Mol. Hum. Reprod. Advance Access published online on January 4, 2008
Molecular Human Reproduction, doi:10.1093/molehr/gam081
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Glycodelin blocks progression to S phase and inhibits cell growth: a possible progesterone-induced regulator for endometrial epithelial cell growth Gycodelin inhibits G1/S progression
1Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, Japan 2Department of Obstetrics and Gynecology, Toho University School of Medicine, Tokyo 143–8541, Japan.
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. E-mail: tetsuo{at}sc.itc.keio.ac.jp
Prolonged exposure to unopposed estrogen in the absence of progesterone gives rise to endometrial hyperplasia and carcinoma. Postovulatory progesterone is necessary for the proper growth and differentiation of endometrial epithelial cells (EECs). Progesterone exposure induces the endometrial production of numerous bioactive substances, one of which is the glycoprotein, glycodelin (Gd). We investigated the role of Gd in cell cycle progression and cell growth to better understand how Gd affects EEC behavior and endometrial cancer pathogenesis. Ishikawa cells, a well-differentiated human endometrial epithelial cancer cell line, were transfected with expression plasmids encoding enhanced green fluorescent protein (EGFP) or EGFP-fused Gd (EGFP-Gd). They were then subjected to a cell proliferation assay, flow cytometry cell-cycle analysis, and RT-PCR analysis of cyclin-dependent kinase inhibitors (CDKIs) including p21, p27, and p16. Overexpression of EGFP-Gd resulted in a reduction of cell proliferation activity, an accumulation of G1-phase cells, and up-regulation of p21, p27, and p16 mRNAs. Furthermore, progesterone-induced inhibition of Ishikawa cell growth was partially attenuated by Gd knockdown using siRNA. These results indicate that Gd causes inhibition of G1/S progression together with up-regulation of CDKIs thereby reducing cell growth. Thus, progesterone-induced expression of Gd may, at least in part, contribute to the suppression of endometrial epithelial growth observed during the secretory phase.
Key Words: glycodelin/endometrium/cell cycle/cyclin-dependent kinase inhibitors/progesterone
Submitted on September 2, 2007; resubmitted on November 4, 2007; accepted on November 26, 2007.
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