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)

Neurotrophins (NTs) promote survival and differentiation of central and peripheral neurons, and display several activities also in non-neuronal cells. Human lungs synthesize and release NTs, which are probably involved in the pathophysiology of pulmonary disturbances. In this article the expression and anatomic localization of nerve growth factor, brain-derived neurotrophic factor, and NT-3 and of corresponding high-affinity receptors TrkA, TrkB (full-length and truncated [TR-] isoforms), TrkC, and of the low-affinity p75 receptor, were assessed in surgical samples from adult human lung by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. NTs and their cognate receptor mRNA and protein transcripts were detected by reverse transcriptase-polymerase chain reaction and immunoblotting, respectively, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA and corresponding protein transcripts being the most expressed. High levels of TrkB-[TR-] mRNA and of its protein transcript were also demonstrated, whereas a low expression of p75 mRNA and of corresponding protein transcript were found. Microanatomic analysis of immunohistochemical study revealed that bronchial epithelial cells were immunoreactive for different NTs, with a higher intensity of BDNF immune staining compared with other NTs, but did not express NT receptor immunoreactivity. Alveolar cells were immunoreactive for TrkA and TrkC receptor protein, but did not display immunoreactivity for NTs or other receptors investigated. Gland cells expressed NT and high-affinity NT receptor immunoreactivity, but not p75 receptor immunoreactivity. NT and low-affinity receptor immunoreactivity was observed within neurons and satellite cells of parasympathetic ganglia as well as in nerve fiber-like structures supplying the bronchopulmonary tree. An obvious immunoreactivity for NTs and NT receptor protein was also observed in intrapulmonary branches of pulmonary artery. Pulmonary lymphocytes and macrophages express nerve growth factor and high-affinity NT receptor immunoreactivity. The role of NTs in non-neuronal tissue including lung has not been clarified yet. The widespread expression of NTs and their receptors in different components of the lung suggests that these factors may contribute to regulate cell function in human lung.
Am J Respir Cell Mol Biol 2004 Jan
PMID:Neurotrophin and neurotrophin receptor protein expression in the human lung. 1279 75

Following metabolic or excitotoxic injury to the striatum, there is de novo expression of the low-affinity p75 neurotrophin receptor (p75NTR). The novel expression of this pan neurotrophin receptor in rodents occurs within the lesion core and surrounding area, creating a division between viable and nonviable tissue. The present series of experiments sought to elucidate whether the p75NTR expression seen following metabolic and excitotoxic injury alters neuronal viability within the striatum. Toward this end, we compared the extent of striatal lesion created with quinolinic acid (QA) or 3-nitropropionic acid (3-NP) in p75NTR null and wild-type mice. Using stereological techniques, we found that the lesion volume and neuronal cell counts between p75NTR null and wild-type mice were similar 1, 2, and 4 weeks post-QA or -3-NP lesion. The results indicate that the expression of p75NTR within reactive astrocytes in the mouse striatum is not a key factor in protecting neuronal cell death following metabolic and excitotoxic insults.
J Mol Neurosci 2003 Apr
PMID:Knockout of p75NTR does not alter the viability of striatal neurons following a metabolic or excitotoxic injury. 1279 3

The c-myb proto-oncogene encodes two alternatively spliced mRNAs, which in turn code for proteins of 75 kDa and 89 kDa. It is at present unclear whether the two isoforms of c-Myb perform identical functions or whether they mediate different biological effects. To assess their role in apoptotic death of hematopoietic cells, we expressed the two isoforms of c-Myb in the murine myeloid cell lines 32Dcl3 and FDCP1. Our results show that while ectopic overexpression of p75 c-Myb results in the acceleration of cell death, similar overexpression of p89 c-Myb results in the protection of cells from apoptotic death. An analysis of gene expression changes with mouse cDNA expression arrays revealed that while p75 c-Myb blocked the expression of glutathione S-transferase micro mRNA, p89 c-Myb greatly enhanced the expression of this gene. These results were further confirmed by Northern blot analysis. Ectopic overexpression of the glutathione S-transferase micro gene in 32Dcl3 cells resulted in protection of cells from interleukin-3 withdrawal-induced cell death similar to that seen with the ectopic overexpression of p89 c-Myb. These results suggest that the two isoforms of c-Myb differentially regulate apoptotic death of myeloid cells through differential regulation of glutathione S-transferase micro gene expression.
Mol Cell Biol 2003 Sep
PMID:Molecular mechanisms associated with the regulation of apoptosis by the two alternatively spliced products of c-Myb. 1294 88

The angiogenic factor thymidine phosphorylase (TP) is highly expressed in human monocytes and macrophages, and its expression has been linked to the pathology and progression of solid tumors, rheumatoid arthritis, and gastric ulcers. In this study, TP mRNA and enzyme activity were found to be up-regulated upon the induction of differentiation of the human monocyte cell line THP-1 by phorbol 12-myristate 13-acetate (PMA). TP expression in THP-1 cells was similarly increased by tumor necrosis factor-alpha (TNFalpha). Because monocytes and macrophages are a predominant source of TNFalpha, the up-regulation of TP upon THP-1 differentiation could have been caused by the autocrine production of TNFalpha. In support of this hypothesis, PMA increased TNFalpha mRNA levels; furthermore, the increase in TP expression with PMA treatment was partially blocked by a neutralizing antibody to TNFalpha, particularly at the earlier time points. This data also suggested there may be additional mechanisms regulating TP expression upon PMA treatment of the cells. The induction of TP by TNFalpha was mimicked by an antibody to the TNFalpha receptor R2 (TNF-R2; p75), but not by an antibody to TNF-R1 (p55), suggesting that the TNF-R2 plays a role in the regulation of TP expression. The PMA-induced increase in TP expression was blocked by aspirin but not by the related agent indomethacin, suggesting that aspirin's effect was not caused by the inhibition of cellular cyclooxygenases. An alternative mechanism by which aspirin inhibits gene expression is the modulation of the transcription factor NFkappaB, and the TNFalpha-induced increase in TP mRNA was blocked by a cell-permeable NFkappaB inhibitory peptide. Furthermore, TNFalpha increased and aspirin (but not indomethacin) decreased NFkappaB DNA-binding activity in THP-1 cells. In conclusion, the modulation of TP expression in monocytes by pro- and anti-inflammatory agents suggests that its angiogenic-related actions could contribute to the inflammatory response associated with a number of pathophysiological conditions.
Mol Pharmacol 2003 Nov
PMID:Expression of the angiogenic factor thymidine phosphorylase in THP-1 monocytes: induction by autocrine tumor necrosis factor-alpha and inhibition by aspirin. 1457 75

Tumor necrosis factor (TNF-alpha) is involved in the inflammation and tissue regeneration occurring after spinal cord injury (SCI). This study tests the specific role of p55 and p75 receptors in mediating the transport of TNF-alpha across the blood-spinal cord barrier (BSCB) after SCI by compression. Transcytosis of 125I-TNF-alpha across a monolayer of the cerebral endothelial cells that compose the blood-brain barrier was significantly reduced in the absence of functional p55 and p75 receptors. At 3 d after SCI, double receptor knockout mice had a significantly reduced increase in TNF-alpha uptake from blood to injured lumbar spinal cord as compared with their inbred controls, despite the similar extent of BSCB disruption (measured by 99mTc-albumin). The p75 single receptor knockout mice had a reduced increase in 125I-TNF-alpha uptake, whereas the p55 receptor knockout mice had no significant increase of 125I-TNF-alpha uptake after SCI, suggesting that the p55 receptor plays a major role. Hence, the increased uptake of TNF-alpha 3 d after SCI is not explained by nonspecific barrier disruption but by receptor-mediated upregulation of transport. Quantitative RT-PCR analysis further showed that upregulation of TNF-alpha transport was related to increased expression of mRNA for p55 and p75 receptors. The increase of p55 receptor expression was more robust and seen between 12 h and 1 wk after SCI, whereas the increase of p75 receptor expression occurred later and involved fewer regions. Thus, the differential upregulation of p55 and p75 receptors indicates that permeation of TNF-alpha across the injured BSCB remains a regulated process. Knowledge of receptor-mediated regulation could facilitate effective therapeutic manipulation of BSCB permeation of vascular cytokines important to CNS regeneration.
J Mol Neurosci 2003
PMID:Upregulation of p55 and p75 receptors mediating TNF-alpha transport across the injured blood-spinal cord barrier. 1459 16

Levels of nerve growth factor (NGF) and neurotrophin-3 (NT-3) protein and neurotrophin receptor mRNA in adult sympathetic neurons were investigated following surgical removal of preganglionic input and/or in vivo administration of NGF. Expression of trkC and p75, but not trkA, was significantly decreased following a 3-week deafferentation of the superior cervical ganglion (SCG). Protein levels of NGF and NT-3 in the SCG were unchanged by deafferentation. A 2-week intracerebroventricular infusion of NGF without deafferentation resulted in enhanced mRNA levels of trkA, trkC, and p75 as well as significantly increased NGF and NT-3 protein in the SCG. When NGF infusion followed deafferentation, both trkA and p75 showed significant increases while trkC levels were similar to control values. NGF protein was not increased in the SCG when deafferentation preceded exogenous NGF, yet NT-3 was elevated and levels were similar to cases receiving NGF infusion only. These results support a role for preganglionic input in trkC and p75 expression in adult sympathetic neurons. The increased levels of NT-3 protein and trkC gene expression observed following NGF infusion suggest that NGF influences NT-3 regulation in adult sympathetic neurons. In addition, the present findings provide evidence that, when preganglionic input is removed prior to the NGF infusion, NT-3 effectively competes with NGF for trkA binding. Taken together, we propose that NT-3 may play a role in the robust sprouting of sympathetic cerebrovascular axons previously observed following NGF administration, particularly when deafferentation precedes the NGF infusion period.
Brain Res Mol Brain Res 2003 Nov 06
PMID:The effects of deafferentation and exogenous NGF on neurotrophins and neurotrophin receptor mRNA expression in the adult superior cervical ganglion. 1459 31

Spindle cell melanoma is a rare and distinctive variant of malignant melanoma that is composed of spindled neoplastic cells and includes desmoplastic and neurotropic melanoma. The lack of expression of several melanoma markers may result in a delayed or wrong diagnosis. In this study, we have analyzed in detail the phenotype of the tumor cells in 9 spindle cell melanomas on both paraffin-embedded and frozen material, using melanocytic, neural, and mesenchymal markers. The neoplastic cells expressed the melanocytic markers S-100, Mel-CAM, and NKIC3, but lacked gp100 and Melan-A; tyrosinase and c-Kit were expressed in 2 of 7 cases. Most cases expressed the neural markers p75-nerve growth factor receptor, neural cell adhesion molecule, and NSE. All cases expressed vimentin but lacked the mesenchymal markers CD34 and alpha-smooth muscle actin. Remarkably, all spindle cell melanomas strongly and diffusely expressed the fibroblastic markers Thy1 (CD90) and aminopeptidase N (CD13) and variably expressed the enzyme prolyl-4-hydroxylase, involved in procollagen formation. The coexpression of melanocytic, neural, and fibroblastic markers suggests bidirectional differentiation of neoplastic melanocytes toward (myo)fibroblasts and Schwann cells, a feature that was confirmed by electron microscopy. Furthermore, the lack of CD90 and CD13 staining in a wide range of melanocytic lesions suggests specificity of these markers for spindle cell melanoma.
Appl Immunohistochem Mol Morphol 2003 Dec
PMID:New phenotypical and ultrastructural findings in spindle cell (desmoplastic/neurotropic) melanoma. 1466 57

The mechanisms of the basolateral targeting of G protein-coupled receptors remain largely unknown. Mutagenesis experiments have allowed us to identify the basolateral sorting signals of the TSH and LH receptors expressed in Madin-Darby canine kidney cells and thyroid follicular FRT cells. Unexpectedly these signals (amino acids 731-746 and 672-689, respectively) share an unusual localization in the distal part of the intracellular domain of the receptors at a marked distance from the membrane. When grafted onto the p75-neurotropin receptor, these signals redirect this normally apically expressed protein to the basolateral cell surface. They are independent of the endocytosis signal. The basolateral sorting signals of TSH, LH, and FSH receptors do not exhibit primary sequence homology with each other or with any other known signal. Furthermore, circular dichroism studies show that the three signals exhibit distinct secondary structures. The TSH receptor has a stable helical structure, the LH receptor has both helix and beta-sheet structures, and the FSH receptor sorting signal has a main random coil structure. This means that even in closely-related receptors different secondary structures can be found for basolateral signals unrelated to internalization signals. This observation contrasts with what is known about basolateral signals related to internalization signals for which a common beta-turn structure has been described. Deletion of the basolateral sorting signals results in apical targeting of the receptors, suggesting the existence of apical sorting information. However, a soluble form of the TSH receptor, which harbors all N- and putative O-linked oligosaccharides, is secreted in a nonpolarized fashion. This implies that apical sorting information must be located elsewhere, either in the transmembrane or in the intracellular domains of the receptor.
Mol Endocrinol 2004 Mar
PMID:The basolateral sorting signals of the thyrotropin and luteinizing hormone receptors: an unusual family of signals sharing an unusual distal intracellular localization, but unrelated in their structures. 1469 83

There is growing evidence that 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is active in the brain but until recently there was a lack of evidence about its role during brain development. Guided by certain features of the epidemiology of schizophrenia, our group has explored the role of 1,25(OH)(2)D(3) in brain development using whole animal models and in vitro culture studies. The expression of the vitamin D receptor (VDR) in the embryonic rat brain rises steadily between embryonic day 15-23, and 1,25(OH)(2)D(3) induces the expression of nerve growth factor and stimulates neurite outgrowth in embryonic hippocampal explant cultures. In the neonatal rat, low prenatal vitamin D(3) in utero leads to increased brain size, altered brain shape, enlarged ventricles, reduced expression of nerve growth factors, reduced expression of the low affinity p75 receptor and increased cellular proliferation. In summary, there is growing evidence that low prenatal levels of 1,25(OH)(2)D(3) can influence critical components of orderly brain development. It remains to be seen if these processes are of clinical relevance in humans, but in light of the high rates of hypovitaminosis D in pregnant women and neonates, this area warrants further scrutiny.
J Steroid Biochem Mol Biol 2004 May
PMID:Vitamin D3-implications for brain development. 1522 38

TNF-alpha is a pleiotropic cytokine with strong proinflammatory and immunomodulatory properties. TNF-alpha plays a critical role in many acute or chronic inflammatory diseases and anti-TNF-strategies have proven to be clinically effective. Two TNF-specific cell surface receptors TNF-R1 and TNF-R2 have been identified and the function of these receptors and the downstream intracellular signal transduction pathways have been extensively studied in vitro. For a long time TNF-R1 was considered to be the predominant mediator of TNF-signaling, whereas TNF-R2 was ascribed only auxilliary function. However, there is increasing clinical and experimental evidence for an important independent role of p80 signaling in chronic inflammatory conditions. It is conceivable that the multiple TNF-mediated chronic inflammatory disorders differ in terms of the ligand form (soluble TNF-alpha versus membrane bound TNF-alpha), the receptor (TNF-R1 versus TNF-R2) and the downstream signaling cascades utilized. The elucidation of the specific characteristics of TNF-signaling in distinct inflammatory disorders will lead to a better understanding ot the pathogenesis of these diseases and will be the basis for the development of more specific and more efficient therapeutic approaches.
Curr Mol Med 2004 Jun
PMID:Differential TNF-signaling in chronic inflammatory disorders. 1535 74


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