title: GnRH activates ERK1/2 leading to the induction of c-fos and LHbeta protein expression in LbetaT2 cells.
abstract: GnRH acts on pituitary gonadotropes to stimulate the synthesis and release of LH and FSH. However, the signaling pathways downstream of the GnRH receptor that mediate these effects are not fully understood. In this paper, we demonstrate that GnRH activates ERK, c-Jun N-terminal kinase, and p38MAPK in the LbetaT2 gonadotrope cell line. Phosphorylation of both ERK and p38MAPK are stimulated rapidly, 30- to 50-fold in 5 min, but activation of c-Jun N-terminal kinase has slower kinetics, reaching only 10-fold after 30 min. Activation of ERK by GnRH is blocked by inhibition of MAPK kinase (MEK) and partially blocked by inhibition of PKC and calcium, but not PI3K or p38MAPK signaling. We demonstrate that phosphorylated ERK accumulates in the nucleus in a PKC-dependent manner. We also show that GnRH induces c-fos and LHbeta subunit protein expression in LbetaT2 cells via MEK. Experiments with EGTA or calcium channel antagonists indicated that calcium influx is important for the induction of both genes by GnRH. In conclusion, these results show that GnRH activates all three MAPK subfamilies in LbetaT2 cells and induces c-fos and LHbeta protein expression through calcium and MEK-dependent mechanisms. These results also demonstrate that the nuclear translocation of ERK by GnRH requires PKC signaling.
authors.affiliation: Department of Medicine, University of California, San Diego, California 92093, USA.
authors.forename: Fujun
authors.initials: F
authors.lastname: Liu
authors.forename: Darrell A
authors.initials: DA
authors.lastname: Austin
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000201:enzymology; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D007986:Luteinizing Hormone / Q000235:genetics*; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002121:Calcium Channel Blockers; D002614:Chelating Agents; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D007987:Gonadotropin-Releasing Hormone; D004533:Egtazic Acid; D011189:Potassium Chloride; D007986:Luteinizing Hormone; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium