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Submitted on January 30, 2007
Accepted on June 29, 2007
Institute of Reproductive and Developmental Biology (M.T., T.G., L.F., A.W., B.C., J.J.B.), Imperial College London, Hammersmith Hospital, London, United Kingdom; the Department of Obstetrics and Gynaecology (J.H.), Imperial College London, St Mary's Hospital, London W2 1PG, United Kingdom; Department of Obstetrics and Gynecology (O. I.), Saitama Medical School, Moroyama, Saitama, Japan; the Cancer Research-UK Labs and Section of Cancer Cell Biology (A. S., E.W.-F.L.), Department of Oncology, Imperial College London, Hammersmith Hospital, London, United Kingdom; the Department of Obstetrics and Gynecology (Z.L., J.H., J.J.K) Division of Reproductive Biology Research, Northwestern University, Chicago, IL, 60611; and Departments of Physiology and Biophysics, and Medicine (T.G.U), University of Illinois at Chicago, College of Medicine and Veterans Affairs Chicago Healthcare System (West Side), Chicago, Illinois 60612
* To whom correspondence should be addressed. E-mail: j.brosens{at}imperial.ac.uk or j-kim4{at}northwestern.edu.
Differentiation of human endometrial stromal cells (HESCs) into decidual cells is associated with induction of the forkhead transcription factor FOXO1. We performed a genomic screen to identify decidua-specific genes under FOXO1 control. Primary HESCs were transfected with small interfering RNA (siRNA) targeting FOXO1 or with non-targeting control siRNA prior to treatment with a cAMP analogue and the progestin medroxyprogesterone acetate (MPA) for 72 h. Total RNA was processed for whole genome analysis using high-density oligonucleotide arrays. We identified 3405 significantly regulated genes upon decidualization of HESCs, 507 (15.3%) of which were aberrantly expressed upon FOXO1 knockdown. Among the most up-regulated FOXO1-dependent transcriptional targets were WNT signaling-related genes (WNT4, WNT16), the insulin receptor (INSR), differentiation markers (PRL, IGFBP1, and LEFTY2), and the cyclin-dependent kinase inhibitor p57Kip2 (CDKN1C). Analysis of FOXO1-dependent down-regulated genes uncovered several factors involved in cell cycle regulation, including CCNB1, CCNB2, MCM5, CDC2 and NEK2. Cell viability assay and cell cycle analysis demonstrated that FOXO1 silencing promotes proliferation of differentiating HESCs. Using a glutathione-S-transferase pull-down assay, we confirmed that FOXO1 interacts with progesterone receptor (PR), irrespectively of the presence of ligand. In agreement, knockdown of PR disrupted the regulation of FOXO1 target genes involved in differentiation (IGFBP1, PRL, and WNT4) and cell cycle regulation (CDKN1, CCNB2 and CDC2) in HESCs treated with either cAMP plus MPA or with cAMP alone. Together, the data demonstrate that FOXO1 engages in transcriptional cross-talk with PR to coordinate cell cycle regulation and differentiation of HESCs.
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