Transduction of leptin growth signals in placental cells is independent of JAK-STAT activation.
We have characterized the transduction pathways induced by leptin in the placenta, using human BeWo cells that express endogenous leptin receptors and synthesize leptin in a regulated manner. We first examined if the JAK-STAT phosphorylation cascade was functional in these cells. Phosphorylated JAK2 was primarily bound to a short 106kDa leptin receptor isoform and to a lesser extent to a 210kDa molecule. Leptin neither enhanced JAK2 phosphorylation nor activated STAT3 and STAT1 proteins indicating that JAK2 is constitutively activated and that the JAK-STAT transduction pathway is not recruited by leptin in BeWo cells. By contrast, leptin stimulated the transcription of the c-fos gene (3-fold) and cell proliferation (2-fold) as measured by DNA synthesis. Both effects were dependent on the rapid phosphorylation of p42-44 MAPK but not p38 MAPK. We conclude that a functional JAK-STAT pathway is not required for leptin to transduce proliferative signals in human placental cells. These findings extend the physiological action of leptin beyond its central effects, to the control of placental gene transcription and cell proliferation.
Caüzac
M
M
Institut Cochin, Departement Endocrinologie et Biologie Cellulaire, 24 rue du Faubourg Saint Jacques, 75014, Paris, France.
Czuba
D
D
Girard
J
J
Hauguel-de Mouzon
S
S
D002455:Cell Division; D002822:Choriocarcinoma / Q000201:enzymology; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D016762:Genes, fos / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D054411:Receptors, Leptin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D020738:Leptin; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2