title: Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LβT2 gonadotrope cells.
abstract: It is known that bone morphogenetic proteins (BMPs) regulate gonadotropin transcription and production by pituitary gonadotrope cells. However, the role of BMPs in gonadotropin-releasing hormone (GnRH)-induced FSH production remains uncertain. Here, we describe a functional link between BMP-6 and BMP-7 signals and FSH transcriptional activity induced by GnRH using mouse gonadotrope LβT2 cells. In LβT2 cells, BMP-6 and BMP-7 increased mouse FSHβ-promoter activity in a concentration-dependent manner. The induction by BMP-6 and BMP-7 was inhibited by treatment with extracellular domains of ActRII but not BMPRII. These findings suggest that the type II receptor ActRII participates in BMP-induced FSHβ transcription regulation. Notably, BMP-6, but not BMP-7, enhanced GnRH-induced FSHβ-promoter activity in LβT2 cells. Since GnRH stimulated MAPK phosphorylation in LβT2 cells, a functional link between MAPK and FSHβ transcription was examined. Inhibition of the ERK pathway, but not that of p38 or SAPK/JNK signaling, suppressed GnRH-induced FSHβ transcription, suggesting that ERK is functionally involved in GnRH-induced FSHβ transcription. Co-treatment with BMP-7, but not with BMP-6, suppressed GnRH-induced MAPK phosphorylation in LβT2 cells. Thus, the difference between BMP-6 and BMP-7 in enhancing GnRH-induced FSHβ transcription may be due to the differential effects of BMP ligands on GnRH-induced ERK signaling. On the other hand, GnRH reduced Smad1/5/8 phosphorylation but increased Smad6/7 expression. These findings imply the presence of a functional link between GnRH action, MAPK signaling and the BMP system in pituitary gonadotropes for fine-tuning of FSH gene expression.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takeda
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lawson
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D052681:Gonadotrophs / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D037201:Follicle Stimulating Hormone, beta Subunit; D051785:Smad Proteins; C525820:bmp7 protein, mouse; D007987:Gonadotropin-Releasing Hormone; D008156:Luciferases; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I