Fibroblast Growth Factor-1 Induces Heme Oxygenase-1 via Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) in Spinal Cord Astrocytes

Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2005; 280(27):25571-9. DOI: 10.1074/jbc.M501920200
Source: PubMed


Fibroblast growth factor-1 (FGF-1) is highly expressed in motor neurons and can be released in response to sublethal cell injury. Because FGF-1 potently activates astroglia and exerts a direct neuroprotection after spinal cord injury or axotomy, we examined whether it regulated the expression of inducible and cytoprotective heme oxygenase-1 (HO-1) enzyme in astrocytes. FGF-1 induced the expression of HO-1 in cultured rat spinal cord astrocytes, which was dependent on FGF receptor activation and prevented by cycloheximide. FGF-1 also induced Nrf2 mRNA and protein levels and prompted its nuclear translocation. HO-1 induction was abolished by transfection of astrocytes with a dominant-negative mutant Nrf2, indicating that FGF-1 regulates HO-1 expression through Nrf2. FGF-1 also modified the expression of other antioxidant genes regulated by Nrf2. Both Nrf2 and HO-1 levels were increased and co-localized with reactive astrocytes in the degenerating lumbar spinal cord of rats expressing the amyotrophic lateral sclerosis-linked SOD1 G93A mutation. Overexpression of Nrf2 in astrocytes increased survival of co-cultured embryonic motor neurons and prevented motor neuron apoptosis mediated by nerve growth factor through p75 neurotrophin receptor. Taken together, these results emphasize the key role of astrocytes in determining motor neuron fate in amyotrophic lateral sclerosis.

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    • "Id1 message levels were higher, however, if cells were treated with FGF and CHX than with CHX alone. This is in contrast to several reports in other systems in which CHX completely abolished FGF-induced transcriptional events (Isaac et al., 2000; Li et al., 2003; Vargas et al., 2005). Further evidence that stimulation of Id1 by FGF does not require new gene expression was obtained using the transcriptional inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB). "
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    ABSTRACT: Fibroblast growth factors (FGFs) play a central role in two processes essential for lens transparency, lens fiber cell differentiation and gap junction-mediated intercellular communication (GJIC). Using serum-free primary cultures of chick lens epithelial cells (DCDMLs), we have investigated how the FGF and bone morphogenetic protein (BMP) signaling pathways positively cooperate to regulate lens development and function. We found that culturing DCDMLs for six days with the BMP blocker noggin inhibits the canonical FGF-to-ERK pathway upstream of FRS2 activation and also prevents FGF from stimulating FRS2- and ERK- independent gene expression, indicating that BMP signaling is required at the level of FGF receptors. Other experiments revealed a second type of BMP/FGF interaction by which FGF promotes expression of BMP target genes as well as of BMP4. Together, these studies reveal a novel mode of cooperation between the FGF and BMP pathways in which BMP keeps lens cells in an optimally FGF-responsive state and, reciprocally, FGF enhances BMP-mediated gene expression. This interaction provides a mechanistic explanation for why disruption of either FGF or BMP signaling in the lens leads to defects in lens development and function. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 05/2015; 26(13). DOI:10.1091/mbc.E15-02-0117 · 4.47 Impact Factor
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    • "As shown in Figure 1, FGF-1 is selectively expressed within the anterior horn gray matter in a fairly intense manner, suggesting a key role in alpha motor neuron physiology. Also known as acidic Fibroblast growth factor, FGF-1 is one of many related polypeptide growth factors that use tyrosine kinase-linked FGF receptors (FGFR1-4) to regulate cell growth, differentiation, and inflammation through tyrosine kinase-linked FGF receptors type 1 to 4.18 As noted by Elde et al.19 FGF-1 is highly expressed within spinal motor neurons, and is especially found in association with the cytoplasmic face of the neuronal cell membrane. As noted by Vargas et al.,18 motor neurons respond to sublethal cell injury by releasing FGF-1 which strongly activates astroglia and renders neuroprotection after spinal cord injury or axonal injury; FGF-1 also stimulates nerve growth factor (NGF) production and secretion in astrocytes. "
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    ABSTRACT: In an effort to find possible new gene candidates involved in the causation of amyotrophic lateral sclerosis (ALS), a prior version of the on-line brain gene expression atlas GENSAT was extensively searched for selectively intense expression within spinal motor neurons. Using autoradiographic data of in-situ hybridization from 3430 genes, a search for selectively intense activity was made for the anterior horn region of murine lumbar spinal cord sectioned in the axial plane. Of 3430 genes, a group of 17 genes was found to be highly expressed within the anterior horn suggesting localization to its primary cellular constituent, the alpha spinal motor neuron. For some genes, an inter-relationship to ALS was already known, such as for heavy, medium, and light neurofilaments, and peripherin. Other genes identified include: Gamma Synuclein, GDNF, SEMA3A, Extended Synaptotagmin-like protein 1, LYNX1, HSPA12a, Cadherin 22, PRKACA, TPPP3 as well as Choline Acetyltransferase, Janus Kinase 1, and the Motor Neuron and Pancreas Homeobox 1. Based on this study, Fibroblast Growth Factor 1 was found to have a particularly selective and intense localization pattern to the ventral horn and may be a good target for development of motor neuron disease therapies; further research is needed.
    Neurology International 04/2014; 6(2):5367. DOI:10.4081/ni.2014.5367
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    • "As previously mentioned, Nrf2 involvement has been shown in neurodegenerative diseases such as AD, PD, Huntington disease [9, 22, 23, 40–48], and also in ALS models [12, 17]. In particular, three polymorphisms (−617, −651, and −653 SNPs) in the gene's promoter were predicted to have functional significance, and one [−617 (C/A)] has been demonstrated to affect significantly basal Nrf2 expression and function [9, 23]. "
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    ABSTRACT: Oxidative stress involvement has been strongly hypothesized among the possible pathogenic mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The intracellular redox balance is finely modulated by numerous complex mechanisms critical for cellular functions, among which the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways. We genotyped, in a cohort of ALS patients (n = 145) and healthy controls (n = 168), three SNPs in Nrf2 gene promoter: −653 A/G, −651 G/A, and −617 C/A and evaluated, in a subset (n = 73) of patients, advanced oxidation protein products (AOPP), iron-reducing ability of plasma (FRAP), and plasma thiols (-SH) as oxidative damage peripheral biomarkers. Nrf2 polymorphisms were not different among patients and controls. Increased levels of AOPP (P < 0.05) and decreased levels of FRAP (P < 0.001) have been observed in ALS patients compared with controls, but no difference in -SH values was found. Furthermore, no association was found between biochemical markers of redox balance and Nrf2 polymorphisms. These data confirm an altered redox balance in ALS and indicate that, while being abnormally modified compared to controls, the oxidative stress biomarkers assessed in this study are independent from the −653 A/G, −651 G/A, and −617 C/A Nrf2 SNPs in ALS patients.
    Oxidative Medicine and Cellular Longevity 02/2014; 2014(5):432626. DOI:10.1155/2014/432626 · 3.36 Impact Factor
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