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Role and Regulation of the Serum- and Glucocorticoid-Regulated Kinase 1 in Fertile and Infertile Human Endometrium

Institute of Reproductive and Developmental Biology (F.F.-Z., L.F., M.T., J.H., M.S.S., T.G., E.W.-F.L., S.K.S., J.J.B.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; Proteomics Core Laboratory (S.E.), Rush University Medical Centre, Chicago, Illinois 60612; Department of Obstetrics and Gynaecology (R.K., P.G.G.), University Hospital Maastricht, University of Maastricht, 6202 AZ Maastricht, The Netherlands; Institute of Physiology (K.M.B, M.P., F.L.) and Molecular Pathology (K.K.) University of Tübingen, D-76072 Tübingen, Germany; and the Department of Pathology (A.M.S), Cambridge CB2 1QP, United Kingdom

Address all correspondence and requests for reprints to: 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.

Using cDNA microarray analysis, we identified SGK1 (serum- and glucocorticoid-regulated kinase 1) as a gene aberrantly expressed in midsecretory endometrium of women with unexplained infertility. SGK1 is a serine/threonine kinase involved primarily in epithelial ion transport and cell survival responses. Real-time quantitative PCR analysis of a larger, independent sample set timed to coincide with the period of uterine receptivity confirmed increased expression of SGK1 transcripts in infertile women compared with fertile controls. We further demonstrate that SGK1 expression is regulated by progesterone in human endometrium in vivo as well as in explant cultures. During the midsecretory phase of the cycle, SGK1 mRNA and protein were predominantly but not exclusively expressed in the luminal epithelium, and expression in this cellular compartment was higher in infertile women. In the stromal compartment, SGK1 expression was largely confined to decidualizing cells adjacent to the luminal epithelium. In primary culture, SGK1 was induced and phosphorylated upon decidualization of endometrial stromal cells in response to 8-bromo-cAMP and progestin treatment. Moreover, overexpression of SGK1 in decidualizing cells enhanced phosphorylation and cytoplasmic translocation of the forkhead transcription factor FOXO1 and inhibited the expression of PRL, a major decidual marker gene. Conversely, knockdown of endogenous SGK1 by small interfering RNA increased nuclear FOXO1 levels and enhanced PRL expression. The observation that SGK1 targets FOXO1 in differentiating human endometrium, together with its distinct temporal and spatial expression pattern and increased expression in infertile patients, suggest a major role for this kinase in early pregnancy events.

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