Lesion-induced increase in nerve growth factor mRNA is mediated by c-fos.

Hengerer, Bastian; Lindholm, Dan; Heumann, Rolf; Rüther, Ulrich; Wagner, Erwin F.; Thoenen, H.

doi:10.1073/pnas.87.10.3899

Cited by 255 publications

(139 citation statements)

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“…AP-1 has been proposed as a master switch for the expression of several genes. Postischemic increase in AP-1 binding activity may underline one of the molecular mechanisms allowing the surviving neurons to adapt to the degenerative processes after ischemic brain injury [65][66][67]. In summary, our studies demonstrate the feasibility of an in vivo antisense strategy to suppress the postischemic expression of an immediate early gene.…”

Section: Discussionmentioning

confidence: 57%

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Liu

Salminen

et al. 1994

Annals of Neurology

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Activation of c-fos, an immediate early gene, and the subsequent expression of the Fos protein have been noted following focal cerebral ischemia. Fos and Jun form a heterodimer as activator protein 1 (AP-1), which transregulates the expression of several genes. To study the postischemic events related to c-fos expression, we suppressed the expression of c-fos by intraventricular infusion of an antisense Oligodeoxynucleotide (anti-rncfosr 115 ) of c-fos mRNA. The effectiveness of antirncfosr 115 was confirmed first by its capability to block in vitro c-fos mRNA translation. In vivo, after intraventricular infusion of 32 P-labeled anti-rncfosr 115 , the oligodeoxynucleotide was internalized within 6 hours and detectable also in the nucleic acids fraction up to 41 hours. Treatment of the recovered nucleic acids with RNase H separated the labeled Oligodeoxynucleotide from the nucleic acid fraction, indicating an association of the antisense Oligodeoxynucleotide and cellular RNA after uptake. When focal cerebral ischemia was induced 16 hours after the infusion of antirncfosr 115 , the postischemic increase in Fos expression and AP-1 binding activity were suppressed. Specificity of the effect of anti-rncfosr 115 was suggested by its failure to suppress the DNA binding activity of nuclear cyclic AMP response elements. These results support the hypothesis that increased AP-1 binding activity following focal cerebral ischemia is dependent on Fos expression and can be inhibited in vivo by antisense c-fos oligodeoxynucleotides.The molecular events of brain adaptation to injury that may underlie functional recovery after stroke remain largely undefined. Recent observations of altered gene expression in ischemic brain using animal stroke models have opened new avenues for exploration of the biochemical cascades after stroke [1][2][3][4][5][6][7][8][9][10][11]. These postischemic events include an increase in extracellular excitatory amino acid neurotransmitters such as glutamate. Glutamate receptor-mediated activation of phospholipases and protein kinases results in the alteration of nuclear regulatory processes, including the expression of immediate early genes such as c-fos, junB, and c-jun [5,12]. The Fos, Jun, and JunB proteins have been shown to form activator protein 1 (AP-1) through a conserved dimerization domain, i.e., the leucine zipper [13]. Transcription regulator AP-1 protein binds a specific DNA motif and is believed to transactivate the expression of a number of late effector genes [14][15][16][17][18][19]. In the ischemic brain, we have previously demonstrated an increase in AP-1 binding activity [9]. A number of genes that bear neurotrophic properties may be regulated by transcription regulator AP-1. These genes, such as heat shock protein [1,4,[19][20][21][22], amyloid [23], neurotrophins [7], and protein tyrosine kinase receptor trkB [24], have been shown to be induced following cerebral ischemia. The causal relationship between the Fos/Jun-AP-1 cascade and the subsequent expression of the late e...

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Section: Discussionmentioning

confidence: 57%

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Liu

Salminen

et al. 1994

Annals of Neurology

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“…CSD could, in part, result in induction of c-fos in the thalamus and hippocampus via activation of corti cothalamic and entorhinal cortex-dentate gyrus projections, respectively. Nerve growth factor (NGF), which has been reported to increase in some models of mechanical brain injury (Hengerer et al, 1990), may mediate the induction of c-fos (Kruijer et al, 1985). Induction of c-fos in glial and ependymal cells has been associated with increased concentrations of cAMP (Dragunow and Faull, 1989); however, the effect of TBI on cellular cAMP is unknown.…”

Section: Discussionmentioning

confidence: 99%

Regional Induction of c-Fosand Heat Shock Protein-72 mRNA following Fluid-Percussion Brain Injury in the Rat

Raghupathi

Welsh

Lowenstein

et al. 1995

J Cereb Blood Flow Metab

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Summary:To evaluate the cellular response to traumatic brain injury, the expression of mRNA for c-fos and the 72-kDa heat shock protein (hsp72) was determined using in situ hybridization following lateral fluid-percussion in jury (2.2-2.4 atm) in rat brain. At 2 h after injury, induc tion of c-fos mRNA was observed throughout the cortex ipsilateral to the site of injury, while increased expression of hsp72 mRNA was restricted to regions of the cortex surrounding the contusion area. An increase in c-fos mRNA, but not hsp72 mRNA, was observed bilaterally in the CA 3 subfield of the hippocampus and the granule cells of the dentate gyrus and in the thalamus ipsilateral to the impact site. By 6 h, increased expression of c-fos mRNA A wide range of pathologic stressors to the brain, including mechanical injury (Dragunow and Robert son, 1988;Brown et al. , 1989), ischemia (Nowak, 1990; Welsh et ai. , 1992), and seizures (Lowenstein et ai. , 1990; Morgan and Curran, 199 1a), induce the expression of immediate early genes (lEGs) and heat shock proteins. lEGs such as c-fos and jun function as transcription factors and may mediate the long-term adaptive response of neurons to acute stimuli (Morgan and Curran, 199 1b). In contrast, heat shock proteins may simply serve as markers of a generalized stress response (Gonzalez et al. , 1989;Nowak, 1990). Although lEGs and heat shock pro teins have been extensively studied in models of Received March 22, 1994; final revision received October 6, 1994; accepted October 14, 1994 Abbreviations used: CSD, cortical spreading depression; hsp72 , 72-kDa heat shock protein; lEG, immediate early gene; NGF, nerve growth factor; TBI, traumatic brain injury. 467was observed only in the corpJ,lS callosum on the impact side; hsp72 mRNA persisted In the deep cortical layers and upper layers of the subcortical white matter below the site of maximal injury. By 24 h, both c-fos and hsp72 mRNA had returned to control levels in all regions of the brain. These results demonstrate that lateral fluid percussion brain injury triggers regionally and temporally specific expression of c-fos and hsp72 mRNA, which may be suggestive of differential neuroche ' mical alterations in neurons and glia following experimental brain injury. Key Words: Brain injury-Heat shock proteins-Immediate early genes-In situ hybridization.cerebral ischemia (Nowak, 1990; Welsh et al. , 1992), less is known about the alteration of their expression following traumatic brain injury (TBI).In a model of midline fluid percussive injury, Fos protein was found to be increased in the CAl neu rons of the hippocampus as early as 15 min follow ing injury (Phillips and Belardo, 1993). However, no data on changes in Fos expression in other brain regions were reported. Using lateral fluid percussion brain injury in the rat, we and others have observed an increase in the expression of 72-kDa heat shock protein (hsp72) mRNA (by North ern analysis) (Lowenstein et ai. , 1994) and Hsp72 protein in neuronal, glial, and endothelial cells (McIntosh ...

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“…In glioma cells PKA, PKC, or increased Ca 2ϩ mediates AP-1 (c-fos/c-jun) binding a consensus sequence in the NGF gene (50). Similarly in fibroblasts, AP-1 binds a consensus sequence in the first intron of NGF, and mutating this binding site reduces NGF promoter activity (51). NGF mRNA synthesis has also been shown to be mediated by cAMP in Schwan cells (52).…”

Section: Tlr2 Regulates Ngf Via Nf-bmentioning

confidence: 99%

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Krock

Currie

Weber

et al. 2016

Journal of Biological Chemistry

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Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1␤ (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1␤ gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1␤ treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-B, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-B signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-B inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

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Lesion-induced increase in nerve growth factor mRNA is mediated by c-fos.

Cited by 255 publications

References 42 publications

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Regional Induction of c-Fosand Heat Shock Protein-72 mRNA following Fluid-Percussion Brain Injury in the Rat

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

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