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Division of Reproductive Biology Research, Department of Obstetrics and Gynecology and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, Illinois 60611
Insulin-like growth factor-binding protein-1 (IGFBP1) is a major secretory product of the decidualized endometrium. In the present study, we investigated the role of two transcription factors, progesterone receptor (PGR) and a member of the forkhead box class O family of transcription factors (FOXO1A), in the regulation of the IGFBP1 gene in endometrial cells. Human endometrial fibroblasts (HuF) expressed FOXO1A, progesterone receptor A (PGRA), and progesterone receptor B (PGRB) proteins, whereas the endometrial adenocarcinoma cell line, HEC-1B cells, expressed only FOXO1A and no detectable PGR proteins. When FOXO1A expression was silenced using small interference RNA, IGFBP1 expression decreased in both HuF and HEC-1B cells. Using the chromatin immunoprecipitation technique, we demonstrated that liganded PGR was recruited to the IGFBP1 promoter region (–358 to –49). In addition, immunoprecipitation of HuF nuclear proteins with a PGR antibody followed by immunoblotting with anti-FOXO1A revealed that these two proteins interact in these cells. Reporter studies demonstrated that whereas liganded PGRA or PGRB increased a progesterone response element-linked reporter construct, pPRE/ GRE.E1b.Luc, coexpression of FOXO1A inhibited the PGRB response in HuF and synergistically increased PGRA and PGRB response in HEC-1B cells. Furthermore, in HEC-1B cells, FOXO1A increased IGFBP1 promoter activity, and coexpression of PGRA or PGRB further increased the promoter activity in a cooperative manner. In HuF, the response to FOXO1A and PGR was not additive; in fact, it was lower than the sum of the individual responses. Thus, FOXO1A and PGR associate with one another, and each influences the transactivating potential of the other. The cell type-dependent responses strongly implicate the involvement of other cofactors.
decidua, female reproductive tract, implantation, progesterone receptor, uterus
2 Correspondence: J. Julie Kim, Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, 303 E. Superior Ave., Suite 4-117, Chicago, IL 60611. FAX: 312 503 0095; j-kim4{at}northwestern.edu
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