Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization.
The integrity of the feto-maternal interface is critical for survival of the conceptus. This interface, consisting of the maternal decidua and the invading placental trophoblast, is exposed to profound changes in oxygen tension during pregnancy. We demonstrate that human endometrial stromal cells become extraordinarily resistant to oxidative stress-induced apoptosis upon decidualization in response to cAMP and progesterone signaling. This differentiation process is associated with the induction of the forkhead transcription factor FOXO1, which in turn increases the expression of the mitochondrial antioxidant manganese superoxide dismutase. However, silencing of FOXO1 did not increase the susceptibility of decidualized cells to oxidative cell death. Comparative analysis demonstrated that hydrogen peroxide, a source of free radicals, strongly induces FOXO3a mRNA and protein expression in undifferentiated human endometrial stromal cells but not in decidualized cells. Expression of a constitutively active FOXO3a mutant elicited apoptosis in decidualized cells. Furthermore, silencing of endogenous FOXO3a in undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These results suggest that the induction of FOXO1 may enhance the ability of decidualized cells to prevent oxidative damage while the simultaneous repression of FOXO3a expression disables the signaling pathway responsible for oxidative cell death. The differential regulation of FOXO expression provides the decidua with a robust system capable of coping with prolonged episodes of oxidative stress during pregnancy.
Kajihara
Takeshi
T
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom.
Jones
Marius
M
Fusi
Luca
L
Takano
Masashi
M
Feroze-Zaidi
Fakhera
F
Pirianov
Grisha
G
Mehmet
Huseyin
H
Ishihara
Osamu
O
Higham
Jenny M
JM
Lam
Eric W-F
EW
Brosens
Jan J
JJ
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers; D004717:Endometrium / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
D017931:DNA Primers; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D011374:Progesterone; D000242:Cyclic AMP; D013482:Superoxide Dismutase