This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 21/10/2334    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takano, M. Articles by Kim, J. J. Search for Related Content PubMed PubMed Citation Articles by Takano, M. Articles by Kim, J. J.

Transcriptional Cross Talk between the Forkhead Transcription Factor Forkhead Box O1A and the Progesterone Receptor Coordinates Cell Cycle Regulation and Differentiation in Human Endometrial Stromal Cells

Institute of Reproductive and Developmental Biology (M.T., T.G., L.F., A.W., B.C., J.F., J.J.B.) and Cancer Research-UK Labs and Section of Cancer Cell Biology (A.V.S., E.W.-F.L.), Department of Oncology, Imperial College London, Hammersmith Hospital, London W12 OHS, United Kingdom; Department of Obstetrics and Gynaecology (J.Hi.), Imperial College London, St Mary’s Hospital, London W2 1PG, United Kingdom; Department of Obstetrics and Gynecology (O.I.), Saitama Medical School, Moroyama, Saitama 350–0495, Japan; Department of Obstetrics and Gynecology (Z.L., J.Ha., J.J.K), Division of Reproductive Biology Research, Northwestern University, Chicago, Illinois 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

Address all correspondence and requests for reprints to: Julie Kim, Ph.D., Department of Obstetrics and Gynecology, Division of Reproductive Biology Research, Northwestern University, 303 East Superior Street, Lurie 4-117, Chicago, Illinois 60611. E-mail: j-kim4{at}northwestern.edu.; or Jan Brosens, M.D., Ph.D., Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: j.brosens{at}imperial.ac.uk.

Differentiation of human endometrial stromal cells (HESCs) into decidual cells is associated with induction of the forkhead transcription factor forkhead box O1A (FOXO1). We performed a genomic screen to identify decidua-specific genes under FOXO1 control. Primary HESCs were transfected with small interfering RNA targeting FOXO1 or with nontargeting control small interfering RNA before treatment with a cAMP analogue and the progestin, medroxyprogesterone acetate 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 p57^Kip2 (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, 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 medroxyprogesterone acetate or with cAMP alone. Together, the data demonstrate that FOXO1 engages in transcriptional cross talk with progesterone receptor to coordinate cell cycle regulation and differentiation of HESCs.

NURSA Molecule Pages Link:

Nuclear Receptors:   PR

This article has been cited by other articles:

				Z. Lu, J. Hardt, and J.J. Kim Global analysis of genes regulated by HOXA10 in decidualization reveals a role in cell proliferation Mol. Hum. Reprod., June 1, 2008; 14(6): 357 - 366. [Abstract] [Full Text] [PDF]

				E. C. Ward, A. V. Hoekstra, L. J. Blok, P. Hanifi-Moghaddam, J. R. Lurain, D. K. Singh, B. M. Buttin, J. C. Schink, and J. J. Kim The Regulation and Function of the Forkhead Transcription Factor, Forkhead Box O1, Is Dependent on the Progesterone Receptor in Endometrial Carcinoma Endocrinology, April 1, 2008; 149(4): 1942 - 1950. [Abstract] [Full Text] [PDF]