Progestins regulate the expression and activity of the forkhead transcription factor FOXO1 in differentiating human endometrium.
Menstruation, or cyclic shedding of nonpregnant endometrial tissue with associated bleeding, occurs only in humans and a few other species. This breakdown of the endometrium in response to falling ovarian progesterone levels is a complex process, characterized by local leukocyte infiltration, expression and activation of matrix metalloproteinases, and apoptosis. Spontaneous decidualization (differentiation) of the stromal compartment precedes the cyclic shedding of the endometrium in various menstruating species but the mechanisms that link these processes are not understood. In this study, we identified FOXO1 as a key transcription factor responsible for mediating apoptosis of decidualized human endometrial stromal cells (HESCs) in response to progesterone withdrawal. We demonstrate that medroxyprogesterone acetate (MPA, a synthetic progestin) enhances the expression of FOXO1 in differentiating HESCs while simultaneously inducing cytoplasmic retention and inactivation of FOXO1. Withdrawal of MPA from decidualized HESCs results in rapid nuclear accumulation of FOXO1, increased BIM expression, a proapoptotic FOXO1 target gene, and cell death. Conversely, silencing of FOXO1 expression completely abolishes cell death induced by MPA withdrawal. In summary, the observation that differentiating HESCs become dependent on progesterone signaling for survival through induction and reversible inactivation of FOXO1 suggests a novel mechanism that links decidualization of the endometrium to menstruation.
Labied
Soraya
S
Institute of Reproductive and Developmental Biology, Wolfson & Weston Research Centre for Family Health, Imperial College London, Faculty of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom.
Kajihara
Takeshi
T
Madureira
Patricia A
PA
Fusi
Luca
L
Jones
Marius C
MC
Higham
Jenny M
JM
Varshochi
Rana
R
Francis
Julia M
JM
Zoumpoulidou
Georgia
G
Essafi
Abdelkader
A
Fernandez de Mattos
Silvia
S
Lam
Eric W-F
EW
Brosens
Jan J
JJ
D021581:Active Transport, Cell Nucleus; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D004717:Endometrium / Q000166:cytology* / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011372:Progestins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011374:Progesterone; D017258:Medroxyprogesterone Acetate; D000242:Cyclic AMP