Exchange protein directly activated by cAMP (EPAC) promotes transcriptional activation of the decidual prolactin gene via CCAAT/enhancer-binding protein in human endometrial stromal cells
Kazuya Kusama A , Kazuhiro Tamura B F , Hanako Bai C , Toshihiro Sakurai D , Hirotaka Nishi E , Keiichi Isaka E , Kazuhiko Imakawa A and Mikihiro Yoshie B
+ Author Affiliations
- Author Affiliations
A Animal Resource Science Centre, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan.
B Department of Endocrine and Neural Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan.
C Laboratory of Animal Genetics and Reproduction, Department of Animal Science, Graduate School of Agriculture, Hokkaido University, Hokkaido, 060-8589, Japan.
D Department of Occupational and Environmental Health, Faculty of Pharmaceutical Science, Tokyo University of Science, Chiba, 278-8510, Japan.
E Department of Obstetrics and Gynaecology, Tokyo Medical University, Tokyo, 160-0023, Japan.
F Corresponding author. Email: hiro@toyaku.ac.jp
Reproduction, Fertility and Development 30(11) 1454-1461 https://doi.org/10.1071/RD17483
Submitted: 26 November 2017 Accepted: 10 April 2018 Published: 8 May 2018
Abstract
Protein kinase A (PKA) signalling accompanies elevated intracellular cAMP levels during endometrial stromal cell (ESC) decidualisation. Exchange protein directly activated by cAMP (EPAC), an alternate mediator of cAMP signalling, promotes PKA analogue-induced decidualisation; however, the precise mechanism by which EPAC and PKA co-operatively stimulate decidualisation has not been characterised. To examine the role of CCAAT/enhancer-binding protein (C/EBP) in EPAC- and PKA-mediated decidualisation of primary human ESCs, a reporter plasmid containing the 332 bp region upstream from the transcription initiation site of the decidual prolactin (dPRL) gene was generated and the promoter activity was evaluated using a luciferase assay. The dPRL promoter activity was increased by treatment of transfected ESCs with the PKA-selective cAMP analogue N6-phenyl-cAMP (Phe) and enhanced further by co-treatment with the EPAC-selective cAMP analogue 8-(4-chlorophenyltio)-2′-O-methyl cAMP (CPT). Treatment with forskolin, an adenylyl cyclase activator, had a similar effect on reporter activity. Site-directed mutagenesis of the C/EBPβ- and/or C/EBPδ-binding site in the dPRL promoter abolished Phe/CPT-mediated elevation of the reporter activity. EPAC2 knockdown markedly reduced Phe-stimulated C/EBPβ and C/EBPδ mRNA levels, as well as forkhead box O1 (FOXO1) protein levels. These results suggest that EPAC signalling enhances PKA-mediated dPRL expression in ESCs by acting on C/EBP response elements in the promoter region of the gene.
Additional keywords: endometrium, decidialisation, protein kinase A, pregnancy.
References
Borland, G., Bird, R. J., Palmer, T. M., and Yarwood, S. J. (2009). Activation of protein kinase Cα by EPAC1 is required for the ERK- and CCAAT/enhancer-binding protein β-dependent induction of the SOCS-3 gene by cyclic AMP in COS1 cells. J. Biol. Chem. 284, 17391–17403.| Activation of protein kinase Cα by EPAC1 is required for the ERK- and CCAAT/enhancer-binding protein β-dependent induction of the SOCS-3 gene by cyclic AMP in COS1 cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXnsVWlu7w%3D&md5=453063bb86604ec39297929a5f5bd884CAS |
Bos, J. L. (2006). EPAC proteins: multi-purpose cAMP targets. Trends Biochem. Sci. 31, 680–686.
| EPAC proteins: multi-purpose cAMP targets.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xht1ClsrfF&md5=d666186508e23f9ee035ef20d9fbf9deCAS |
Brosens, J. J., Hayashi, N., and White, J. O. (1999). Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells. Endocrinology 140, 4809–4820.
| Progesterone receptor regulates decidual prolactin expression in differentiating human endometrial stromal cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXmtFGqsbs%3D&md5=76c529b8e158af3a8dc8b5cd59f4cfc6CAS |
Christian, M., Zhang, X., Schneider-Merck, T., Unterman, T. G., Gellersen, B., White, J. O., and Brosens, J. J. (2002). Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein β in differentiating human endometrial stromal cells. J. Biol. Chem. 277, 20825–20832.
| Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein β in differentiating human endometrial stromal cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XkslWnsrc%3D&md5=64671182de26209b73dc28300251c39bCAS |
Dey, S. K. (2010). How we are born. J. Clin. Invest. 120, 952–955.
| How we are born.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXksVChsrs%3D&md5=673a609c0fe660aacab40a795ae84647CAS |
Gellersen, B., and Brosens, J. (2003). Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J. Endocrinol. 178, 357–372.
| Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXotFOhsbw%3D&md5=f7562131578e43e6c24946d62de5f893CAS |
Ghosh, A. K., Lacson, R., Liu, P., Cichy, S. B., Danilkovich, A., Guo, S., and Unterman, T. G. (2001). A nucleoprotein complex containing CCAAT/enhancer-binding protein beta interacts with an insulin response sequence in the insulin-like growth factor- binding protein-1 gene and contributes to insulin-regulated gene expression. J Biol Chem 276, 8507–8515.
| A nucleoprotein complex containing CCAAT/enhancer-binding protein beta interacts with an insulin response sequence in the insulin-like growth factor- binding protein-1 gene and contributes to insulin-regulated gene expression.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXitFKgtLg%3D&md5=2b9e5f5a5465c49987151121a45ce3c2CAS |
Kajihara, T., Brosens, J. J., and Ishihara, O. (2013). The role of FOXO1 in the decidual transformation of the endometrium and early pregnancy. Med. Mol. Morphol. 46, 61–68.
| The role of FOXO1 in the decidual transformation of the endometrium and early pregnancy.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXptlKktL0%3D&md5=81c883ff1b8708e5b10f9748b40a66f3CAS |
Kawarabayashi, Y., Hai, L., Honda, A., Horiuchi, S., Tsujioka, H., Ichikawa, J., and Inoue, R. (2012). Critical role of TRPC1-mediated Ca2+ entry in decidualization of human endometrial stromal cells. Mol. Endocrinol. 26, 846–858.
| Critical role of TRPC1-mediated Ca2+ entry in decidualization of human endometrial stromal cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xmsl2nsbw%3D&md5=7385b80eefe7f87a8ce467c0fb3cfadbCAS |
Kooistra, M. R., Dubé, N., and Bos, J. L. (2007). Rap1: a key regulator in cell–cell junction formation. J. Cell Sci. 120, 17–22.
| Rap1: a key regulator in cell–cell junction formation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXht1Gmsrc%3D&md5=5d972340fd5630956db519bee8d89ce1CAS |
Kusama, K., Yoshie, M., Tamura, K., Kodaka, Y., Hirata, A., Sakurai, T., Bai, H., Imakawa, K., Nishi, H., Isaka, K., Nagai, T., Nagao, T., and Tachikawa, E. (2013). Regulation of decidualization in human endometrial stromal cells through exchange protein directly activated by cyclic AMP (EPAC). Placenta 34, 212–221.
| Regulation of decidualization in human endometrial stromal cells through exchange protein directly activated by cyclic AMP (EPAC).Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhs1CgurY%3D&md5=dfcd46841dcfd385309674f5e6453311CAS |
Kusama, K., Yoshie, M., Tamura, K., Nakayama, T., Nishi, H., Isaka, K., and Tachikawa, E. (2014a). The role of exchange protein directly activated by cyclic AMP 2-mediated calreticulin expression in the decidualization of human endometrial stromal cells. Endocrinology 155, 240–248.
| The role of exchange protein directly activated by cyclic AMP 2-mediated calreticulin expression in the decidualization of human endometrial stromal cells.Crossref | GoogleScholarGoogle Scholar |
Kusama, K., Yoshie, M., Tamura, K., Daikoku, T., Takarada, T., and Tachikawa, E. (2014b). Possible roles of the cAMP-mediators Epac and Rap1 in decidualization of rat uterus. Reproduction 147, 897–906.
| Possible roles of the cAMP-mediators Epac and Rap1 in decidualization of rat uterus.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhtVKjurnN&md5=ea17db1778eae74898fe6760a5167e2bCAS |
Labied, S., Kajihara, T., Madureira, P. A., Fusi, L., Jones, M. C., Higham, J. M., Varshochi, R., Francis, J. M., Zoumpoulidou, G., Essafi, A., Fernandez de Mattos, S., Lam, E. W., and Brosens, J. J. (2006). Progestins regulate the expression and activity of the forkhead transcription factor FOXO1 in differentiating human endometrium. Mol. Endocrinol. 20, 35–44.
| Progestins regulate the expression and activity of the forkhead transcription factor FOXO1 in differentiating human endometrium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XjslemtQ%3D%3D&md5=65e22e966bc2c034db4c4d4fdeda51a0CAS |
Lynch, V. J., May, G., and Wagner, G. P. (2011). Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB. Nature 480, 383–386.
| Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhsVKjsbrO&md5=8d277b17b659945b5a3235ab958f05b6CAS |
Mantena, S. R., Kannan, A., Cheon, Y. P., Li, Q., Johnson, P. F., Bagchi, I. C., and Bagchi, M. K. (2006). C/EBPβ is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proc. Natl. Acad. Sci. USA 103, 1870–1875.
| C/EBPβ is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhslehtLw%3D&md5=7a5db0d149db3fc8b1eb99f623c30a13CAS |
Mayr, B., and Montminy, M. (2001). Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2, 599–609.
| Transcriptional regulation by the phosphorylation-dependent factor CREB.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXlvVOqs70%3D&md5=b5b137faef13c8965b21d5ba5ee3a4edCAS |
Pohnke, Y., Kempf, R., and Gellersen, B. (1999). CCAAT/enhancer-binding proteins are mediators in the protein kinase A-dependent activation of the decidual prolactin promoter. J Biol Chem 274, 24808–24818.
| CCAAT/enhancer-binding proteins are mediators in the protein kinase A-dependent activation of the decidual prolactin promoter.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXls1ymsrg%3D&md5=bd3557f57b6be4299ea25faea502908fCAS |
Ramathal, C. Y., Bagchi, I. C., Taylor, R. N., and Bagchi, M. K. (2010). Endometrial decidualization: of mice and men. Semin. Reprod. Med. 28, 017–026.
| Endometrial decidualization: of mice and men.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlahs70%3D&md5=b000cb464fc2edb2058e7e9c7da4c98aCAS |
Salker, M., Teklenburg, G., Molokhia, M., Lavery, S., Trew, G., Aojanepong, T., Mardon, H. J., Lokugamage, A. U., Rai, R., Landles, C., Roelen, B. A., Quenby, S., Kuijk, E. W., Kavelaars, A., Heijnen, C. J., Regan, L., Macklon, N. S., and Brosens, J. J. (2010). Natural selection of human embryos: impaired decidualization of endometrium disables embryo–maternal interactions and causes recurrent pregnancy loss. PLoS One 5, e10287.
| Natural selection of human embryos: impaired decidualization of endometrium disables embryo–maternal interactions and causes recurrent pregnancy loss.Crossref | GoogleScholarGoogle Scholar |
Tamura, K., Yoshie, M., Nishi, H., Osakabe, Y., Isaka, K., Hara, T., and Kogo, H. (2006). Expression of stathmin in human uterus and decidualizing endometrial stromal cells. Reproduction 132, 625–636.
| Expression of stathmin in human uterus and decidualizing endometrial stromal cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xht1ahs7rI&md5=7205825ec4c399515ca90b56886026bfCAS |
Tamura, I., Sato, S., Okada, M., Tanabe, M., Lee, L., Maekawa, R., Asada, H., Yamagata, Y., Tamura, H., and Sugino, N. (2014). Importance of C/EBPβ binding and histone acetylation status in the promoter regions for induction of IGFBP-1, PRL, and Mn-SOD by cAMP in human endometrial stromal cells. Endocrinology 155, 275–286.
| Importance of C/EBPβ binding and histone acetylation status in the promoter regions for induction of IGFBP-1, PRL, and Mn-SOD by cAMP in human endometrial stromal cells.Crossref | GoogleScholarGoogle Scholar |
Tang, B., Guller, S., and Gurpide, E. (1993). Mechanisms involved in the decidualization of human endometrial stromal cells. Acta Eur. Fertil. 24, 221–223.
| 1:STN:280:DyaK2M%2Fns1Olsg%3D%3D&md5=92707f53ae8c67ad1f77009930da3e36CAS |
Tapia-Pizarro, A., Archiles, S., Argandoña, F., Valencia, C., Zavaleta, K., Cecilia Johnson, M., González-Ramos, R., and Devoto, L. (2017). hCG activates Epac-Erk1/2 signaling regulating progesterone receptor expression and function in human endometrial stromal cells. Mol. Hum. Reprod. 23, 393–405.
| hCG activates Epac-Erk1/2 signaling regulating progesterone receptor expression and function in human endometrial stromal cells.Crossref | GoogleScholarGoogle Scholar |
Tsukada, J., Yoshida, Y., Kominato, Y., and Auron, P. E. (2011). The CCAAT/ enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine 54, 6–19.
| The CCAAT/ enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXjsFClsrs%3D&md5=e86a3d1961aefbbfb77630003f1b8c88CAS |
Wang, W., Li, Q., Bagchi, I. C., and Bagchi, M. K. (2010). The CCAAT/enhancer binding protein β is a critical regulator of steroid-induced mitotic expansion of uterine stromal cells during decidualization. Endocrinology 151, 3929–3940.
| The CCAAT/enhancer binding protein β is a critical regulator of steroid-induced mitotic expansion of uterine stromal cells during decidualization.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXht1Oju73M&md5=f1731687374a5b931d73f6ac4b707e62CAS |
Woolson, H. D., Thomson, V. S., Rutherford, C., Yarwood, S. J., and Palmer, T. M. (2009). Selective inhibition of cytokine-activated extracellular signal-regulated kinase by cyclic AMP via Epac1-dependent induction of suppressor of cytokine signalling-3. Cell. Signal. 21, 1706–1715.
| Selective inhibition of cytokine-activated extracellular signal-regulated kinase by cyclic AMP via Epac1-dependent induction of suppressor of cytokine signalling-3.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtVKmu7bO&md5=147875de88fdb45bfee2cbb62c8fcf40CAS |
Yang, S., Fang, Z., Suzuki, T., Sasano, H., Zhou, J., Gurates, B., Tamura, M., Ferrer, K., and Bulun, S. (2002). Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAAT/enhancer binding proteins (C/EBPs): decreased C/EBPbeta in endometriosis is associated with overexpression of aromatase. J. Clin. Endocrinol. Metab. 87, 2336–2345.
| 1:CAS:528:DC%2BD38XjsFGgsro%3D&md5=782ada3c171d942e9446e44e0500991fCAS |
Yarwood, S. J., Borland, G., Sands, W. A., and Palmer, T. M. (2008). Identification of CCAAT/enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene. J. Biol. Chem. 283, 6843–6853.
| Identification of CCAAT/enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXivFyjtrk%3D&md5=363a3b7a32cf0ab76bff215fef96621dCAS |
Yoshie, M., Kaneyama, K., Kusama, K., Higuma, C., Nishi, H., Isaka, K., and Tamura, K. (2010). Possible role of the exchange protein directly activated by cyclic AMP (EPAC) in the cyclic AMP-dependent functional differentiation and syncytialization of human placental BeWo cells. Hum. Reprod. 25, 2229–2238.
| Possible role of the exchange protein directly activated by cyclic AMP (EPAC) in the cyclic AMP-dependent functional differentiation and syncytialization of human placental BeWo cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtVGrurfF&md5=e481d18d01b82bcc67aa553e932ca83aCAS |
