Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A xenoantiserum raised in rabbits by immunization with strain 13 guinea-pig antigen-activated T-lymphocytes was previously found to recognize a non-immunoglobulin, 75,000 mol. wt glycoprotein synthesized by guinea-pig T-cells. This protein, p75, has been further characterized to determine its biochemical properties and its expression by various cell types. p75 was found to be a single-chain protein which could be bound by the lectin Lens culinaris hemagglutinin. It has an apparent mol. wt slightly greater than mu-chain as assessed by SDS-polyacrylamide gel electrophoresis and could not be precipitated by anti-guinea-pig immunoglobulin reagents. It exhibited considerable charge heterogeneity during isoelectric focusing and was not affected by neuraminidase treatment, p75 was synthesized by thymus, spleen and lymph node cells, by antigen-stimulated T-cells from strain 13 and strain 2 guinea-pigs, and by guinea-pig B-cell L2C leukemia lines, but not by normal B-lymphocytes or macrophages. No differences between the isoelectric focusing patterns of p75 molecules isolated from different cell types could be demonstrated. The chemical properties of p75 and its expression by the cell types so far examined indicate that p75 is a possible candidate for the guinea-pig homologue of the murine Lyt-1 antigen.
Mol Immunol 1982 Dec
PMID:Characterization of a 75,000 mol. wt glycoprotein synthesized by guinea-pig T-lymphocytes: a possible homologue of Lyt-1 antigen. 698 89

Androgen receptor (AR) brings about a ligand-dependent inhibition of low-affinity neurotrophin receptor (p75) promoter constructs in cultured cells, with the greatest inhibition being achieved with a reporter gene containing 1050 nucleotides (nt) of the promoter. The receptor domain critical for trans-repression localizes to the same region (amino acids 147-296) as that mandatory for transactivation. In contrast to trans-activation, AR does not interact directly with specific DNA elements to elicit trans-repression of p75 promoter constructs, although an intact DNA-binding domain of the receptor is required for both actions. In a search for interacting partners, both extensively purified full-length AR and AR-DNA binding domain were found to inhibit c-Jun/AP-1 site interaction without themselves binding to the AP-1 element. Prior binding of c-Jun to the AP-1 element protected the complex from the receptor's interference. Repression was not mutual, as c-Jun did not inhibit AR-androgen response element interaction or trans-activation through an androgen response element-containing promoter. The 1050-nt-long p75 promoter sequence does not contain an AP-1 element; an AP-1-like site in the vector backbone mediates the trans-repression by the AR in recipient cells. Intriguingly, an AR form with a large N-terminal deletion (the delta 46-408 mutant) behaved as a transcriptional activator of the p75 promoter through a mechanism that was also independent of specific DNA binding. Collectively, these data indicate that, in a proper context, AR is able to elicit both transrepression and trans-activation without interacting directly with specific DNA elements. Sequences responsible for the down-regulation of p75 mRNA by androgens in vivo are, however, not located in the proximal 1050 nt of the p75 promoter.
Mol Endocrinol 1995 Aug
PMID:Androgen receptor-mediated transcriptional regulation in the absence of direct interaction with a specific DNA element. 747 76

Previous studies have demonstrated that interaction of interleukin-2 (IL-2) with the beta chain (p75) of the IL-2 receptor on CD56+ cells is necessary for the development of lymphokine-activated killer (LAK) activity and proliferation of CD56+ LAK cells in response to IL-2. Human pulmonary macrophages (PM) are potent inhibitors of LAK cells in vitro, and purified resident human lung lymphocytes show limited LAK activity in response to IL-2, suggesting that IL-2-p75 interactions may be altered locally in vivo. In the current study, human PM or anti-p75 inhibited LAK activity and proliferation of CD56+ cells in response to IL-2. This effect was produced by either live or paraformaldehyde-fixed PM, but not peripheral blood monocytes, suggesting that a membrane signal on PM was responsible for inhibition. Suppression of LAK function and proliferation in response to IL-2 occurred despite a rapid up-regulation of p75 on CD56+ cells after 24 h of incubation with PM. Greater than 70% of CD56+ cells expressed p75 after culture with either live or fixed PM, compared with 10 to 15% at 0 h or after 24 h of incubation in IL-2 alone. p75 dim and p75 bright cells increased equally, suggesting that p75 was being up-regulated on previously p75- cells rather than an overexpansion of one subset of p75+ cells. The increase in p75 expression in the presence of PM paralleled with an increase in IL-2 binding to these lymphocytes. These results suggest that PM inhibit the activation of LAK cells at a point distal to IL-2-p75 binding.
Am J Respir Cell Mol Biol 1994 Feb
PMID:Inhibition of lymphokine-activated killer cells by human pulmonary macrophages: discordance between up-regulation of the beta chain (p75) of the interleukin-2 receptor on CD56+ cells and limited response to interleukin-2. 750 62

In addition to its intra-cellular functions, cAMP-dependent protein kinase (PKA) may well have an extra-cellular regulatory role in blood. This suggestion is based on the following experimental findings: (a) Physiological stimulation of blood platelets brings about a specific release of PKA, together with its co-substrates ATP and Mg++; (b) In human serum, an endogenous phosphorylation of one protein (p75, M(r) 75 kDa) occurs; this phosphorylation is enhanced by addition of cAMP and blocked by the Walsh-Krebs specific PKA inhibitor; (c) No endogenous phosphorylation of p75 occurs in human plasma devoid of platelets, but the selective labeling of p75 can be reproduced by adding to plasma the pure catalytic subunit of PKA; (d) p75 was shown to be vitronectin (V), a multifunctional protein implicated in processes associated with platelet activation, and thus a protein whose function may require modulation for control; (e) The phosphorylation of vitronectin occurs at one site (Ser378) which, at physiological pH, is buried in its two-chain form (V65 + 10) but it becomes 'exposed' in the presence of glycosaminoglycans (GAGs) e.g. heparin or heparan sulfate. Such a transconformation may be used for targeting the PKA phosphorylation to vitronectin molecules bound to GAGs, for example in the extracellular matrix or on cell surfaces; (f) From the biochemical point of view (Km values and physiological concentrations) the phosphorylation of vitronectin can take place at the locus of a hemostatic event; (g) The phosphorylation of Ser378 in vitronectin alters its function, since it significantly reduces its ability to bind the inhibitor-1 of plasminogen activator(s) (PAI-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1993 Nov
PMID:Evidence for an extra-cellular function for protein kinase A. 752 49

Purine analogues are protein kinase inhibitors, and they block with varying potency and specificity certain of the biological actions of nerve growth factor (NGF). The analogue 6-thioguanine (6-TG) has been shown to inhibit with high specificity protein kinase N (PKN), a serine/threonine protein kinase activated by NGF in several cellular systems. In the present work, immunoprecipitates of p75 NGF receptors from PC12 cells (+/-NGF treatment) were assayed for protein kinase activity using the substrate myelin basic protein under phosphorylating conditions optimal for PKN and in the presence or absence of purine analogues. An NGF-inducible activity was detected, and approximately 80% was inhibited by purine analogues. This activity was maximally stimulated by NGF within 5-10 min, partially decreased by 60 min, and returned to basal levels after 15 h of NGF treatment. The analogue 6-TG inhibited the NGF-inducible p75-associated kinase activity with an IC50 in the range of 15-35 microM. In mutant PC12 nnr-5 cells that lack the Trk NGF receptor, the purine-analogue-sensitive p75-associated kinase activity was not inducible by NFG. In normal PC12 cells, cyclic AMP analogues and epidermal growth factor failed to induce the same activity. Application of either 2-aminopurine or 6-TG to intact cells only slightly inhibit the NGF-dependent induction of the purine-analogue-inhibited p75-associated kinase activity. This activity shares many similarities but also displays some significant differences with cytosolic PKN. Our findings therefore indicate the association of a purine-analogue-sensitive protein kinase with p75 NGF receptors.
Mol Biol Cell 1993 Jan
PMID:Association of a purine-analogue-sensitive protein kinase activity with p75 nerve growth factor receptors. 768 Feb 48

Fusion between HeLa cells and normal human fibroblasts results in the suppression of tumorigenicity. Under prolonged culture conditions, rare tumorigenic segregants arise and have been shown to reexpress a cell surface antigen, p75, which is also present in the HeLa parent but not in the fibroblast parent or in the nontumorigenic HeLa x fibroblast hybrid. Expression of p75 strictly correlates with tumorigenicity in HeLa and human somatic cell hybrids, as has been shown by chromosomal segregation and after gamma-irradiation. Using insertional mutagenesis, we induced expression of p75 in the nontumorigenic hybrid. Three cell clones were isolated that expressed p75 at different levels. Two of these clones exhibited a high level of p75 expression and displayed an altered morphology similar to that of the previously characterized tumorigenic segregants and consistent with the appearance of tumorigenicity. When injected into athymic nude mice, two clones were found to be tumorigenic, one from the onset of subculturing and the second only after further propagation for approximately 50 population doublings. The third clone showed very low p75 expression, had no altered morphology, and was nontumorigenic.
Mol Carcinog 1993
PMID:Effect of retroviral integration on control of expression of a tumor marker in HeLa cells. 769 Oct 70

Androgen alters neurite outgrowth, synaptic organization, and cell survival in various portions of the brain and spinal cord. However, examination of the specific effects of androgen on neurons in vivo has been difficult. Previously, an in vitro model for the effects of estrogen on neurons was developed and characterized, using an estrogen receptor (ER)-transfected PC12 rat pheochromocytoma cell line. This model demonstrated estrogenic regulation of neurite outgrowth, spine formation, and gap junction formation. Similarly, an in vitro model for the effects of androgen on neurons is now described. Wild-type cells (PC12-WT) were stably transfected with an expression vector coding for the full-length cDNA for the human androgen receptor (AR). Resultant clones were isolated, screened for incorporation of vector and expression of AR mRNA and protein, and analyzed for morphologic responses to androgen. PC12-WT, NE09 (ER-negative, AR-negative), SER8 (ER-positive, AR-negative), and AR8 (ER-negative, AR-positive) cells were exposed to 10 ng/ml nerve growth factor (NGF), along with 0-10(-7) M dihydrotestosterone (DHT) for 2 days. AR8 cells demonstrated an androgen dose-dependent increase in mean neurite length, branch order, and neurite field area, whereas neurite branch segment length and soma area were not affected by androgen. PC12-WT, NE09, and SER8 cells exhibited no alterations in cell morphology with DHT exposure. Because of the synergistic effects of DHT and NGF, the regulation of NGF receptor mRNA by DHT was evaluated; however, no significant induction of either trkA or p75 mRNA expression by androgen was documented. The results suggest that in AR-positive PC12 cells, androgen acts additively with NGF to increase neurite outgrowth; but androgen effects are mediated specifically through branching and arborization. These responses are similar to developmental studies of androgen effects in vivo. Thus, androgen appears to induce an inherent neural morphologic program in AR-containing cells, which increases the receptive field of these cells, increasing the likelihood for interneural communication, although not promoting communication itself. These cell lines will provide a unique in vitro system for studying mechanisms of androgen-neuron interactions.
Mol Cell Neurosci 1994 Dec
PMID:An in vitro model for the effects of androgen on neurons employing androgen receptor-transfected PC12 cells. 770 33

T-cell proliferation is regulated by the autocrine ligand interleukin-2 (IL-2), for which these cells possess dual, low-affinity and high-affinity receptor populations. Proliferation stimulated by IL-2 is dependent upon ligand binding to p75, a component of the high-affinity receptor. As with other cells exhibiting dual receptor systems, a central question is, therefore: what is the role of the low-affinity receptor population? We apply a mathematical modeling approach to examine three alternative mechanisms that have been suggested for the role of low-affinity receptors: a ligand reservoir, a receptor reservoir, and a ligand carrier. Using model parameter values specific to the IL-2/T-cell system, we find that only the ligand carrier mechanism leads to binding of autocrine ligand to high-affinity receptors that is increased over levels found on a single, pre-formed high-affinity receptor population. With the ligand reservoir and the receptor reservoir mechanisms, the presence of the low-affinity receptors actually diminishes high-affinity receptor binding due to competition. In contrast, excess low-affinity receptors can act to enhance the level of high-affinity receptor complexes when membrane transport is included, indicating that should this mechanism be inhibited, cell response could potentially be reduced or eliminated. The ligand carrier effect is especially significant for cells expressing a large number (> 10(5) receptors/cell) low-affinity receptors, and at low cell densities (< 10(4) cells/ml). This may at least partially account for the behavior demonstrated by early phase adult T-cell leukemia cells.
Mol Immunol 1994 Jul
PMID:The role of low-affinity interleukin-2 receptors in autocrine ligand binding: alternative mechanisms for enhanced binding effect. 803 36

Sex steroid hormones play a role in the complex network of immune responses but the mechanism of their action is still unclear. Effects of a wide range of doses of 17 beta-estradiol (E2: 0.2-100 ng/ml) on human tonsillar lymphocyte cultures were examined. B and T lymphocyte enriched preparations were stimulated with various concentrations of interleukin-2 and the production of immunoglobulin was measured. Addition of E2 increased B cell immunoglobulin production in a T cell dependent way with intact T cells being obligatory. The effects of E2 were also examined on DNA synthesis by tonsillar T cells. E2 alone caused a significant increase in T cell DNA synthesis. With phytohaemagglutinin-stimulated T cell cultures there was a significant increase in DNA synthesis with E2 at pharmacological doses. Different cell surface and activation markers (including CD25, p75, HLA-DR, CD28) on tonsillar lymphocytes were also studied after exposure to E2. The presence of E2 made no significant difference in the expression of the markers either alone or when the activation antigens were induced by other stimuli. We have shown that intact T cells are needed for the action of E2 on tonsillar B lymphocyte differentiation and have excluded several mechanisms of action of E2 since common activation antigens are unaffected.
J Steroid Biochem Mol Biol 1994 Feb
PMID:Effect of 17 beta-estradiol on immunoglobulin secretion by human tonsillar lymphocytes in vitro. 814 92

Endogenous proteins phosphorylated in vitro with nuclear extracts prepared from skin fibroblasts of familial and sporadic AD subjects and age/sex-matched controls show qualitative/quantitative changes which were dependent upon the addition of natural and synthetic double-stranded DNA (dsDNA) to assay mixtures. Control and AD cell-free homogenates showed a pronounced increase in four proteins migrating with molecular weights of 180- (p180), 75-(p75), 65- (p65), and 34-kD (p34). Optimal stimulation of each protein required a different concentration of dsDNA. In AD samples, an additional dsDNA-stimulated protein, p40, was observed. In extracts prepared from sporadic AD individuals, synthetic dsDNA stimulated the phosphorylation of two additional proteins, with molecular weights of 73- and 37-kD, which were not found in familial AD or control samples. These results suggest that dsDNA-stimulated phosphoprotein changes may be used to distinguish between familial and sporadic forms of AD.
Biochem Mol Biol Int 1993 Oct
PMID:Studies of biochemical changes in cultured skin fibroblasts derived from sporadic and familial Alzheimer's disease individuals: qualitative and quantitative changes in double-stranded DNA-stimulated phosphorylation of endogenous nucleoproteins. 827 15


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