Regulation of decidualization in human endometrial stromal cells through exchange protein directly activated by cyclic AMP (Epac).
BACKGROUND
Human endometrial stromal cells (ESCs) undergo differentiation during the decidualization process. Decidualization is characterized by their enhanced production of IGF binding protein-1 (IGFBP-1), prolactin (PRL), and the forkhead transcriptional factor FOXO1, and transformation into more rounded cells, during the secretory phase of the menstrual cycle and subsequent pregnancy. Protein kinase A (PKA)-mediated cAMP signaling is crucial for this process. The present study was undertaken to examine the involvement of a mediator of cAMP signaling, exchange protein directly activated by cAMP (Epac), in decidualization of cultured ESCs.


RESULTS
Treatment of ESCs with the Epac-selective cAMP analog 8-CPT-2-OMe-cAMP (CPT) had no effect on IGFBP-1, PRL, and FOXO1 mRNA expression. However, CPT potentiated IGFBP-1 and PRL expression stimulated by the PKA-selective cAMP analog N(6)-Phe-cAMP (Phe) and activated Rap1, a downstream regulator of Epac signaling. Knock-down of Epac1, Epac2, or Rap1 significantly inhibited the Phe- or Phe/CPT-induced increase in IGFBP-1 and PRL expression, as well as Rap1 activation. Furthermore, CPT enhanced IGFBP-1 and PRL expression and the morphological differentiation induced by ovarian steroids, whereas Epac1, Epac2, or Rap1 knock-down suppressed these events.


CONCLUSIONS
These data provide evidence for the involvement of the Epac/Rap1 signaling pathway in cAMP-mediated decidualization of human ESCs.
Department of Endocrine and Neural Pharmacology, Tokyo University of Pharmacy and Life Sciences, Japan.
K
K
Kusama
M
M
Yoshie
K
K
Tamura
Y
Y
Kodaka
A
A
Hirata
T
T
Sakurai
H
H
Bai
K
K
Imakawa
H
H
Nishi
K
K
Isaka
T
T
Nagai
T
T
Nagao
E
E
Tachikawa
D002454:Cell Differentiation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003656:Decidua / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D020662:Guanine Nucleotide Exchange Factors; D018970:Insulin-Like Growth Factor Binding Protein 1; C116122:RAPGEF3 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D011388:Prolactin; D000242:Cyclic AMP