Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line

Differentiation of human placental mononuclear trophoblasts into a multinucleate syncytium involves up-regulation of key proteins promoting cell fusion and increased capacity for placental hormonogenesis. It is well established that the activation of adenylyl cyclase leads to increased expression of...

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Published in:	Molecular and cellular endocrinology Vol. 332; no. 1-2; pp. 213 - 220
Main Authors:	Delidaki, M., Gu, M., Hein, A., Vatish, M., Grammatopoulos, D.K.
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier Ireland Ltd 30-01-2011 Elsevier
Subjects:	adenylate cyclase BeWo cAMP cell fusion Cell Line, Tumor Choriocarcinoma Chorionic Gonadotropin - secretion Colforsin - pharmacology Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Enzyme Inhibitors - pharmacology Extracellular Signal-Regulated MAP Kinases - metabolism Female forskolin gene expression Gene Expression Regulation genes giant cells hCG human chorionic gonadotropin Humans MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - physiology MAPK messenger RNA mitogen-activated protein kinase neuroglia p38 Mitogen-Activated Protein Kinases - metabolism phosphorylation Placenta Placenta - cytology Placenta - physiology Pregnancy proteins Proto-Oncogene Proteins c-akt - metabolism secretion signal transduction Syncytin transcription factors trophoblast Trophoblasts - cytology Trophoblasts - drug effects Trophoblasts - physiology Placenta BeWo cAMP MAPK hCG Syncytin syncytin placenta
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Summary:	Differentiation of human placental mononuclear trophoblasts into a multinucleate syncytium involves up-regulation of key proteins promoting cell fusion and increased capacity for placental hormonogenesis. It is well established that the activation of adenylyl cyclase leads to increased expression of trophoblast fusogenic gene machinery and human chorionic gonadotropin (hCG) secretion. We used the forskolin-induced syncytialisation of BeWo choriocarcinoma cells as a model to characterise in detail the signalling pathway downstream of adenylyl cyclase. Forskolin treatment induced a rapid and potent ERK1/2 and p38MAPK phosphorylation; this cascade required PKA–AKAP interactions and led to downstream CREB-1/ATF-1 phosphorylation via ERK1/2-dependent but p38MAPK-independent mechanisms. Interestingly both p38MAPK and ERK1/2 were involved in forskolin-induced hCG-secretion, suggesting the presence of additional p38MAPK-dependent but CREB-1/ATF-1-independent pathways. Forskolin treatment of BeWo cells significantly up-regulated the expression of various fusogenic gene mRNAs, including syncytin-1 and -2 (by 3- and 10-fold, respectively) the transcription factors old astrocyte specifically induced substance (OASIS) and glial cells missing a (GCMa) (by 3- and 6-fold, respectively) and the syncytin-2 receptor, major facilitator superfamily domain containing 2 (MFSD2) (by 2-fold). Up-regulation of AKAP79 and AKAP250 (by 2.5- and 4-fold, respectively) was also identified in forskolin-treated BeWo cells. Forskolin effects on all these genes were suppressed by chemical inhibition of p38MAPK whereas only specific genes were sensitive to ERK1/2 inhibition. This data provide novel insights into the signalling molecules and mechanisms regulating fusogenic gene expression by the adenylyl cyclase pathway.
Bibliography:	http://dx.doi.org/10.1016/j.mce.2010.10.013 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0303-7207 1872-8057 0303-7207
DOI:	10.1016/j.mce.2010.10.013