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Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it works as an autocrine hormone. In this work, we demonstrated that human chorionic gonadotropin (hCG) added to JEG-3 cell line or to placental explants induces endogenous leptin expression. We also found that hCG increased cAMP intracellular levels in BeWo cells in a dose-dependent manner, stimulated cAMP response element (CRE) activity and the cotransfection with an expression plasmid of a dominant negative mutant of CREB caused a significant inhibition of hCG stimulation of leptin promoter activity. These results demonstrate that hCG indeed activates cAMP/PKA pathway, and that this pathway is involved in leptin expression. Nevertheless, we found leptin induction by hCG is dependent on cAMP levels. Treatment with (Bu)2cAMP in combination with low and non stimulatory hCG concentrations led to an increase in leptin expression, whereas stimulatory concentrations showed the opposite effect. We found that specific PKA inhibition by H89 caused a significant increase of hCG leptin induction, suggesting that probably high cAMP levels might inhibit hCG effect. It was found that hCG enhancement of leptin mRNA expression involved the MAPK pathway. In this work, we demonstrated that hCG leptin induction through the MAPK signaling pathway is inhibited by PKA. We observed that ERK1/2 phosphorylation increased when hCG treatment was combined with H89. In view of these results, the involvement of the alternative cAMP/Epac signaling pathway was studied. We observed that a cAMP analogue that specifically activates Epac (CPT-OMe) stimulated leptin expression by hCG. In addition, the overexpression of Epac and Rap1 proteins increased leptin promoter activity and enhanced hCG. In conclusion, we provide evidence suggesting that hCG induction of leptin gene expression in placenta is mediated not only by activation of the MAPK signaling pathway but also by the alternative cAMP/Epac signaling pathway. © 2012 Maymó et al.


Documento: Artículo
Título:The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells
Autor:Maymó, J.L.; Pérez Pérez, A.; Maskin, B.; Dueñas, J.L.; Calvo, J.C.; Sánchez Margalet, V.; Varone, C.L.
Filiación:Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Departamento de Bioquímica Médica y Biología Molecular, Hospital Universitario Virgen Macarena, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina
Servicio de Ginecología y Obstetricia, Hospital Universitario Virgen Macarena, Sevilla, Spain
Instituto de Biología y Medicina Experimental (IBYME), Buenos Aires, Argentina
Palabras clave:chorionic gonadotropin; cyclic AMP; cyclic AMP dependent protein kinase; cyclic AMP dependent protein kinase inhibitor; cyclic AMP derivative; cyclic AMP responsive element binding protein; EPAC protein; exchange protein directly activated by cyclic AMP; leptin; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase 1; n [2 (4 bromocinnamylamino)ethyl] 5 isoquinolinesulfonamide; protein; Rap1 protein; unclassified drug; article; Bewo cell; cell line; cell strain JEG 3; controlled study; cyclic AMP responsive element; enzyme activation; enzyme inhibition; enzyme phosphorylation; explant; gene activity; genetic transfection; human; human cell; human tissue; placenta; plasmid; promoter region; protein expression; protein induction; signal transduction; Base Sequence; Blotting, Western; Cell Line, Tumor; Chorionic Gonadotropin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DNA Primers; Enzyme Activation; Female; Guanine Nucleotide Exchange Factors; Humans; Leptin; MAP Kinase Signaling System; Placenta; Pregnancy; Real-Time Polymerase Chain Reaction
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
CAS:chorionic gonadotropin, 9002-61-3; cyclic AMP, 60-92-4; cyclic AMP responsive element binding protein, 130428-87-4, 130939-96-7; mitogen activated protein kinase, 142243-02-5; mitogen activated protein kinase 1, 137632-08-7; n [2 (4 bromocinnamylamino)ethyl] 5 isoquinolinesulfonamide, 127243-85-0; protein, 67254-75-5; Chorionic Gonadotropin; Cyclic AMP, 60-92-4; Cyclic AMP-Dependent Protein Kinases,; DNA Primers; Guanine Nucleotide Exchange Factors; Leptin; RAPGEF3 protein, human


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---------- APA ----------
Maymó, J.L., Pérez Pérez, A., Maskin, B., Dueñas, J.L., Calvo, J.C., Sánchez Margalet, V. & Varone, C.L. (2012) . The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells. PLoS ONE, 7(10).
---------- CHICAGO ----------
Maymó, J.L., Pérez Pérez, A., Maskin, B., Dueñas, J.L., Calvo, J.C., Sánchez Margalet, V., et al. "The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells" . PLoS ONE 7, no. 10 (2012).
---------- MLA ----------
Maymó, J.L., Pérez Pérez, A., Maskin, B., Dueñas, J.L., Calvo, J.C., Sánchez Margalet, V., et al. "The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells" . PLoS ONE, vol. 7, no. 10, 2012.
---------- VANCOUVER ----------
Maymó, J.L., Pérez Pérez, A., Maskin, B., Dueñas, J.L., Calvo, J.C., Sánchez Margalet, V., et al. The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells. PLoS ONE. 2012;7(10).