FGF9-induced changes in cellular redox status and HO-1 upregulation are FGFR-dependent and proceed through both ERK and AKT to induce CREB and Nrf2 activation

Jih-Ing Chuang, Jui Yen Huang, Shaw-Jenq Tsai, Hsiao-Fang Sun, Shang-Hsun Yang, Pei Chin Chuang, Bu-Miin Huang, Cheng Hsin Ching

研究成果: Article

16 引文 (Scopus)

摘要

Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) protects cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative insult by upregulation of γ-glutamylcysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced γ-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO-1 and γ-GCS expression. We found that FGF9-induced HO-1 and γ-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FGFR). FGF9 treatment induced the phosphorylation of FGFR downstream signals of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT in a dose- and time-dependent manner. The inhibition of MEK/ERK1/2 or PI3K/AKT activity by U0126 or wortmannin, but not the inhibition of phospholipase Cγ by U73122, prevented FGF9-induced γ-GCS and HO-1 upregulation, changes in cellular redox status, and neuroprotection against MPP+ toxicity in primary cortical and dopaminergic neurons. Furthermore, FGF9 treatment enhanced the promoter activity of the cAMP-response element binding protein (CREB) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and this phenomenon was blocked by PD173014 or U0126 or wortmannin. Knockdown of CREB and Nrf2 by shRNA blocked FGF9-induced γ-GCS and HO-1 upregulation, but not ERK and AKT phosphorylation. An in vivo study consistently showed that FGF9 overexpression using a lentivirus delivery system induced ERK1/2 phosphorylation and HO-1 upregulation and protected dopaminergic neurons against MPP+ toxicity in rat substantia nigra. These results indicate that FGF9-induced HO-1 and γ-GCS upregulation is mediated by binding to FGFR and activation of two parallel downstream signaling pathways, ERK and AKT, which reconverge to induce CREB and Nrf2 transcriptional activity.

原文English
文章編號12550
頁(從 - 到)274-286
頁數13
期刊Free Radical Biology and Medicine
89
DOIs
出版狀態Published - 2015 十二月 1

指紋

Fibroblast Growth Factor 9
Fibroblast Growth Factor Receptors
Cyclic AMP Response Element-Binding Protein
Heme Oxygenase-1
Oxidation-Reduction
Up-Regulation
Chemical activation
Phosphorylation
Mitogen-Activated Protein Kinase 3
Dopaminergic Neurons
Mitogen-Activated Protein Kinase 1
Neurons
Toxicity
1-Methyl-4-phenylpyridinium
Glutamate-Cysteine Ligase
Lentivirus
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Type C Phospholipases
Substantia Nigra

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

引用此文

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title = "FGF9-induced changes in cellular redox status and HO-1 upregulation are FGFR-dependent and proceed through both ERK and AKT to induce CREB and Nrf2 activation",
abstract = "Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) protects cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative insult by upregulation of γ-glutamylcysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced γ-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO-1 and γ-GCS expression. We found that FGF9-induced HO-1 and γ-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FGFR). FGF9 treatment induced the phosphorylation of FGFR downstream signals of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT in a dose- and time-dependent manner. The inhibition of MEK/ERK1/2 or PI3K/AKT activity by U0126 or wortmannin, but not the inhibition of phospholipase Cγ by U73122, prevented FGF9-induced γ-GCS and HO-1 upregulation, changes in cellular redox status, and neuroprotection against MPP+ toxicity in primary cortical and dopaminergic neurons. Furthermore, FGF9 treatment enhanced the promoter activity of the cAMP-response element binding protein (CREB) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and this phenomenon was blocked by PD173014 or U0126 or wortmannin. Knockdown of CREB and Nrf2 by shRNA blocked FGF9-induced γ-GCS and HO-1 upregulation, but not ERK and AKT phosphorylation. An in vivo study consistently showed that FGF9 overexpression using a lentivirus delivery system induced ERK1/2 phosphorylation and HO-1 upregulation and protected dopaminergic neurons against MPP+ toxicity in rat substantia nigra. These results indicate that FGF9-induced HO-1 and γ-GCS upregulation is mediated by binding to FGFR and activation of two parallel downstream signaling pathways, ERK and AKT, which reconverge to induce CREB and Nrf2 transcriptional activity.",
author = "Jih-Ing Chuang and Huang, {Jui Yen} and Shaw-Jenq Tsai and Hsiao-Fang Sun and Shang-Hsun Yang and Chuang, {Pei Chin} and Bu-Miin Huang and Ching, {Cheng Hsin}",
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T1 - FGF9-induced changes in cellular redox status and HO-1 upregulation are FGFR-dependent and proceed through both ERK and AKT to induce CREB and Nrf2 activation

AU - Chuang, Jih-Ing

AU - Huang, Jui Yen

AU - Tsai, Shaw-Jenq

AU - Sun, Hsiao-Fang

AU - Yang, Shang-Hsun

AU - Chuang, Pei Chin

AU - Huang, Bu-Miin

AU - Ching, Cheng Hsin

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) protects cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative insult by upregulation of γ-glutamylcysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced γ-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO-1 and γ-GCS expression. We found that FGF9-induced HO-1 and γ-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FGFR). FGF9 treatment induced the phosphorylation of FGFR downstream signals of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT in a dose- and time-dependent manner. The inhibition of MEK/ERK1/2 or PI3K/AKT activity by U0126 or wortmannin, but not the inhibition of phospholipase Cγ by U73122, prevented FGF9-induced γ-GCS and HO-1 upregulation, changes in cellular redox status, and neuroprotection against MPP+ toxicity in primary cortical and dopaminergic neurons. Furthermore, FGF9 treatment enhanced the promoter activity of the cAMP-response element binding protein (CREB) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and this phenomenon was blocked by PD173014 or U0126 or wortmannin. Knockdown of CREB and Nrf2 by shRNA blocked FGF9-induced γ-GCS and HO-1 upregulation, but not ERK and AKT phosphorylation. An in vivo study consistently showed that FGF9 overexpression using a lentivirus delivery system induced ERK1/2 phosphorylation and HO-1 upregulation and protected dopaminergic neurons against MPP+ toxicity in rat substantia nigra. These results indicate that FGF9-induced HO-1 and γ-GCS upregulation is mediated by binding to FGFR and activation of two parallel downstream signaling pathways, ERK and AKT, which reconverge to induce CREB and Nrf2 transcriptional activity.

AB - Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) protects cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative insult by upregulation of γ-glutamylcysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced γ-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO-1 and γ-GCS expression. We found that FGF9-induced HO-1 and γ-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FGFR). FGF9 treatment induced the phosphorylation of FGFR downstream signals of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT in a dose- and time-dependent manner. The inhibition of MEK/ERK1/2 or PI3K/AKT activity by U0126 or wortmannin, but not the inhibition of phospholipase Cγ by U73122, prevented FGF9-induced γ-GCS and HO-1 upregulation, changes in cellular redox status, and neuroprotection against MPP+ toxicity in primary cortical and dopaminergic neurons. Furthermore, FGF9 treatment enhanced the promoter activity of the cAMP-response element binding protein (CREB) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and this phenomenon was blocked by PD173014 or U0126 or wortmannin. Knockdown of CREB and Nrf2 by shRNA blocked FGF9-induced γ-GCS and HO-1 upregulation, but not ERK and AKT phosphorylation. An in vivo study consistently showed that FGF9 overexpression using a lentivirus delivery system induced ERK1/2 phosphorylation and HO-1 upregulation and protected dopaminergic neurons against MPP+ toxicity in rat substantia nigra. These results indicate that FGF9-induced HO-1 and γ-GCS upregulation is mediated by binding to FGFR and activation of two parallel downstream signaling pathways, ERK and AKT, which reconverge to induce CREB and Nrf2 transcriptional activity.

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