Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0009443 (cold)
92,137 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Src protein is essential for the regulation of bone turnover primarily via bone resorption because it is required in osteoclast differentiation and function. We followed temporal changes of Src protein abundance in marrow stromal cells induced to mineralize by dexamethasone (DEX), growth in cold temperature, or both. Given the tyrosine kinase function of Src and its numerous substrates, profiles of phosphotyrosine-containing proteins were followed as well. On day 11 of stimulation, specific alkaline phosphatase (ALP) activity at 30 degrees C decreased under DEX relative to 37 degrees C cultures, in accord with increased cell counts. Mineralization per well under DEX increased by 25% at 37 degrees C, whereas at 30 degrees C it increased by more than threefold regardless of the DEX stimulation. At 30 degrees C, on a per cell basis mineralization increased 2.5 and 3 times with and without DEX, respectively. Cultures at 37 degrees C showed a general drop per cell of many phosphotyrosine-containing proteins on day 3 relative to days 1 and 2 in both DEX-stimulated and nonstimulated cultures; several proteins did recover (recuperate) thereafter. On days 1 and 2, the phosphotyrosine signal was higher in several proteins under DEX stimulation; this trend became inverted after day 3. The changes in abundance per cell of Src protein (pp60src) followed a similar trend, and in addition a truncated Src molecule, p54/52src, was detected as a putative cleavage product presumably representing its carboxy terminus. The pp60src was most abundant, relative to its truncated product, in day 7 nonstimulated cultures, whereas under DEX stimulation the truncated species pp54/52src showed the highest relative abundance on days 7. At 30 degrees C, DEX stimulation accentuated the increase in Src protein on day 3, showed no change on day 7, and returned to increase Src protein on day 10. Potassium ionophorvalinomycin, considered to select against mineralizing osteoprogenitors at 30 degrees C, showed on day 10 in the absence of DEX a relative increase in truncated Src protein compared to both DEX-stimulated and nonstimulated cultures in the absence of valinomycin. On day 7 of DEX stimulation, the presence of valinomycin resulted in low p54/52src. Among phosphotyrosine-containing proteins, a 32-34 kDa band, as yet unidentified, showed the most concordant changes with mineralization induction. P32-34 decreased by DEX on days 2 and 8 and increased by low temperature alone or combined with DEX on day 3. On day 7, p32-34 did not change under DEX, but valinomycin selected cells with less phoshpotyrosine-containing p32-34. Taken together, high Src abundance at the start of osteogenic induction followed by a decrease 1 week later is probably related to energy metabolism-dependent induction of mineralization. This is in temporal accord with the increase in Src truncation and fluctuation in mitochondrial membrane potential (which affects mineralization). The reported binding of amino-terminal Src oligopeptide to p32 ADP/ATP carrier in the mitochondrial inner membrane raises the question of its possible involvement in mitochondria-regulated mineralization.
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PMID:Src protein and tyrosine-phosphorylated protein profiles in marrow stroma during osteogenic stimulation. 958 70

Nerve growth factor (NGF) has a well characterized role in the development of the nervous system and there is evidence that it interacts with nociceptive primary afferent fibres. Here we applied a synthetic tyrosine kinase A IgG (trkA-IgG) fusion molecule for 10-12 days to the innervation territory of the purely cutaneous saphenous nerve in order to bind, and thereby neutralize endogenous NGF in adult rats. Using neurophysiological analysis of 152 nociceptors we now show that sequestration of NGF results in specific changes of their receptive field properties. The percentage of nociceptors responding to heat dropped significantly from a normal 57% to 32%. This was accompanied by a rightward shift and a reduced slope of the stimulus response function relating the intracutaneous temperature to the neural response. The number of nociceptors responding to application of bradykinin was also significantly reduced from a normal of 28% to 8%. In contrast, the threshold for mechanical stimuli and the response to suprathreshold stimuli remained unaltered, as did the percentage of nociceptors responding to noxious cold. The reduced sensitivity of primary afferent nociceptors was accompanied by a reduction in the innervation density of the epidermis by 44% as assessed with quantitative immunocytochemical analysis of the panaxonal marker PGP 9.5. This demonstrates that endogenous NGF in the adult specifically modulates the terminal arborization of unmyelinated fibres and the sensitivity of primary afferent nociceptors to thermal and chemical stimuli in vivo.
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PMID:Endogenous nerve growth factor regulates the sensitivity of nociceptors in the adult rat. 974 82

Meeting's Report -- June 2, 1998, Sugarload Estate Conference Center, Philadelphia, Pennsylvania, USA. A symposium on Normal Development, Oncogenesis and Programmed Cell Death, was held at the Sugarload Estate Conference Center, Philadelphia, Pennsylvania, USA sponsored by the Fels Cancer Institute, Temple University School of Medicine, with the support of the Alliance Pharmaceutical Corporation. The symposium was organized by Drs Dan A Liebermann and Barbara Hoffman at the Fels. Invited speakers included: Dr Andrei V Gudkov (University of Illinois) who started the symposium talking about 'New cellular factors modulating the tumor suppressor function of p53'; Dr Yuri Lazebnik (Cold Spring Harbor Laboratories) spoke about 'Caspases considered as enemies within'; Dr E Premkumar Reddy (Fels Institute, Temple University) talked about recent exciting findings in his laboratory regarding 'JAK-STATs dedicated signaling pathways'; Dr Michael Greenberg (Harvard University) spoke about 'Signal transduction pathways that regulate differentiation and survival in the developing nervous system'; Dr Richard Kolesnick's (Memorial Sloan-Kettering Cancer Center) talk has been focused at 'Stress signals for apoptosis, including Ceramide and c-Jun Kinase/Stress-activated Protein Kinase'; Dr Barbara Hoffman (Fels Institute, Temple University) described research, conducted in collaboration with Dr Dan A Liebermann, aimed at deciphering the roles of 'myc, myb, and E2F as negative regulators of terminal differentiation', using hematopoietic cells as model system. Dr Daniel G Tenen (Harvard Medical School), described studies aimed at understanding the 'Regulation of hematopoietic cell development by lineage specific transcription regulators'. Dr George C Prendergast (The Wistar Institute) talked about the 'Myc-Bin1 signaling pathway in cell death and differentiation. Dr Ruth J Muschel (University of Pennsylvania) spoke about work, conducted in collaboration with Dr WG McKenna, aimed at gaining a better understanding of 'Radioresistance and the cell cycle'. Finally Dr Donald Kufe concluded the symposium (Dana Farber Cancer Institute, Harvard Medical School) describing studies that were performed in his laboratory addressing the 'Role for the c-Abl tyrosine kinase in genetic recombination'.
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PMID:Normal development, oncogenesis and programmed cell death. 977 61

Increased epithelial permeability is associated with intestinal inflammation, but there is little information on factors that regulate barrier function in the absence of or before inflammation. We examined if interleukin (IL)-4, or serum from atopic individuals, could alter the barrier function of human colonic epithelial (T84) monolayers to antigenic-sized macromolecules. IL-4 and atopic serum significantly decreased T84 monolayer resistance and increased transepithelial horseradish peroxidase (HRP) transport. Bidirectional transport studies demonstrated that IL-4 selectively enhanced apical-to-basal movement of HRP. HRP transport induced by IL-4 was inhibited by cold (4 degrees C) and the tyrosine kinase inhibitor genistein, but not the protein kinase C inhibitor staurosporine. Electron microscopic analysis demonstrated that both transcellular and paracellular pathways were affected. Anti-IL-4 antibodies abolished the increase in HRP transport in response to both IL-4 and serum. We speculate that enhanced production of IL-4 in allergic conditions may be a predisposing factor to inflammation by allowing uptake of luminal antigens that gain access to the mucosal immune system.
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PMID:Role for IL-4 in macromolecular transport across human intestinal epithelium. 1032 51

Protein kinases play central roles in the regulation of eukaryotic and prokaryotic cell growth, division, and differentiation. The Caulobacter crescentus divL gene encodes a novel bacterial tyrosine kinase essential for cell viability and division. Although the DivL protein is homologous to the ubiquitous bacterial histidine protein kinases (HPKs), it differs from previously studied members of this protein kinase family in that it contains a tyrosine residue (Tyr-550) in the conserved H-box instead of a histidine residue, which is the expected site of autophosphorylation. DivL is autophosphorylated on Tyr-550 in vitro, and this tyrosine residue is essential for cell viability and regulation of the cell division cycle. Purified DivL also catalyzes phosphorylation of CtrA and activates transcription in vitro of the cell cycle-regulated fliF promoter. Suppressor mutations in ctrA bypass the conditional cell division phenotype of cold-sensitive divL mutants, providing genetic evidence that DivL function in cell cycle and developmental regulation is mediated, at least in part, by the global response regulator CtrA. DivL is the only reported HPK homologue whose function has been shown to require autophosphorylation on a tyrosine, and, thus, it represents a new class of kinases within this superfamily of protein kinases.
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PMID:A novel bacterial tyrosine kinase essential for cell division and differentiation. 1055 74

Nef protein of HIV/SIV lentiviruses affects G-protein-mediated signaling, and physically associates to Lck, a myristoylated and palmitoylated Src-like tyrosine kinase. To assess whether Nef interacts with alpha-subunits of heterotrimeric G proteins (Galpha), carrying the same lipidation motif as Lck, we transiently expressed Nef and G(o)alpha (wild-type or nonpalmitoylated C3S mutant), individually or in combination, in transfected COS-7 cells. Recombinant Nef was mostly recovered in particulate fractions, and a Nef-Green Fluorescent Protein chimera was localized at the plasmalemma by in vivo fluorescence imaging. Moreover, Nef and C3S were entirely solubilized by cold Triton X-100, and excluded from low buoyant density sucrose gradient fractions, containing caveolin-1, whereas wild-type G(o)alpha was partially resistant to Triton extraction, and colocalized with caveolin-1. After coexpression, Nef recruited soluble C3S to membranes, and the two proteins were coimmunoprecipitated by G(o)alpha and Nef antisera. We conclude that Nef interacts with nonpalmitoylated G(o)alpha, presumably outside caveolin-rich microdomains of the plasma membrane.
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PMID:Interaction between HIV-1 NEF and G(o) proteins in transfected COS-7 cells. 1075 65

The HER-2/neu oncoprotein, a 185 kDa membrane-associated tyrosine kinase with extensive homology to the epidermal growth factor receptor (EGF-R), is overexpressed in breast and ovarian carcinomas. Its overexpression is closely associated with poor prognosis in the course of disease. Here we demonstrate HER-2/neu overexpression in both established cell lines and biopsy material obtained from renal epithelial tumors. Immunohistochemical analysis of human kidney tumor lesions using 2 HER-2/neu-specific antibodies revealed HER-2/neu expression in more than 40% of primary epithelial renal tumors and more than 30% of primary renal cell carcinoma (RCC) specimens. A distinctive HER-2/neu expression pattern was found in different subtypes of kidney tumors with the highest frequency in chromophilic and chromophobic RCC, but neither associated with disease stage nor tumor grade. Eight of 10 RCC cell lines expressed significant levels of HER-2/neu mRNA and protein, but at a lower level compared with HER-2/neu overexpressing ovarian carcinoma cells. To evaluate the immune response against HER-2/neu expressing HLA-A2-positive (HLA-A2(+)) RCC cells, allogeneic HLA-A2-restricted cytotoxic T-lymphocyte (CTL) lines generated by pulsing dendritic cells with 3 different HER-2/neu-derived peptides, (HER-2(9.369), HER-2(9.435) and HER-2(9.689), were utilized in chromium-release assays. Specific lysis of HER-2/neu expressing HLA-A2(+) RCC cell lines was mediated by CTL lines specific for each of these 3 HER-2/neu-derived epitopes. The fine specificity of 2 CTL clones was defined to the epitopes HER-2(9.435) and HER-2(9.689). Their specificity was then confirmed by cold target inhibition assays. In addition, CTL-mediated lysis was enhanced by pulsing tumor cells with exogenous HER-2/neu-specific peptides. Our data suggest that (i) HER-2/neu is heterogeneously expressed in different subtypes of RCC, (ii) HER-2/neu is naturally processed by RCC and (iii) HER-2/neu epitopes presented by RCC can be recognized by HLA-A2-restricted, HER-2/neu-specific CTL.
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PMID:HER-2/neu is expressed in human renal cell carcinoma at heterogeneous levels independently of tumor grading and staging and can be recognized by HLA-A2.1-restricted cytotoxic T lymphocytes. 1089 39

To determine whether fish have an insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6-P) receptor similar to that of mammals, we have performed binding, cross-linking, and immunoprecipitation experiments with wheat-germ-agglutinin- and mannose 6-phosphate (M6-P)-affinity-purified receptor preparations from fish embryos. In both receptor preparations, IGF-II binding was specific, because labeled IGF-II could only be completely displaced by cold IGF-II but not by IGF-I or insulin. Labeled IGF-II bound to a protein with a molecular mass of approximately 250 kDa, which could be immunoprecipitated with an antibody against the rat IGF-II receptor. IGF-II stimulated tyrosine kinase activity in wheat germ agglutinin preparations and was more potent than insulin or IGF-I, but neither peptide stimulated tyrosine kinase activity in M6-P preparations. Two fish cell lines (CHSE-214 and EPC) were used to confirm the IGF-II binding data obtained in the receptor preparations, revealing the presence of highly specific IGF-II binding and the absence of insulin binding. Furthermore, a decrease of the IGF-I receptors on the cell surface did not alter IGF-II binding in EPC cells. In conclusion, we have detected the presence of IGF-II/M6-P receptors in fish embryos that are similar in structure and specificity for their ligand to those found in mammals.
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PMID:Identification of a type II insulin-like growth factor receptor in fish embryos. 1118 23

Effects of acute cold stress (5 degrees C for 24 h) on the functions of peritoneal macrophages and the mechanisms for controlling host homeostasis were investigated in mice. Phagocytic activity and expression of the cell surface adhesion molecule CD11b/CD18 were markedly increased in peritoneal exudate cells by acute cold stress. These alterations were attributable to an increased number and phenotypical changes of adherent cells from acute cold-stressed mice. On the other hand, a lipopolysaccharide-induced activity of src-family tyrosine kinase Fgr, an expression of interleukin-1beta (IL-1 beta) mRNA, and a bioactivity of IL-1 in the culture supernatants of adherent cells from acute cold-stressed mice were markedly lower than those from control mice. A time course study revealed that the number of adherent cells in peritoneal exudate cells was markedly increased in mice exposed to cold for 24 h but returned to normal numbers when mice were exposed to cold for 72 h. DNA fragmentation and Annexin-V(+) cells were observed in peritoneal exudate cells from acute-cold stressed mice. Thus, cold stress activated macrophages but these macrophages were destined to be eliminated by apoptosis.
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PMID:Activation and apoptosis of murine peritoneal macrophages by acute cold stress. 1134 82

Recent evidence has suggested that plasma membrane sphingolipids and cholesterol spontaneously coalesce into raft-like microdomains and that specific proteins, including CD4 and some other T-cell signaling molecules, sequester into these rafts. In agreement with these results, we found that CD4 and the associated Lck tyrosine kinase of peripheral blood mononuclear cells and H9 leukemic T cells were selectively and highly enriched in a low-density lipid fraction that was resistant at 0 degrees C to the neutral detergent Triton X-100 but was disrupted by extraction of cholesterol with filipin or methyl-beta-cyclodextrin. In contrast, the CXCR4 chemokine receptor, a coreceptor for X4 strains of human immunodeficiency virus type 1 (HIV-1), was almost completely excluded from the detergent-resistant raft fraction. Accordingly, as determined by immunofluorescence with confocal microscopy, CD4 and CXCR4 did not coaggregate into antibody-induced cell surface patches or into patches of CXCR4 that formed naturally at the ruffled edges of adherent cells. The CXCR4 fluorescent patches were extracted with cold 1% Triton X-100, whereas the CD4 patches were resistant. In stringent support of these data, CD4 colocalized with patches of cholera toxin bound to the raft-associated sphingoglycolipid GM1, whereas CXCR4 did not. Addition of the CXCR4-activating chemokine SDF-1 alpha did not induce CXCR4 movement into rafts. Moreover, binding of purified monomeric gp120 envelope glycoproteins from strains of HIV-1 that use this coreceptor did not stimulate detectable redistributions of CD4 or CXCR4 between their separate membrane domains. However, adsorption of multivalent gp120-containing HIV-1 virion particles appeared to destabilize the local CD4-containing rafts. Indeed, adsorbed HIV-1 virions were detected by immunofluorescence microscopy and were almost all situated in nonraft regions of the cell surface. We conclude that HIV-1 initially binds to CD4 in a raft domain and that its secondary associations with CXCR4 require shifts of proteins and associated lipids away from their preferred lipid microenvironments. Our evidence suggests that these changes in protein-lipid interactions destabilize the plasma membrane microenvironment underlying the virus by at least several kilocalories per mole, and we propose that this makes an important contribution to fusion of the viral and cellular membranes during infection. Thus, binding of HIV-1 may be favored by the presence of CD4 in rafts, but the rafts may then disperse prior to the membrane fusion reaction.
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PMID:Segregation of CD4 and CXCR4 into distinct lipid microdomains in T lymphocytes suggests a mechanism for membrane destabilization by human immunodeficiency virus. 1179 76


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