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
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
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DOI：
10.1016/j.freeradbiomed.2015.08.011
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发表时间：
2015-12-01
影响因子：
7.4
通讯作者：
Ching, Cheng-Hsin
中科院分区：
文献类型：
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作者：
Chuang, Jih-Ing;Huang, Jui-Yen;Ching, Cheng-Hsin
我们之前的研究表明，成纤维细胞生长因子9 （FGF9）通过上调γ -谷氨酰半胱氨酸合成酶（γ - gcs）和血红素加氧酶-1 (HO-1)，保护皮层和多巴胺能神经元免受1-甲基-4-苯基吡啶（MPP+）诱导的氧化损伤。然而，fgf9诱导γ - gcs和HO-1上调的机制尚未明确。在本研究中，我们展示了FGF9上调HO-1和γ - gcs表达的信号通路。我们发现fgf9诱导的HO-1和γ - gcs表达被FGF受体（FUR）抑制剂PD173014阻止。FGF9处理诱导细胞外信号调节激酶1/2 （ERK1/2）和AKT的FUR下游信号磷酸化，并呈剂量和时间依赖性。U0126或wortmannin抑制MEK/ERK1/2或PI3K/AKT活性，而1173122不抑制磷脂酶C γ，可阻止fgf9诱导的γ - gcs和HO-1上调、细胞氧化还原状态的改变以及初级皮质和多巴胺能神经元对MPP+毒性的神经保护。此外，FGF9处理增强了camp反应元件结合蛋白（CREB）和核因子红细胞衍生2-样2 （Nrf2）的启动子活性，这一现象被PD173014、110126或wortmannin阻断。shRNA敲低CREB和Nrf2可阻断fgf9诱导的γ - gcs和HO-1上调，但对ERK和AKT磷酸化不起作用。一项体内研究一致表明，使用慢病毒传递系统过表达FGF9可诱导ERK1/2磷酸化和HO-1上调，并保护大鼠黑质多巴胺能神经元免受MPP+毒性。这些结果表明，fgf9诱导的HO-1和γ - gcs上调是通过与FGFR结合和激活两个平行的下游信号通路ERK和AKT介导的，这些信号通路重新聚集诱导CREB和Nrf2的转录活性。(C) 2015爱思唯尔公司版权所有。
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 gamma-glutamylcysteine synthetase (gamma-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced gamma-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO-1 and gamma-GCS expression. We found that FGF9-induced HO-1 and gamma-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FUR). FGF9 treatment induced the phosphorylation of FUR 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 C gamma by 1173122, prevented FGF9-induced gamma-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 110126 or wortmannin. Knockdown of CREB and Nrf2 by shRNA blocked FGF9-induced gamma-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 gamma-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. (C) 2015 Elsevier Inc. All rights reserved.