Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells

Masaya Takeda, Fumio Otsuka, Hiroyuki Otani, Kenichi Inagaki, Tomoko Miyoshi, Jiro Suzuki, Yukari Mimura, Toshio Ogura, Hirofumi Makino

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Abstract

Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ) 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 PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line LβT2, which expresses activin/BMP receptors, transcription factor Smads, PPARα, and PPAKγ. In LβT2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by LβT2; whereas the PPARα 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 PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ, LHβ, and GnRHR. Activation of PPARα and PPARAγ 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-βB mR-NA in LβT2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

Original languageEnglish
Pages (from-to)87-99
Number of pages13
JournalJournal of Endocrinology
Volume194
Issue number1
DOIs
Publication statusPublished - Jul 2007

Fingerprint

Bone Morphogenetic Proteins
Peroxisome Proliferator-Activated Receptors
Gonadotropins
Mitosis
pioglitazone
Activins
Follistatin
Ligands
Cell Proliferation
Bone Morphogenetic Protein Receptors
Messenger RNA
Pituitary Neoplasms
Transcription Factors
Phosphorylation

ASJC Scopus subject areas

  • Endocrinology

Cite this

@article{67b4efc97ec94773875ca6ecba6fe7ac,
title = "Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells",
abstract = "Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ) 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 PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line LβT2, which expresses activin/BMP receptors, transcription factor Smads, PPARα, and PPAKγ. In LβT2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by LβT2; whereas the PPARα 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 PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ, LHβ, and GnRHR. Activation of PPARα and PPARAγ 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-βB mR-NA in LβT2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.",
author = "Masaya Takeda and Fumio Otsuka and Hiroyuki Otani and Kenichi Inagaki and Tomoko Miyoshi and Jiro Suzuki and Yukari Mimura and Toshio Ogura and Hirofumi Makino",
year = "2007",
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language = "English",
volume = "194",
pages = "87--99",
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T1 - Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells

AU - Takeda, Masaya

AU - Otsuka, Fumio

AU - Otani, Hiroyuki

AU - Inagaki, Kenichi

AU - Miyoshi, Tomoko

AU - Suzuki, Jiro

AU - Mimura, Yukari

AU - Ogura, Toshio

AU - Makino, Hirofumi

PY - 2007/7

Y1 - 2007/7

N2 - Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ) 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 PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line LβT2, which expresses activin/BMP receptors, transcription factor Smads, PPARα, and PPAKγ. In LβT2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by LβT2; whereas the PPARα 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 PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ, LHβ, and GnRHR. Activation of PPARα and PPARAγ 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-βB mR-NA in LβT2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

AB - Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ) 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 PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line LβT2, which expresses activin/BMP receptors, transcription factor Smads, PPARα, and PPAKγ. In LβT2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by LβT2; whereas the PPARα 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 PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ, LHβ, and GnRHR. Activation of PPARα and PPARAγ 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-βB mR-NA in LβT2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

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