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At least 19 recordsLinked to original sources
PubMed1986

Chromatin binding of epidermal growth factor, nerve growth factor, and platelet-derived growth factor in cells bearing the appropriate surface receptors.

We analyzed the uptake and intracellular distribution of 125I-labeled epidermal growth factor, nerve growth factor, and platelet-derived growth factor in different cell lines that express or do not express the respective surface receptors for these factors. After 1 hr of incubation, all three growth factors were detected in the cytoplasmic fraction and in the nucleus, tightly bound to chromatin. The amount of chromatin-bound growth factors continued to increase during the incubation, and analysis at 48 hr revealed each chromatin-bound labeled growth factor in a nondegraded form. After limited digestion of chromatin with DNase II (10-20% digested sequences), specific release of all three growth factors was detected only after 1 hr of incubation but not after 24 and 48 hr, suggesting that the DNA regions involved in growth factor binding became nuclease-resistant. Binding of labeled epidermal growth factor and nerve growth factor to isolated chromatin was inhibited by monoclonal antibodies specific for the respective growth factor receptor. The data suggest that chromatin binding may represent an important step in the pathway of growth factor action.

Biological Transport↗
PubMed1994

Expression of basic fibroblast growth factor, nerve growth factor, platelet-derived growth factor and transforming growth factor-beta in human brain abscess.

We correlated the histopathological findings of six human brain abscesses with the expression of basic fibroblast growth factor (bFGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF beta). The clinical courses ranged from 1 month to 1 year and viridans streptococcus was the major pathogen. In early abscesses, we demonstrated strong bFGF and moderate NGF and PDGF immunoreactivities in neutrophils and monocytes/macrophages infiltrating the abscess wall and in the fibrin layer lining the abscess center. In the subacute cases, growth of capillaries and fibroblasts into the fibrin layer and deposition of collagen resulted in the formation of a mesodermal layer between the abscess center and the outer gliotic layer. The proliferative non-neural cells (endothelial cells, fibroblasts and glial cells) expressed mild to strong bFGF, NGF and PDGF immunoreactivities, while strong TGF beta staining was seen in the extracellular matrix. A loss of growth factor expression and increased fibrosis was seen in the chronic case. These findings suggest that bFGF, NGF, PDGF and TGF beta produced by the continued influx of leukocytes and by the proliferating non-neural cells may mediate various steps of defense mechanisms and wound healing such as angiogenesis, fibrogenesis and gliosis.

Antibody Specificity↗
PubMed1997

Dexamethasone regulates basic fibroblast growth factor, nerve growth factor and S100beta expression in cultured hippocampal astrocytes.

Glucocorticoids regulate hippocampal neuron survival during fetal development, in the adult, and during aging; however, the mechanisms underlying the effects are unclear. Since astrocytes contain adrenocortical receptors and synthesize and release a wide variety of growth factors, we hypothesized that glucocorticoids may alter neuron-astrocyte interactions by regulating the expression of growth factors in hippocampal astrocytes. In this study, three growth factors, which are important for hippocampal neuron development and survival, were investigated: basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and S100beta. Enriched type I astrocyte cultures were treated with 1 microM dexamethasone (DEX), a synthetic glucocorticoid, for up to 120 h. Cells and culture medium were collected and total RNA and protein were measured at 6, 12, 24, 48, 72, 96 and 120 h after the initiation of hormone treatment. Growth factor mRNA levels were measured and quantified using solution hybridization-RNase protection assays and protein levels were quantified using ELISA methods. We report that DEX stimulates the bFGF mRNA levels over the 120-h treatment. In contrast, DEX suppresses NGF mRNA continuously over the same period of treatment. DEX induces a biphasic response in S100beta mRNA levels. In addition, some of the changes in gene expression are translated into parallel changes in protein levels of these growth factors. Our results demonstrate that dexamethasone can differentially regulate the expression of growth factors in hippocampal astrocytes in vitro. This suggests that one of the mechanisms through which glucocorticoids affect hippocampal functions may be by regulating the expression of astrocyte-derived growth factors.

Animals↗
PubMed1994

Early changes in protein synthesis induced by basic fibroblast growth factor, nerve growth factor, and epidermal growth factor in PC12 pheochromocytoma cells.

Nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) stimulate neuronal differentiation, whereas epidermal growth factor (EGF) promotes only mitogenic responses in PC12 pheochromocytoma cells. The early changes in protein synthesis induced by bFGF, NGF, and EGF in these cells have been determined by two-dimensional PAGE of [35S]methionine-labeled proteins and computerized image analysis. The rate of synthesis of only 29 proteins (out of approximately 1500 identified) was found to be modulated during the first several hours of growth factor stimulation. Individually, 12 were affected by EGF, 23 were affected by bFGF, and 20 were affected by NGF. Eight of these were regulated by all three growth factors, while 10 proteins were commonly induced by bFGF and NGF, in accordance with the essentially identical morphological responses induced by these two factors. In addition, the effects of bFGF and NGF were about equally divided between increases and decreases in the rate of synthesis of individual proteins, whereas EGF caused significantly more positive (increased) responses. All proteins modulated by NGF or FGF alone were negative in their response and those induced by only EGF were positive. Of particular interest, the rate of synthesis of two proteins of 55 kDa and pI 5.45 and 5.50 was dramatically and transiently induced during the first 2 hr of bFGF and NGF treatment and was not affected by EGF. This study indicates that all three factors elicit early increases and decreases in the synthesis of a quite limited number of proteins and provides molecular evidence for the specificity of a differentiative vs. a proliferative growth factor-induced signaling pathway in these cells.

Adrenal Gland Neoplasms↗
PubMed1994

Expression and function of nerve growth factor and nerve growth factor receptor on cultured keratinocytes.

Keratinocytes, a key cellular component both for homeostasis and pathophysiologic processes of the skin, secrete a number of cytokines and are stimulated by several growth factors. Nerve growth factor (NGF) is synthesized in the skin and basal keratinocytes express the low-affinity nerve growth factor receptor (NGF-R). We present evidence that normal human keratinocytes in culture express the low- and the high-affinity NGF-R both at the mRNA level, as determined by reverse-transcription polymerase chain reaction and at the protein level, as shown by cytofluorimetric analysis. NGF significantly stimulates the proliferation of normal human keratinocytes in culture in a dose-dependent manner. This effect can be prevented by the addition of both an anti-NGF neutralizing antibody and a high-affinity NGF-R (trk) specific inhibitor, the natural alkaloid K252a. By contrast, keratinocyte proliferation is not inhibited by an anti-low-affinity NGF-R monoclonal antibody, thus suggesting that NGF effect on human keratinocytes is mediated by the high-affinity NGF-R. Moreover, NGF mRNA is expressed in normal human keratinocytes and NGF is secreted by keratinocytes in increasing amounts during growth, as detected by enzyme-linked immunosorbent assay. These results suggest that NGF could act as a cytokine in human skin and take part in disorders of keratinocyte proliferation.

Antibodies, Monoclonal↗
PubMed2001

The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor.

Nerve growth factor is an essential neurotrophic factor required for the growth and maintenance of cutaneous sensory nerves. In the skin, keratinocytes are a significant source of nerve growth factor; however, the regulation of cutaneous nerve growth factor production still remains to be fully understood. In this study we tested the hypothesis that neuropeptides released by cutaneous sensory nerves have the capacity to modulate directly the expression of keratinocyte nerve growth factor, which would have important implications for the maintenance and repair of nerves in the skin. In order to address this question experimentally we examined the effect of the neuropeptides, substance P and neurokinin A, on nerve growth factor expression in human keratinocytes and the murine keratinocyte PAM 212 cell line by quantitative reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and the PC-12 nerve growth factor bioassay. The results of these studies indicated that substance P and neurokinin A can directly induce nerve growth factor mRNA expression and the secretion of bioactive nerve growth factor protein in both human and murine keratinocytes. The specificity of these responses was demonstrated using neuropeptide receptor antagonists and nerve growth factor blocking antibodies. Additional studies also demonstrated a significant in vivo upregulation of keratinocyte nerve growth factor expression in murine epidermis after the topical application of the neuropeptide releasing agent capsaicin. This is the first report demonstrating the induction of cutaneous nerve growth factor by sensory nerve-derived neuropeptides such as substance P and neurokinin A. This direct effect of the neurosensory system on keratinocyte nerve growth factor production may have important consequences for the maintenance and regeneration of cutaneous nerves in normal skin and during inflammation and wound healing.

Animals↗
PubMed1990

Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor.

Nerve growth factor plays an important part in neuron-target interactions in the late embryonic and adult brain. We now report that this growth factor controls the proliferation of neuronal precursors in a defined culture system of cells derived from the early embryonic brain. Neuronal precursor cells were identified by expression of the intermediate filament protein nestin. These cells proliferate in response to nerve growth factor but only after they have been exposed to basic fibroblast growth factor. On withdrawal of nerve growth factor, the proliferative cells differentiate into neurons. Thus, in combination with other growth factors, nerve growth factor regulates the proliferation and terminal differentiation of neuroepithelial stem cells.

Animals↗
PubMed1993

Cross talk among tyrosine kinase receptors in PC12 cells: desensitization of mitogenic epidermal growth factor receptors by the neurotrophic factors, nerve growth factor and basic fibroblast growth factor.

We have studied the effects of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) on epidermal growth factor (EGF) binding to PC12 cells. We show that NGF and bFGF rapidly induce a reduction in 125I-EGF binding to PC12 cells in a dose-dependent manner. This decrease amounts to 50% for NGF and 35% for bFGF. Both factors appear to act through a protein kinase C(PKC)-independent pathway, because their effect persists in PKC-downregulated PC12 cells. Scatchard analysis indicates that NGF and bFGF decrease the number of high affinity EGF binding sites. In addition to their effect on EGF binding, NGF and bFGF activate in intact PC12 cells one or several serine/threonine kinases leading to EGF receptor threonine phosphorylation. Using an in vitro phosphorylation system, we show that NGF- or bFGF-activated extracellular regulated kinase 1 (ERK1) is able to phosphorylate a kinase-deficient EGF receptor. Phosphoamino acid analysis indicates that this phosphorylation occurs mainly on threonine residues. Furthermore, two comparable phosphopeptides are observed in the EGF receptor, phosphorylated either in vivo after NGF treatment or in a cell-free system by NGF-activated ERK1. Finally, a good correlation was found between the time courses of ERK1 activation and 125I-EGF binding inhibition after NGF or bFGF treatment. In conclusion, in PC12 cells the NGF- and bFGF-stimulated ERK1 appears to be involved in the induction of the threonine phosphorylation of the EGF receptor and the decrease in the number of high affinity EGF binding sites.

Animals↗
PubMed2003

Programmed cell death in the developing inner ear is balanced by nerve growth factor and insulin-like growth factor I.

Nerve growth factor induces cell death in organotypic cultures of otic vesicle explants. This cell death has a restricted pattern that reproduces the in vivo pattern of apoptosis occurring during inner ear development. In this study, we show that binding of nerve growth factor to its low affinity p75 neurotrophin receptor is essential to achieve the apoptotic response. Blockage of binding to p75 receptor neutralized nerve-growth-factor-induced cell death, as measured by immunoassays detecting the presence of cytosolic oligonucleosomes and by TUNEL assay to visualize DNA fragmentation. Nerve growth factor also induced a number of cell-death-related intracellular events including ceramide generation, caspase activation and poly-(ADP ribose) polymerase cleavage. Again, p75 receptor blockade completely abolished all of these effects. Concerning the intracellular pathway, ceramide increase depended on initiator caspases, whereas its actions depended on both initiator and effector caspases, as shown by using site-specific caspase inhibitors. Conversely, insulin-like growth factor I, which promotes cell growth and survival in the inner ear, abolished apoptosis induced by nerve growth factor. Insulin-like growth factor cytoprotective actions were accomplished, at least in part, by decreasing endogenous ceramide levels and activating Akt. Taken together, these results strongly suggest that regulation of nerve-growth-factor-induced apoptosis in the otocysts occurs via p75 receptor binding and is strictly controlled by the interaction with survival signalling pathways.

Animals↗
PubMed1996

Regulation of gamma-glutamylcysteine synthetase activity by nerve growth factor.

Nerve growth factor is a neurotrophic factor that regulates neuronal cell development, maintenance, and injury responses in the peripheral and central nervous system. Nerve growth factor reduces injury owing to oxidative stress in rat pheochromocytoma (PC12) cells by increasing intracellular glutathione, in part owing to its stimulation of the activity of gamma-glutamylcysteine synthetase, which is the rate-limiting enzyme in the synthesis of glutathione. Here we show that nerve growth factor did not increase the activity of gamma-glutamylcysteine synthetase in PC12 cells at the transcriptional level. Rather, nerve growth factor enhanced the stability of gamma-glutamylcysteine synthetase mRNA in PC12 cells. These results suggest that, during oxidative stress, nerve growth factor extended the half-life of gamma-glutamylcysteine synthetase mRNA, thus increasing gamma-glutamylcysteine synthetase mRNA levels compared to nerve growth factor-deprived PC12 cells.

Animals↗
PubMed1997

Commercial mouse and human nerve growth factors contain nerve growth factor prohormone isoforms.

Highly sensitive chemiluminescence immunoblot analysis was utilized to examine the purity of mouse 2.5S-, beta- and 7S nerve growth factors as well as that of recombinant human beta-nerve growth factor obtained from commercial vendors. Three polyclonal antisera and two monoclonal antibodies to 13 kDa nerve growth factor (2.5S NGF and beta-NGF) were employed for assessing the purity of each preparation. In addition, polyclonal antisera against two prepro-NGF specific domains were used for immunoblotting analysis to ascertain the identity of high molecular weight nerve growth factor immunoreactive proteins as prohormones. Both the mouse and human NGF preparations contained 53 and 60 kDa immunoreactive proteins. Of these, the mouse 60 kDa and the human 53 kDa proteins strongly immunoreacted with both prepro-nerve growth factor specific domain antibodies suggesting that they are two NGF prohormone isoforms. In addition, both the mouse and human nerve growth factor preparations contained proteins that were immunoreactive to polyclonal antisera and monoclonal antibodies to mouse 2.5S and/or beta-NGF. High molecular weight aggregates of prohormones were also observed in mouse and human nerve growth factor samples. In summary, none of the ten NGF samples examined were pure as stated. Our study cautions investigators in the field to be aware of the presence of nerve growth factor prohormones and other proteins in various mouse and human nerve growth factors sold commercially.

Animals↗
PubMed1986

Comparison of 7S nerve growth factor and nerve growth factor I from mouse submandibular glands.

7S nerve growth factor (7S NGF) and nerve growth factor I (NGFI) are NGF-containing protein complexes isolated from mouse submandibular glands by different protocols, and reports suggest that the molecules differ chemically. In this study, we compared the molecular properties and subunit compositions of the two proteins. Purified 7S NGF and NGFI electrophoresed to identical positions on polyacrylamide gels in nondissociating buffers, with electrophoretic mobilities indistinguishable from that of unpurified NGF in salivary gland extracts. Ultraviolet absorption curves were identical, and sedimentation coefficients were similar (7.3 +/- 0.25 S for 7S NGF; 7.2 +/- 0.2 S for NGFI) as determined by sedimentation velocity analysis. By sedimentation equilibrium analysis, molecular weights of 135 000-140 000 were obtained for both complexes at protein concentrations in the centrifuge cell greater than 85 micrograms/mL; when protein concentrations within the centrifuge cell ranged from approximately 30 to 100 micrograms/mL at equilibrium, both complexes dissociated. Molecular weight values determined by gel filtration on Bio-Gel P300 and Sephadex G200 resins were similar for both proteins, and the values determined on Sephadex agreed with those obtained by ultracentrifugation. The subunit compositions of the complexes were also similar as determined by nonequilibrium isoelectric focusing, NGFI being composed of proteins that migrated to positions identical with those of the alpha, beta, and gamma subunits of 7S NGF. Furthermore, the stoichiometry of the subunits was similar in the two complexes as determined by radioimmunoassays to each of the subunits and by densitometric analysis of electrophoretic gels. Both methods showed that the complexes contain approximately 2 mol of the alpha and gamma subunits per mole of beta-NGF.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed2000

Effect of brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 on functional recovery and regeneration after spinal cord injury in adult rats.

This study examined whether continuous intramedullary infusion of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), or neurotrophin-3 (NT-3) had either an early neuroprotective effect or a delayed effect on regeneration after spinal cord injury (SCI) in adult rats. BDNF, NGF, NT-3 or vehicle was infused at a rate of 625 ng/h into the SCI site at T3 through an implanted cannula attached to an osmotic pump. This infusion was maintained for 14 days after a 35-g clip compression injury. At 4 weeks after injury, the axonal tracer fluorogold (FG) was introduced into the spinal cord caudal to the lesion and the animals sacrificed 3 days later following behavioral assessment. The inclined plane score was significantly higher in BDNF-treated animals (45 +/- 3 degrees) compared to control animals (36 -/+ 1 degrees) at 1 week after injury (p < 0.05), although the scores were not significantly different at later times. BDNF-treated animals also showed more FG-labeled cells in the red nucleus and sensorimotor cortex (1,638 +/- 350 and 124 +/- 83, respectively) compared to controls (1,228 +/- 217 and 36 +/- 15, respectively) and a lower percent cavitation at the injury site (21.4 +/- 10.4%) compared to control animals (32.3 +/- 11.7%). Invasion & proliferation of Schwann cells and formation of peripheral myelin were more prominent at the injury site in the BDNF-treated animals than in the other groups. These results indicate that continuous intramedullary infusion of BDNF provides neuroprotection and enhances some regenerative activity after SCI.

Animals↗
PubMed1992

Regulation of nerve growth factor and nerve growth factor receptor production by NMDA in C6 glioma cells.

The synthesis of nerve growth factor (NGF) and nerve growth factor receptor (NGFR) were studied in a C6 glioma cell line by Northern blot hybridization. In response to a glutamate agonist N-methyl-D-aspartic acid (NMDA), NGF mRNA increased by up to 2-fold after 4-12 h of culture. The non-NMDA receptor agonists, quisqualate and kainate, did not induce any increase of NGF mRNA, and kainate actually produced a decrease. The increase in NGF mRNA in response to NMDA was dose-dependent at 1, 5 and 10 microM. NGF receptor (NGFR) mRNA showed changes in expression which were similar to those for NGF mRNA, but were less marked. The specific glutamate antagonist 2-aminophosphonovaleric acid (APV) blocked the increase of NGF mRNA produced by NMDA. In the absence of Ca2+, an increase of NGF mRNA was still observed but in the presence of 1 mM ethylglycol-bis-(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA), NGF mRNA production abolished. The mechanism producing an increase in NGF mRNA by NMDA may be mediated by cyclic AMP since intracellular cyclic AMP and NGF mRNA levels both increased following treatment with NMDA or dibutyryl cyclic AMP.

2-Amino-5-phosphonovalerate↗
PubMed1976

alpha-Adrenergic regulation of secretion of mouse saliva rich in nerve growth factor.

Nerve growth factor has been quantified by both bioassay and radial immunodiffusion in mouse saliva elicited by several secretagogues. The concentrations by bioassay of nerve growth factor in both epinephrine- and norepinephrine-induced saliva (3400 and 900 mug/ml, respectively) are higher than reported in any other source. In contrast, the concentrations of nerve growth factor in isoproterenol- and pilocarpine-induced saliva are relatively low (17 and 2 mug/ml, respectively). The specific activity of the salivary nerve growth factor was 41, 36, 2, and 0.6 mug/mg of protein in secretions elicited by epinephrine, norepinephrine, pilocarpine, and isoproterenol, respectively. Salivation after administration of either epinephrine or norepinephrine was completely inhibited by the alpha-adrenergic blocker, phenoxybenzamine. These results suggest that the release of saliva rich in nerve growth factor is primarily regulated through alpha-adrenergic receptors.

Animals↗