title: The ERK1/2 signaling pathway regulates 11beta-hydroxysteroid dehydrogenase type 2 expression in human trophoblast cells through a transcriptional mechanism.
abstract: The placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2; encoded by the HSD11B2 gene) plays a key role in fetal development, but its regulation is incompletely understood. We previously demonstrated that p38 MAPK was a positive regulator of placental 11beta-HSD2. However, it remains unknown if the other two MAPKs, ERK1/2 and JNK, were also involved. In the present study, we identified ERK1/2 as an important regulator of placental 11beta-HSD2. We showed that inhibition of ERK1/2 with the pharmacological inhibitor U0126 led to a 3-fold increase in 11beta-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. In contrast, the JNK inhibitor SP600125 had no effect. Furthermore, U0126 increased the HSD11B2 promoter activity by 300%, indicating that ERK1/2 regulates placental 11beta-HSD2 expression through a transcriptional mechanism. Importantly, siRNA-mediated knockdown of ERK1/2 caused a similar increase in 11beta-HSD2 protein. In addition, given that we previously showed that cadmium reduced placental 11beta-HSD2 expression via a transcriptional mechanism, but the signal transduction pathways involved remain unclear, we also addressed this question and found that treatment of trophoblast cells with cadmium led to rapid activation of ERK1/2. Importantly, U0126 completely abrogated the inhibitory effects of cadmium on placental 11beta-HSD2. Taken together, the present study not only identifies the ERK1/2 signaling pathway as a potent negative regulator of placental 11beta-HSD2 but also demonstrates that this pathway mediates cadmium repression of placental 11beta-HSD2. Thus, our present study reveals 11beta-HSD2 as an important target through which ERK1/2 may regulate human placental function and consequently fetal development.
authors: Children's Health Research Institute & Lawson Health Research Institute, Departments of Obstetrics & Gynaecology and Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada.
authors: Haiyan
authors: H
authors: Guan
authors: Kang
authors: K
authors: Sun
authors: Kaiping
authors: K
authors: Yang
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019256:Cadmium Chloride / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D019256:Cadmium Chloride
keywords: ERK1/2; MAPK; gene expression; glucocorticoid receptor; glucocorticoids; placenta; pregnancy; signal transduction; trophoblast