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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

ABSTRACT 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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    • "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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    Oxidative Medicine and Cellular Longevity 02/2014; 2014(5):432626. DOI:10.1155/2014/432626 · 3.36 Impact Factor
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    • "Further, NaHS treated group showed 1.8 fold increases in Nrf-2 expression as seen with western blotting and increased activation as observed by increased co-localization of Nrf-2 in the nucleus. Study by another group has also reported increased activation of Nrf-2 and further upregulation after spinal cord injury (Duan et al., 2009; Vargas et al., 2005; Li et al., 2005a; Mao et al., 2010, 2012; Wang et al., 2012; Benedict et al., 2012; Liu et al., 2008). At present we do not know the exact mechanism of up-regulation and activation of Nrf-2 after NaHS treatment but we hypothesize that it might be due to a shift in the redox state of the cell by NaHS due to the presence of sulfur atom. "
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    Brain research 06/2013; DOI:10.1016/j.brainres.2013.06.023 · 2.83 Impact Factor
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