors, described in aim 1, in the promoters of prolactin (PRL), PR, and fibronectin (FN) in stromal/decidual.
Aim 3 will determine how these transcription factors act on the endogenous gene, IGFBP-1, PRL, PR and FN.
Aim 4 will determine the effects of estrogen, progesterone and synthetic steroids, agonists/antagonists on the mRNA levels of the functional transcription factors. Results obtained from the proposed study will help us to understand how the transcription factors control the process of decidualization in the human endometrial stromal/decidual cells. This information can be applied to improving the fertility regulation, tissue-specific fertility control, treatment of implantation failure and pregnancy disorder.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Reproductive Endocrinology Study Section (REN)
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Yoshinaga, Koji
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State University New York Stony Brook
Obstetrics & Gynecology
Schools of Medicine
Stony Brook
United States
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Zhang, Wei; Mazella, James; Kloosterboer, Helenius J et al. (2006) Progestagenic effects of tibolone are target gene-specific in human endometrial cells. J Soc Gynecol Investig 13:459-65
Tang, Meiyi; Mazella, James; Zhu, Hui Hui et al. (2005) Ligand activated relaxin receptor increases the transcription of IGFBP-1 and prolactin in human decidual and endometrial stromal cells. Mol Hum Reprod 11:237-43
Mazella, J; Tang, M; Tseng, L (2004) Disparate effects of relaxin and TGFbeta1: relaxin increases, but TGFbeta1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells. Hum Reprod 19:1513-8
Tseng, Linda; Tang, Meiyi; Wang, Zuncai et al. (2003) Progesterone receptor (hPR) upregulates the fibronectin promoter activity in human decidual fibroblasts. DNA Cell Biol 22:633-40
Tang, Meiyi; Mazella, James; Gao, Jiaguo et al. (2002) Progesterone receptor activates its promoter activity in human endometrial stromal cells. Mol Cell Endocrinol 192:45-53
Palejwala, Smita; Tseng, Linda; Wojtczuk, Andrea et al. (2002) Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells. Biol Reprod 66:1743-8
Gao, J; Mazella, J; Seppala, M et al. (2001) Ligand activated hPR modulates the glycodelin promoter activity through the Sp1 sites in human endometrial adenocarcinoma cells. Mol Cell Endocrinol 176:97-102
Gao, J; Mazella, J; Tang, M et al. (2000) Ligand-activated progesterone receptor isoform hPR-A is a stronger transactivator than hPR-B for the expression of IGFBP-1 (insulin-like growth factor binding protein-1) in human endometrial stromal cells. Mol Endocrinol 14:1954-61
Tseng, L; Mazella, J; Goligorsky, M S et al. (2000) Dopamine and morphine stimulate nitric oxide release in human endometrial glandular epithelial cells. J Soc Gynecol Investig 7:343-7
Tseng, L; Mazella, J (1999) Prolactin and its receptor in human endometrium. Semin Reprod Endocrinol 17:23-7

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