TY - JOUR
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, H. Sunny
AU - Yang, Shang Hsun
AU - Chuang, Pei Chin
AU - Huang, Bu Miin
AU - Ching, Cheng Hsin
N1 - Funding Information:
This work was supported by National Science Council Grants NSC101-2320-B-006-001-MY2 and NSC102-2320-B-006-012-MY3 . Appendix A
Publisher Copyright:
© 2015 Elsevier Inc.
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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U2 - 10.1016/j.freeradbiomed.2015.08.011
DO - 10.1016/j.freeradbiomed.2015.08.011
M3 - Article
C2 - 26424114
AN - SCOPUS:84943149251
VL - 89
SP - 274
EP - 286
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
M1 - 12550
ER -