Mitogen-activated protein kinase activation induces corticotrophin-releasing hormone gene expression in human placenta.
Corticotropin-releasing hormone (CRH) gene expression in human placental cells is induced by activation of the cyclic AMP and protein kinase C signal transduction pathways, but the role of the mitogen-activated kinase (MAPK) pathway is unknown. In this study, we showed that the MAPK inhibitor, PD098059, causes a dose-dependent inhibition of placental CRH gene expression. In contrast, overexpression of RAF in human choriocarcinoma JEG cells stimulates CRH promoter activity by 15-fold, and the stimulation is inhibited by 65% by co-transfection of the cells with a plasmid expressing a RAF dominant/negative protein. The stimulation by RAF was completely abolished by mutation of the cyclic AMP response element (CRE) in the proximal region of the CRH promoter. Taken together, these results strongly suggest that the MAPK signal transduction pathway plays a pivotal role in the regulation of CRH gene expression in human placenta, and that the CRE binding site in the proximal CRH promoter acts as a point of convergence for different signal transduction pathways in the regulation of CRH gene expression in placenta cells.
Cheng
You-Hong
YH
Department of Pediatrics, University of Cincinnati College of Medicine and Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Handwerger
Stuart
S
D000328:Adult; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D010920:Placenta / Q000166:cytology / Q000201:enzymology*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D003346:Corticotropin-Releasing Hormone; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases