title: Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LbetaT2 cells.
abstract: Involvement of peroxisome proliferator-activated receptor-gamma (PPAR-gamma ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPARalpha and PPARgamma in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lbeta T2, which expresses activin/BMP receptors, transcription factor Smads, PPARalpha , and PPARgamma . In Lbeta T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARgamma agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lbeta T2; whereas the PPARalpha agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)9-Luc activity. Both PPARalpha and PPARgamma ligands directly suppressed transcriptional activities of FSHbeta , LHbeta , and GnRHR. Activation of PPARalpha and PPARgamma increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-beta B mRNA in Lbeta T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City 700-8558, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takeda
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otani
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Jiro
authors.initials: J
authors.lastname: Suzuki
authors.forename: Yukari
authors.initials: Y
authors.lastname: Mimura
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D038681:Follistatin / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006062:Gonadotropins / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D008938:Mitosis; D020411:Oligonucleotide Array Sequence Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D019485:Bone Morphogenetic Proteins; D038681:Follistatin; D006062:Gonadotropins; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D028341:Activins