Author:
Kusama Kazuya,Yoshie Mikihiro,Tamura Kazuhiro,Imakawa Kazuhiko,Tachikawa Eiichi
Abstract
The proper production of the implantation-related factors, leukemia inhibitory factor (LIF), cyclooxygenase 2 (COX2, PTGS2), and prostaglandin E2 (PGE2) in the uterine glands is essential for embryo implantation and the establishment of endometrial receptivity. It has been shown that cAMP-mediated protein kinase A (PKA) signaling regulates the production of these factors. We have previously reported that exchange protein directly activated by cAMP 2 (EPAC2, RAPGEF4), another cAMP mediator, is involved in the differentiation of endometrial stromal cells through the regulation of the expression of calreticulin (CALR). To address whether EPAC2–CALR signaling is involved in the expression of implantation-related factors, we examined the effect of EPAC2 and CALR knockdown on their expression in cultured human endometrial glandular epithelial EM1 cells, treated with forskolin, an adenylyl cyclase activator, an EPAC-selective cAMP analog (8-(4-chlorophenylthio)-2′-O-methyl cAMP (CPT)), or a PKA-selective cAMP analog (N6-phenyl-cAMP (Phe)). In addition, the status of cell senescence was examined. EPAC2 knockdown suppressed the expression of CALR protein and mRNA in EM1 cells. Forskolin- or Phe-, but not CPT-, induced expression of LIF or PTGS2 and secretion of PGE2 was inhibited in EPAC2- or CALR-silenced EM1 cells. In addition, knockdown of EPAC2 or CALR increased senescence-associated beta galactosidase activity and expression of p21 but decreased expression of p53. These findings indicate that expression of CALR regulated by EPAC2 in endometrial glandular epithelial cells is critical for the expression of LIF and PTGS2-mediated production of PGE2 through cAMP signaling. Furthermore, EPAC2 and CALR could play a role in the maintenance of gland function.
Subject
Endocrinology,Molecular Biology
Cited by
19 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献