Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nerve growth factor (NGF) induces differentiation of the rat pheochromocytoma clone (PC12) by activating the high affinity receptor, p140(trkA), linked to mitogen-activated protein kinase. While the physiological role of the low affinity NGF receptor (p75) has not been clearly defined, this receptor promotes activation of nuclear factor (NF) kappaB in Schwann cells. PC12 cells express the A(2A) adenosine receptor (AR), whose expression is significantly decreased by NGF treatment. In this study, we determined whether TrkA or p75 is involved in NGF-mediated regulation of A(2A)AR expression. NGF treatment decreased A(2A)AR in a time-dependent manner, with maximal effects observed by 1 day, and continued down-regulation of the receptor for up to 3 days in the presence of NGF. The decrease in A(2A)AR was associated with a more delayed decrease in the steady-state levels of the A(2A)AR mRNA. Down-regulation of the A(2A)AR at 1 day was mimicked by activators of NFkappaB, such as H(2)O(2), and ceramide, and was attenuated by the inhibitor pyrrolidine dithiocarbamate or following transient transfection of PC12 cells with a dominant negative IkappaBalpha mutant. Moreover, NGF stimulated nuclear accumulation of p65 subunits of NFkappaB (but not p50 subunits) in PC12 cells, as determined by electrophoretic mobility shift assays and by Western blotting. In contrast, inhibition of TrkA by AG879 or of TrkA-dependent mitogen-activated protein kinase mitogen-activated protein kinase kinase with PD98059 blocked PC12 cell differentiation without affecting A(2A)AR down-regulation, suggesting dissociation between these two phenomena. Taken together, these data provide strong support for the involvement of the p75/NFkappaB pathway in NGF-mediated down-regulation of A(2A)AR in PC12 cells.
Mol Pharmacol 1999 Nov
PMID:A role of p75 in NGF-mediated down-regulation of the A(2A) adenosine receptors in PC12 cells. 1053 99

The capacity for the neurotrophic factor PACAP38 to regulate expression of nerve growth factor (NGF)-trkA receptors in PC12 cells has been examined. Treatment of PC12 cells with 5 nM PACAP38 for 48 h elicited a 2.5-fold increase in 125I-NGF binding sites. FACS and Western analysis of trkA receptor protein indicate an abundance of receptors. The PACAP38-selective antagonist PACAP 6-38 blocked trkA receptor upregulation elicited by PACAP38. The expression of epidermal growth factor receptors was not affected by PACAP38 suggesting that upregulation of trkA represents a selective effect of this neurotrophic peptide. Similarly, expression of the pan-neurotrophin binding receptor p75 was not altered by PACAP38 treatment. In addition to effects on trkA observed in wild-type PC12 cells, PACAP38 stimulated an increase in the level of expressed human trkA receptors stably transfected into PC12 cells. PACAP38 provoked an increase in basal and NGF-stimulated phosphorylation of trkA. Enhanced phosphorylation of trkA was detected as early as 6 h following addition of PACAP38 and was maximal at 48 h. Increased incorporation of phosphate occurs on both serine and tyrosine residues of trkA. These results suggest that PACAP38 is able to promote upregulation of trkA receptors, an event associated with elevated serine/tyrosine phosphorylation of trkA.
Mol Cell Biol Res Commun 1999 Aug
PMID:Heterologous upregulation of nerve growth factor-TrkA receptors in PC12 cells by pituitary adenylate cyclase-activating polypeptide (PACAP). 1054 32

Membrane-associated tumor necrosis factor (mTNF) has recently been shown to induce inflammatory cellular responses previously attributed to the soluble form. The present study measures for the first time the expression and function of mTNF on the surface of alveolar macrophages (AMs) to determine whether it is associated with the development of acute respiratory distress syndrome (ARDS). TNF expression was determined by flow cytometry, and the function of mTNF on the surface of AMs was determined by an in vitro cytotoxicity assay. Tumor necrosis factor (TNF)-alpha bioactivity was measured by bioassay. Soluble TNF receptor (TNFR) protein and messenger RNA (mRNA) expression were measured by enzyme-linked immunosorbent assay and reverse transcriptase/polymerase chain reaction, respectively. Increased detection of mTNF was observed on the surface of AMs derived from subjects with ARDS (mean percentage increase in fluorescence 22.30 +/- 3.50% for subjects with ARDS compared with 7.09 +/- 1.70% for At Risk subjects [P < 0.003]). mTNF cytotoxicity in the bioassay positively correlated with the mTNF expression determined by flow cytometry (r(2) = 0.97). Although there was increased mTNF expression and cytotoxic function in ARDS, there was no significant increase in soluble TNF expression in the bronchoalveolar lavage fluid or the AM supernatants. Lower levels of CD120b-soluble TNFR were detected in the AM supernatants derived from subjects with ARDS compared with At Risk (mean 0.264 +/- 0.058 versus 0.593 +/- 0.143 ng/ml, respectively [P < 0.05]). By contrast, there was increased CD120b mRNA expression in AMs derived from subjects with ARDS (P < 0.03), suggesting that increased surface expression of this receptor may be important in mediating the signal of mTNF. These data demonstrate for the first time the presence of functionally active mTNF on the surface of AMs in ARDS and highlight a potential mechanism for TNF-mediated lung injury.
Am J Respir Cell Mol Biol 2000 Jan
PMID:Increased expression of functionally active membrane-associated tumor necrosis factor in acute respiratory distress syndrome. 1061 67

We hypothesized that tumor necrosis factor (TNF)-alpha signaling is essential to inflammation and host defense during Escherichia coli pneumonia. We tested this hypothesis by instilling E. coli into the lungs of wild-type (WT) mice and gene-targeted mice that lack both p55 and p75 receptors for TNF-alpha. The emigration of neutrophils 6 h after instillation of E. coli was not decreased, but rather was significantly increased (167% of WT), in TNF receptor (TNFR)-deficient mice. This increased neutrophil emigration did not result from peripheral blood neutrophilia or enhanced neutrophil sequestration, inasmuch as the numbers of neutrophils in the circulating blood and in the pulmonary capillaries did not differ between TNFR-deficient and WT mice. The accumulation of pulmonary edema fluid was not inhibited in TNFR-deficient compared with WT mice. Nuclear factor-kappaB (NF-kappaB) translocation in the lungs was not prevented in TNFR-deficient mice. Thus, signaling pathways independent of TNFRs can mediate the acute inflammatory response during E. coli pneumonia. However, despite this inflammatory response, bacterial clearance was impaired in TNFR-deficient mice (109 +/- 8% versus 51 +/- 14% of the original inoculum viable after 6 h in TNFR-deficient and WT mice, respectively). Increased neutrophil emigration during E. coli pneumonia in TNFR-deficient mice may thus result from an increased bacterial burden in the lungs. During acute E. coli pneumonia, the absence of TNFR signaling compromised bacterial killing, but did not prevent inflammation, as measured by the accumulation of edema fluid and neutrophils.
Am J Respir Cell Mol Biol 2000 Jan
PMID:Roles of tumor necrosis factor receptor signaling during murine Escherichia coli pneumonia. 1061 69

Efficient gene transfer of lymphocytes is extremely difficult. Apoptosis may play a role in this gene transfer resistance of lymphocytes. Here we show that transfection of lymphocytes via non-viral vectors leads to induction of apoptosis in a significant proportion of cells. Since apoptosis may be mediated via tumor necrosis factor d (TNF-alpha) and the TNF-alpha receptor pathway, we studied the amount of TNF-alpha secreted by lymphocytes transfected without gene insert. TNF-alpha secretion was dependent on the gene transfer method used. High amounts were detected using receptor-mediated gene transfer and lipofection. In contrast, only low amounts of TNF-alpha were detected after electroporation and retroviral gene transfer. In receptor-mediated gene transfer, TNF-alpha secretion was due to the use of anti-CD3 antibody. Transfection of lymphocytes led to selective decrease in CD120b/TNF-alpha receptor II (TNFR-2)-positive cells. Induction of apoptosis and necrosis mediated by TNF-alpha via TNFR-2 (p80) was partially blocked using a neutralizing anti-TNF-alpha antibody. Blockage of apoptosis and necrosis could be further increased by adding anti-Fas-ligand (FasL) antibody, suggesting that induction of apoptosis via FasL and Fas receptor (Apo-1/CD95) may also play a role. This blockage led to a significant increase in the proliferation rate of lymphocytes transfected with cytokine genes. In conclusion, various gene transfer techniques led to TNF-alpha secretion, apoptosis and necrosis of lymphocytes. Apoptosis and necrosis could be partially blocked using a neutralizing anti-TNF-alpha antibody.
Cytokines Cell Mol Ther 1999 Sep
PMID:TNF-alpha secretion and apoptosis of lymphocytes mediated by gene transfer. 1064 75

Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRAF1 and TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (MIHC) were recently identified as proteins that associate with the TNF-alpha receptors TNFRI (p55) and TNFRII (p75) and inhibit TNF-alpha-induced programmed cell death or apoptosis. In the original reports, TRAF1 expression, unlike the ubiquitous TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF-alpha is increased in the lung in many forms of pulmonary disease. In the current study, Western analysis, immunohistochemistry, and ribonuclease protection assays were used to determine whether TNF-alpha regulates the expression of these TNFR-associated proteins in lung cells. We demonstrate for the first time TNF-alpha dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441 and A549 pulmonary adenocarcinoma cell lines, as well as in lung cells of C57BL/6J mice after intratracheal administration of TNF-alpha. In contrast to the epithelial cells, TRAF1 was not induced by TNF-alpha in U937 cells, a human monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2 mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells but not in U937 cells. TNF-alpha is a primary mediator of acute pulmonary inflammation and contributes to the pathophysiology of chronic lung diseases such as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely born infants. Immunohistochemical staining of human neonatal lung tissue demonstrated increased TRAF1 in lungs of infants dying of pneumonia or BPD in comparison with those dying of congenital malformation. These studies support the hypothesis that the TRAF1 and cIAP2 genes are highly regulated in pulmonary cells and may play a role in human lung disease.
Am J Respir Cell Mol Biol 2000 Feb
PMID:Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes TRAF1 and cIAP2. 1065 35

Biological agents that inhibit the activity of proinflammatory cytokines are being investigated for use in the treatment of rheumatoid arthritis. Thus far, two of these agents, both of which neutralize tumor necrosis factor alpha (TNF-alpha), have received US Food and Drug Administration approval for the treatment of the disease. Etanercept is a bioengineered fusion protein of the p75 soluble TNF receptor, and infliximab is a chimeric monoclonal antibody to TNF-alpha. Other agents that target proinflammatory cytokines are also being developed. By allowing earlier treatment and better-tolerated long-term therapy, biologics might help slow or prevent disease progression and joint destruction.
Mol Med Today 2000 Aug
PMID:Cytokines in rheumatoid arthritis: trials and tribulations. 1090 49

Tumor necrosis factor (TNF) receptor 2 (TNF-R2) has been implicated in insulin resistance and metabolic syndrome disorders, one of which is hypertension (HT). We therefore decided to test markers in and near the TNF-R2 gene (TNFRSF1B) for linkage and association with HT, as well as hypercholesterolemia, and plasma levels of the shed soluble receptor (sTNF-R2). The linkage study, which involved 200 HT Anglo-Celtic Caucasian sibpairs, indicated a sharp, significant linkage peak centered at TNFRSF1B (multipoint maximum LOD score = 2. 6 and 3.1 by weighted and unweighted MAPMAKER/SIBS, respectively; two-point LOD scores = 2.9 and 3.9 by weighted and unweighted SPLINK, respectively; P = 10(-4) by identical-by-state chi(2)). The case-control study in 134 unrelated HTs who were the offspring of two HT parents and 197 normotensives (NTs) whose parents were both NTs, indicated possible association of TNFRSF1B with HT by haplotype analysis (P = 0.008). Plasma sTNF-R2 was elevated in HTs (P < 0. 0001) and showed a correlation with systolic and diastolic blood pressure (BP) (P < 0.0002). A genotypic effect of TNFRSF1B on plasma sTNF-R2, as well as total, low and high density lipoprotein cholesterol, and diastolic BP was observed. These observations are consistent with a scheme leading to raised BP and hypercholesterolemia. In conclusion, TNFRSF1B may be a candidate gene for HT and other metabolic syndrome abnormalities.
Hum Mol Genet 2000 Aug 12
PMID:Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor. 1094 22

Neurotrophins (NTs) and their receptors play an essential role in the differentiation and survival of defined neuronal populations of the central and peripheral nervous systems. Their actions, however, do not appear to be limited to the nervous system, as both NTs and their receptors have been found in non neuronal cells, including cells of the endocrine system. At least four of the five known neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), and their receptors (p75 NTR, trkA, trkB and trkC) are present in the developing ovary. Using mice carrying null mutations of the genes encoding neurotrophins (NGF, NT-4, BDNF) or the receptor that mediates the actions of NT-4 and BDNF (trkB), we have obtained initial results consistent with the notion that neurotrophins are required for the growth of primordial follicles. NGF-deficient mice show a decreased formation of both primary and secondary preantral follicles. Null mutation of the NT-4 gene failed to affect either folliculogenesis or follicular development. However, formation of primary and secondary follicles was compromised in mice carrying a null mutation of both the NT-4 and BDNF genes, suggesting compensation of function by BDNF in NT-4 knockouts. Support for this concept is provided by the similar deficiency in follicular growth observed in animals carrying a null mutation of the gene encoding trkB, the receptors mediating NT-4 and BDNF actions. Initial experiments, using differential display, to isolate genes that may be involved in the process of folliculogenesis and/or early follicular development, resulted in the isolation of a recently identified cell adhesion molecule and a novel transcription factor originally shown to induce cell transformation. It thus appears that formation and development of mammalian follicles requires the concerted action of genes originally thought to be only involved in cell differentiation/survival of neuronal cells, and genes that may control the growth, differentiation, and cell-cell interactions of somatic and germ cells in the ovary.
Mol Cell Endocrinol 2000 May 25
PMID:Neurotrophic and cell-cell dependent control of early follicular development. 1096 76

Neuronal survival during the developmental period of naturally occurring cell death is mediated through a successful competition for limiting concentrations of neurotrophic factors, and the deprived neurons will die. New results show that induced death through the p75 neurotrophin receptor (p75(NTR)), a member of the p55TNF/Fas family of cell death receptors, may also influence survival during development. We find that eliminating p75(NTR) or neurotrophin 4 (NT4) in mice leads to a marked attenuation of apoptosis during the programmed cell death period of the trigeminal ganglion neurons, suggesting that NT4 can induce the death of these neurons through the p75(NTR). These in vivo findings were reproduced in primary cell cultures, where NT4 was found to induce death in a p75(NTR)-dependent pathway. Analysis of p75 deficient and wild-type cells revealed two separate cell death pathways, a p75(NTR)- and caspase-3-independent pathway activated by trophic factor deprivation, and a p75(NTR)- and caspase-3-dependent pathway initiated by NT4. Crossing in the NT4 null alleles in brain-derived neurotrophic factor (BDNF) null mutant mice led to a rescue of a large proportion of BDNF-dependent neurons from excessive cell death, indicating that trophic factor deprivation is not sufficient for the death of many neurons and that additional death inducing signals might be required. Our results suggest that NT4 competitively signals survival and death of sensory neurons through trkB and p75(NTR), respectively.
Mol Cell Neurosci 2000 Sep
PMID:Attenuation of a caspase-3 dependent cell death in NT4- and p75-deficient embryonic sensory neurons. 1099 52


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