Silencing of the JNK pathway maintains progesterone receptor activity in decidualizing human endometrial stromal cells exposed to oxidative stress signals.
Survival of the conceptus is dependent on continuous progesterone signaling in the maternal decidua but how this is achieved under conditions of oxidative stress that characterize early pregnancy is unknown. Using primary cultures, we show that modest levels of reactive oxygen species (ROS) increase sumoylation in human endometrial stromal cells (HESCs), leading to enhanced modification and transcriptional inhibition of the progesterone receptor (PR). The ability of ROS to induce a sustained hypersumoylation response, or interfere with PR activity, was lost upon differentiation of HESCs into decidual cells. Hypersumoylation in response to modest levels of ROS requires activation of the JNK pathway. Although ROS-dependent JNK signaling is disabled on decidualization, the cells continue to mount a transcriptional response, albeit distinct from that observed in undifferentiated HESCs. We further show that attenuated JNK signaling in decidual cells is a direct consequence of altered expression of key pathway modulators, including induction of MAP kinase phosphatase 1 (MKP1). Overexpression of MKP1 dampens JNK signaling, prevents hypersumoylation, and maintains PR activity in undifferentiated HESCs exposed to ROS. Thus, JNK silencing uncouples ROS signaling from the SUMO conjugation pathway and maintains progesterone responses and cellular homeostasis in decidual cells under oxidative stress conditions imposed by pregnancy.
Leitao
Beatriz
B
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Rd., London W12 0NN.
Jones
Marius C
MC
Fusi
Luca
L
Higham
Jenny
J
Lee
Yun
Y
Takano
Masashi
M
Goto
Tomoko
T
Christian
Mark
M
Lam
Eric W-F
EW
Brosens
Jan J
JJ
D002454:Cell Differentiation; D003656:Decidua / Q000166:cytology / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D004717:Endometrium / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D011980:Receptors, Progesterone / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism
D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D006861:Hydrogen Peroxide; D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1