Maymó, J.L.; Pérez Pérez, A.; Maskin, B.; Dueñas, J.L.; Calvo, J.C.; Sánchez Margalet, V.; Varone, C.L. "The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells" (2012) PLoS ONE. 7(10)
Artículo de Acceso Abierto. Puede ser descargado en su versión final
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


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


  • Fitzgerald, J.S., Busch, S., Wengenmayer, T., Foerster, K., de la Motte, T., Signal transduction in trophoblast invasion (2005) Chem Immunol Allergy, 88, pp. 181-199
  • Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Positional cloning of the mouse obese gene and its human homologue (1994) Nature, 372, pp. 425-432
  • Houseknecht, K.L., Portocarrero, C.P., Leptin and its receptors: regulators of whole-body energy homeostasis (1998) Domest Anim Endocrinol, 15, pp. 457-475
  • Reitman, M.L., Bi, S., Marcus-Samuels, B., Gavrilova, O., Leptin and its role in pregnancy and fetal development-an overview (2001) Biochem Soc Trans, 29, pp. 68-72
  • Henson, M.C., Castracane, V.D., Leptin in Pregnancy: An Update (2005) Biol Reprod
  • Cervero, A., Horcajadas, J.A., Dominguez, F., Pellicer, A., Simon, C., Leptin system in embryo development and implantation: a protein in search of a function (2005) Reprod Biomed Online, 10, pp. 217-223
  • Masuzaki, H., Ogawa, Y., Sagawa, N., Hosoda, K., Matsumoto, T., Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans (1997) Nat Med, 3, pp. 1029-1033
  • Senaris, R., Garcia-Caballero, T., Casabiell, X., Gallego, R., Castro, R., Synthesis of leptin in human placenta (1997) Endocrinology, 138, pp. 4501-4504
  • Coya, R., Martul, P., Algorta, J., Aniel-Quiroga, M.A., Busturia, M.A., Effect of leptin on the regulation of placental hormone secretion in cultured human placental cells (2006) Gynecol Endocrinol, 22, pp. 620-626
  • Perez-Perez, A., Gambino, Y., Maymo, J., Goberna, R., Fabiani, F., MAPK and PI3K activities are required for leptin stimulation of protein synthesis in human trophoblastic cells (2010) Biochem Biophys Res Commun, 396, pp. 956-960
  • Magarinos, M.P., Sanchez-Margalet, V., Kotler, M., Calvo, J.C., Varone, C.L., Leptin promotes cell proliferation and survival of trophoblastic cells (2007) Biol Reprod, 76, pp. 203-210
  • Perez-Perez, A., Maymo, J., Duenas, J.L., Goberna, R., Calvo, J.C., Leptin prevents apoptosis of trophoblastic cells by activation of MAPK pathway (2008) Arch Biochem Biophys, 477, pp. 390-395
  • Perez-Perez, A., Maymo, J., Gambino, Y., Duenas, J.L., Goberna, R., Leptin stimulates protein synthesis-activating translation machinery in human trophoblastic cells (2009) Biol Reprod, 81, pp. 826-832
  • Sagawa, N., Yura, S., Itoh, H., Mise, H., Kakui, K., Role of leptin in pregnancy-a review (2002) Placenta, 23 (SUPPL.), pp. 80-86
  • Bajoria, R., Sooranna, S.R., Ward, B.S., Chatterjee, R., Prospective function of placental leptin at maternal-fetal interface (2002) Placenta, 23, pp. 103-115
  • Coya, R., Gualillo, O., Pineda, J., Garcia, M.C., Busturia, M.A., Effect of cyclic 3′,5′-adenosine monophosphate, glucocorticoids, and insulin on leptin messenger RNA levels and leptin secretion in cultured human trophoblast (2001) Biol Reprod, 65, pp. 814-819
  • Bi, S., Gavrilova, O., Gong, D.W., Mason, M.M., Reitman, M., Identification of a placental enhancer for the human leptin gene (1997) J Biol Chem, 272, pp. 30583-30588
  • Maymo, J.L., Perez Perez, A., Sanchez-Margalet, V., Duenas, J.L., Calvo, J.C., Up-regulation of placental leptin by human chorionic gonadotropin (2009) Endocrinology, 150, pp. 304-313
  • Maymo, J.L., Perez Perez, A., Duenas, J.L., Calvo, J.C., Sanchez-Margalet, V., Regulation of placental leptin expression by cyclic adenosine 5′-monophosphate involves cross talk between protein kinase A and mitogen-activated protein kinase signaling pathways (2010) Endocrinology, 151, pp. 3738-3751
  • Hoeffler, J.P., Meyer, T.E., Yun, Y., Jameson, J.L., Habener, J.F., Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA (1988) Science, 242, pp. 1430-1433
  • Taylor, S.S., Buechler, J.A., Yonemoto, W., cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes (1990) Annu Rev Biochem, 59, pp. 971-1005
  • Renstrom, E., Eliasson, L., Rorsman, P., Protein kinase A-dependent and -independent stimulation of exocytosis by cAMP in mouse pancreatic B-cells (1997) J Physiol, 502 (1), pp. 105-118
  • Cass, L.A., Summers, S.A., Prendergast, G.V., Backer, J.M., Birnbaum, M.J., Protein kinase A-dependent and -independent signaling pathways contribute to cyclic AMP-stimulated proliferation (1999) Mol Cell Biol, 19, pp. 5882-5891
  • Staples, K.J., Bergmann, M., Tomita, K., Houslay, M.D., McPhee, I., Adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent inhibition of IL-5 from human T lymphocytes is not mediated by the cAMP-dependent protein kinase A. J Immunol (2001), 167, pp. 2074-2080; Ge, Y.C., Li, J.N., Ni, X.T., Guo, C.M., Wang, W.S., Cross talk between cAMP and p38 MAPK pathways in the induction of leptin by hCG in human placental syncytiotrophoblasts (2011) Reproduction, 142, pp. 369-375
  • Gloerich, M., Bos, J.L., Epac: defining a new mechanism for cAMP action (2010) Annu Rev Pharmacol Toxicol, 50, pp. 355-375
  • Kawasaki, H., Springett, G.M., Mochizuki, N., Toki, S., Nakaya, M., A family of cAMP-binding proteins that directly activate Rap1 (1998) Science, 282, pp. 2275-2279
  • de Rooij, J., Zwartkruis, F.J., Verheijen, M.H., Cool, R.H., Nijman, S.M., Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP (1998) Nature, 396, pp. 474-477
  • Stork, P.J., Schmitt, J.M., Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation (2002) Trends Cell Biol, 12, pp. 258-266
  • Christensen, A.E., Selheim, F., de Rooij, J., Dremier, S., Schwede, F., cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension (2003) J Biol Chem, 278, pp. 35394-35402
  • Roscioni, S.S., Elzinga, C.R., Schmidt, M., Epac: effectors and biological functions (2008) Naunyn Schmiedebergs Arch Pharmacol, 377, pp. 345-357
  • Yoshie, M., Kaneyama, K., Kusama, K., Higuma, C., Nishi, H., 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 (2010) Hum Reprod, 25, pp. 2229-2238
  • Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding (1976) Anal Biochem, 72, pp. 248-254
  • Mellon, P.L., Clegg, C.H., Correll, L.A., McKnight, G.S., Regulation of transcription by cyclic AMP-dependent protein kinase (1989) Proc Natl Acad Sci U S A, 86, pp. 4887-4891
  • Clegg, C.H., Abrahamsen, M.S., Degen, J.L., Morris, D.R., McKnight, G.S., Cyclic AMP-dependent protein kinase controls basal gene activity and steroidogenesis in Y1 adrenal tumor cells (1992) Biochemistry, 31, pp. 3720-3726
  • Zwartkruis, F.J., Wolthuis, R.M., Nabben, N.M., Franke, B., Bos, J.L., Extracellular signal-regulated activation of Rap1 fails to interfere in Ras effector signalling (1998) EMBO J, 17, pp. 5905-5912
  • Gonzalez, G.A., Montminy, M.R., Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133 (1989) Cell, 59, pp. 675-680
  • Livak, K.J., Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method (2001) Methods, 25, pp. 402-408
  • Cauzac, M., Czuba, D., Girard, J., Hauguel-de Mouzon, S., Transduction of leptin growth signals in placental cells is independent of JAK-STAT activation (2003) Placenta, 24, pp. 378-384
  • Wang, H., Segaloff, D.L., Ascoli, M., Lutropin/choriogonadotropin down-regulates its receptor by both receptor-mediated endocytosis and a cAMP-dependent reduction in receptor mRNA (1991) J Biol Chem, 266, pp. 780-785
  • Daniel, P.B., Walker, W.H., Habener, J.F., Cyclic AMP signaling and gene regulation (1998) Annu Rev Nutr, 18, pp. 353-383
  • Cameo, P., Srisuparp, S., Strakova, Z., Fazleabas, A.T., Chorionic gonadotropin and uterine dialogue in the primate (2004) Reprod Biol Endocrinol, 2, p. 50
  • Cameron, M.R., Foster, J.S., Bukovsky, A., Wimalasena, J., Activation of mitogen-activated protein kinases by gonadotropins and cyclic adenosine 5′-monophosphates in porcine granulosa cells (1996) Biol Reprod, 55, pp. 111-119
  • Faure, M., Voyno-Yasenetskaya, T.A., Bourne, H.R., cAMP and beta gamma subunits of heterotrimeric G proteins stimulate the mitogen-activated protein kinase pathway in COS-7 cells (1994) J Biol Chem, 269, pp. 7851-7854
  • Lange-Carter, C.A., Pleiman, C.M., Gardner, A.M., Blumer, K.J., Johnson, G.L., A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf (1993) Science, 260, pp. 315-319
  • Hattori, M., Minato, N., Rap1 GTPase: functions, regulation, and malignancy (2003) J Biochem, 134, pp. 479-484
  • Enserink, J.M., Christensen, A.E., de Rooij, J., van Triest, M., Schwede, F., A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK (2002) Nat Cell Biol, 4, pp. 901-906
  • Schubring, C., Englaro, P., Siebler, T., Blum, W.F., Demirakca, T., Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels (1998) Horm Res, 50, pp. 276-283
  • Hardie, L., Trayhurn, P., Abramovich, D., Fowler, P., Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy (1997) Clin Endocrinol (Oxf), 47, pp. 101-106
  • Domali, E., Messinis, I.E., Leptin in pregnancy (2002) J Matern Fetal Neonatal Med, 12, pp. 222-230
  • Henson, M.C., Castracane, V.D., Leptin in pregnancy (2000) Biol Reprod, 63, pp. 1219-1228
  • Henson, M.C., Castracane, V.D., Leptin: roles and regulation in primate pregnancy (2002) Semin Reprod Med, 20, pp. 113-122
  • Henson, M.C., Castracane, V.D., Leptin in pregnancy: an update (2006) Biol Reprod, 74, pp. 218-229
  • Gambino, Y.P., Maymo, J.L., Perez Perez, A., Calvo, J.C., Sanchez-Margalet, V., Elsevier Trophoblast Research Award Lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells- Focus on leptin expression (2012) Placenta
  • Maymo, J.L., Perez, A.P., Gambino, Y., Calvo, J.C., Sanchez-Margalet, V., Review: Leptin gene expression in the placenta-regulation of a key hormone in trophoblast proliferation and survival (2011) Placenta, 32 (SUPPL. 2), pp. S146-S153
  • Monjo, M., Pujol, E., Roca, P., alpha2- to beta3-Adrenoceptor switch in 3T3-L1 preadipocytes and adipocytes: modulation by testosterone, 17beta-estradiol, and progesterone (2005) Am J Physiol Endocrinol Metab, 289, pp. E145-E150
  • Popovic, V., Casanueva, F.F., Leptin, nutrition and reproduction: new insights (2002) Hormones (Athens), 1, pp. 204-217
  • Ambrosini, G., Nath, A.K., Sierra-Honigmann, M.R., Flores-Riveros, J., Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1 (2002) J Biol Chem, 277, pp. 34601-34609
  • Gambino, Y.P., Maymo, J.L., Perez-Perez A.Duenas, J.L., Sanchez-Margalet, V., 17Beta-Estradiol Enhances Leptin Expression in Human Placental Cells Through Genomic and Nongenomic Actions (2010) Biol Reprod
  • Rebut-Bonneton, C., Segond, N., Demignon, J., Porquet, D., Evain-Brion, D., Effects of calcitonin on human trophoblastic cells in culture: absence of autocrine control (1992) Mol Cell Endocrinol, 85, pp. 65-71
  • Standley, P.R., Standley, C.A., Identification of a functional Na+/Mg2+ exchanger in human trophoblast cells (2002) Am J Hypertens, 15, pp. 565-570
  • Zygmunt, M., Hahn, D., Munstedt, K., Bischof, P., Lang, U., Invasion of cytotrophoblastic JEG-3 cells is stimulated by hCG in vitro (1998) Placenta, 19, pp. 587-593
  • Syme, M.R., Paxton, J.W., Keelan, J.A., Drug transfer and metabolism by the human placenta (2004) Clin Pharmacokinet, 43, pp. 487-514
  • Terasaki, T., Hosoya, K., Conditionally immortalized cell lines as a new in vitro model for the study of barrier functions (2001) Biol Pharm Bull, 24, pp. 111-118
  • Serrano, M.A., Macias, R.I., Briz, O., Monte, M.J., Blazquez, A.G., Expression in human trophoblast and choriocarcinoma cell lines, BeWo, Jeg-3 and JAr of genes involved in the hepatobiliary-like excretory function of the placenta (2007) Placenta, 28, pp. 107-117
  • Pidoux, G., Gerbaud, P., Tsatsaris, V., Marpeau, O., Ferreira, F., Biochemical characterization and modulation of LH/CG-receptor during human trophoblast differentiation (2007) J Cell Physiol, 212, pp. 26-35
  • Shi, Q.J., Lei, Z.M., Rao, C.V., Lin, J., Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts (1993) Endocrinology, 132, pp. 1387-1395
  • Randeva, H.S.J.A., Karteris, E., Hillhouse, E.W., hCG production and activity during pregnancy (2001) Fetal Matern Med Rev, 12, pp. 198-208
  • Rao, C.V., An overview of the past, present, and future of nongonadal LH/hCG actions in reproductive biology and medicine (2001) Semin Reprod Med, 19, pp. 7-17
  • Segaloff, D.L., Ascoli, M., The lutropin/choriogonadotropin receptor 4 years later (1993) Endocr Rev, 14, pp. 324-347
  • Menon, K.M., Munshi, U.M., Clouser, C.L., Nair, A.K., Regulation of luteinizing hormone/human chorionic gonadotropin receptor expression: a perspective (2004) Biol Reprod, 70, pp. 861-866
  • Demers, L.M., Gabbe, S.G., Villee, C.A., Greep, R.O., Human chorionic gonadotropin-mediated glycogenolysis in human placental villi: a role of prostaglandins (1973) Biochim Biophys Acta, 313, pp. 202-210
  • Menon, K.M., Jaffe, R.B., Chorionic gonadotropin sensitive adenylate cyclase in human term placenta (1973) J Clin Endocrinol Metab, 36, pp. 1104-1109
  • Shaywitz, A.J., Greenberg, M.E., CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals (1999) Annu Rev Biochem, 68, pp. 821-861
  • Hunzicker-Dunn, M., Maizels, E.T., FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A. Cell Signal (2006), 18, pp. 1351-1359; Seminara, S.B., Dipietro, M.J., Ramaswamy, S., Crowley Jr., W.F., Plant, T.M., Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications (2006) Endocrinology, 147, pp. 2122-2126
  • Strauss III, J.F., Kido, S., Sayegh, R., Sakuragi, N., Gafvels, M.E., The cAMP signalling system and human trophoblast function (1992) Placenta, 13, pp. 389-403
  • Srisuparp, S., Strakova, Z., Brudney, A., Mukherjee, S., Reierstad, S., Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells (2003) Biol Reprod, 68, pp. 457-464
  • Salvador, L.M., Maizels, E., Hales, D.B., Miyamoto, E., Yamamoto, H., Acute signaling by the LH receptor is independent of protein kinase C activation (2002) Endocrinology, 143, pp. 2986-2994
  • Amsterdam, A., Hanoch, T., Dantes, A., Tajima, K., Strauss, J.F., Mechanisms of gonadotropin desensitization (2002) Mol Cell Endocrinol, 187, pp. 69-74
  • Bornfeldt, K.E., Krebs, E.G., Crosstalk between protein kinase A and growth factor receptor signaling pathways in arterial smooth muscle (1999) Cell Signal, 11, pp. 465-477
  • Sevetson, B.R., Kong, X., Lawrence Jr., J.C., Increasing cAMP attenuates activation of mitogen-activated protein kinase (1993) Proc Natl Acad Sci U S A, 90, pp. 10305-10309
  • Cook, S.J., McCormick, F., Inhibition by cAMP of Ras-dependent activation of Raf (1993) Science, 262, pp. 1069-1072
  • Wu, J., Dent, P., Jelinek, T., Wolfman, A., Weber, M.J., Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3′,5′-monophosphate (1993) Science, 262, pp. 1065-1069
  • Graves, L.M., Bornfeldt, K.E., Raines, E.W., Potts, B.C., Macdonald, S.G., Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells (1993) Proc Natl Acad Sci U S A, 90, pp. 10300-10304
  • Burgering, B.M., Pronk, G.J., van Weeren, P.C., Chardin, P., Bos, J.L., cAMP antagonizes p21ras-directed activation of extracellular signal-regulated kinase 2 and phosphorylation of mSos nucleotide exchange factor (1993) EMBO J, 12, pp. 4211-4220
  • Vossler, M.R., Yao, H., York, R.D., Pan, M.G., Rim, C.S., cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway (1997) Cell, 89, pp. 73-82
  • York, R.D., Yao, H., Dillon, T., Ellig, C.L., Eckert, S.P., Rap1 mediates sustained MAP kinase activation induced by nerve growth factor (1998) Nature, 392, pp. 622-626
  • Houslay, M.D., Kolch, W., Cell-type specific integration of cross-talk between extracellular signal-regulated kinase and cAMP signaling (2000) Mol Pharmacol, 58, pp. 659-668
  • Dugan, L.L., Kim, J.S., Zhang, Y., Bart, R.D., Sun, Y., Differential effects of cAMP in neurons and astrocytes. Role of B-raf (1999) J Biol Chem, 274, pp. 25842-25848
  • MacNicol, M.C., MacNicol, A.M., Nerve growth factor-stimulated B-Raf catalytic activity is refractory to inhibition by cAMP-dependent protein kinase (1999) J Biol Chem, 274, pp. 13193-13197
  • Ohtsuka, T., Shimizu, K., Yamamori, B., Kuroda, S., Takai, Y., Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein (1996) J Biol Chem, 271, pp. 1258-1261
  • Vaillancourt, R.R., Gardner, A.M., Johnson, G.L., B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP (1994) Mol Cell Biol, 14, pp. 6522-6530
  • Galabova-Kovacs, G., Matzen, D., Piazzolla, D., Meissl, K., Plyushch, T., Essential role of B-Raf in ERK activation during extraembryonic development (2006) Proc Natl Acad Sci U S A, 103, pp. 1325-1330


---------- 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).