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: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biochemical and cellular properties of three immortalized Schwann cell lines expressing different levels of the myelin-associated glycoprotein (MAG) were compared. The S16 line generated by repetitive passaging was described previously and expresses a level of MAG comparable to that in adult sciatic nerve. The S42 line was generated independently by the same procedure, divides more slowly than the S16 line, and expresses an even higher level of MAG. The S16Y line arose spontaneously from a passage of the S16 cells, divides much more rapidly, and does not express MAG. The levels of MAG expression in the three lines are inversely related to their rates of proliferation, and MAG mRNA levels parallel the amounts of MAG. The S16 and S42 lines consist mainly of flat cells at low density and develop many processes at high density, whereas most of the S16Y cells are spindle-shaped, resembling primary Schwann cells in appearance. Surface immunostaining with the O4 antibody was positive for the S16 and S42 cells and negative for the S16Y cells, but all three lines were negative for surface staining with the O1 antibody. The overall protein compositions of the three lines are very similar, but the S16 and S42 cells express larger amounts of several glycoproteins than the S16Y cells, including the adhesion proteins, neural cell adhesion molecule, L1, and laminin. S16 and S42 cells (but not S16Y cells) also express P0 glycoprotein, galactocerebroside, and sulfatide, but, unlike MAG, these other myelin-related components were present at much lower levels than in adult nerve. Myelin basic protein and proteolipid protein were not detected in any of the lines, although all three lines contained proteolipid protein mRNA. 2',3'-Cyclic nucleotide 3'-phosphodiesterase and glial fibrillary acidic protein were present in all three lines. Conditions have not yet been found in which any of the lines will myelinate dorsal root ganglion neurons in vitro, but the S16 and S42 cells differ from the S16Y cells by clustering around neurons after 1 week in coculture. In many respects, the S16 and S42 cells biochemically resemble Schwann cells at an early stage in their preparation to myelinate and should be useful for investigating the cell biology of MAG and other myelin-related components.
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PMID:Biochemical and cellular properties of three immortalized Schwann cell lines expressing different levels of the myelin-associated glycoprotein. 752 97

The secreted cyclic nucleotide phosphodiesterase (PDE) and its glycoprotein inhibitor (PDI) are among the first genes expressed when Dictyostelium amoebae begin their development. We used a series of mutants with defects in signal transduction to ask whether cAMP receptors 1 and 3, G alpha2, G beta, adenylyl cyclase (ACA), or the protein kinase A catalytic subunit (PKAcat) are required for the initial appearance or later regulation of the PDE and the PDI transcripts. The PDE gene produces a 1.9-kb transcript during vegetative growth and then a 2.4-kb transcript during the early hours of development. Regulation of the 2.4-kb transcript in CAR1, G alpha2, G beta, and ACA mutants is similar to that of isogenic parental strains, although its level is reduced in strains that carry the CAR1 mutation. CAR1/CAR3 double mutants also produce less PDE transcript, but the PDE gene remains inducible by cAMP. The PKAcat mutant produces the 2.4-kb PDE transcript, but in this mutant the vegetative transcript is retained in development. CAR1 and CAR3 are not required for transcription of the PDI gene, but deleting CAR1 leads to overproduction of the PDI transcript. Induction or repression of the PDI gene does not require G alpha2, G beta, or ACA. PKAcat is required for synthesis of the PDI transcript. The results suggest a two-stage regulation of these early genes through a G alpha2/G beta-independent mechanism and an absolute dependence of PDI on the PKAcat.
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PMID:Regulation of Dictyostelium early development genes in signal transduction mutants. 755 91

Dictyostelium discoideum secretes a cyclic nucleotide phosphodiesterase to control cAMP levels during development. Three promoters control expression of the gene--one during vegetative growth, one during aggregation, and one which constrains phosphodiesterase synthesis to prestalk cells. In this report we show that the expression of phosphodiesterase (PDE) in prestalk cells is necessary for morphogenesis. A gene that codes for a specific glycoprotein inhibitor of the phosphodiesterase (Kd = 0.1 nM) was fused to the prestalk-specific promoter of the PDE gene. Transformants carrying multiple copies of this construct secreted inhibitor in 100-fold excess after the aggregation process had occurred. The first effect seen was an elongated tip, followed by a block in slug formation and an inability to culminate. Stalk and spores cells are produced but morphogenesis is uncoupled from cellular differentiation. Overproduction of inhibitor during earlier stages delayed aggregation, but did not affect fruiting body formation. A phosphodiesterase mutant was transformed with a plasmid that expresses PDE only during aggregation and not in prestalk cells. The defect in aggregation was rescued, but the defect in later development was not. The combined results indicate that PDE expression in prestalk cells is critical to morphogenesis. To ask whether the inhibitor gene under its normal regulation had a role in aggregation or later morphogenesis, it was destroyed by homologous recombination. The loss of the gene did not prevent development under the conditions used.
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PMID:The phosphodiesterase secreted by prestalk cells is necessary for Dictyostelium morphogenesis. 785 34

A human cDNA clone encoding autotaxin, a tumor cell motility-stimulating protein, reveals that this protein is an ecto/exo-enzyme with significant homology to the plasma cell membrane differentiation antigen PC-1. ATX is a 125-kDa glycoprotein, previously isolated from a human melanoma cell line (A2058), which elicits chemotactic and chemokinetic responses at picomolar to nanomolar concentrations. Affinity-purified antipeptide antibodies to the ATX peptide, ATX-102, were employed to screen an A2058 cDNA expression library made in lambda gt11. The partial cDNA sequence which was obtained was then extended by utilizing reverse transcriptase on total cellular RNA followed by polymerase chain reaction amplification. The isolated cDNA clone contained 3251 base pairs, and the mRNA message size was approximately 3.3 kilobases. The deduced amino acid sequence of autotaxin matched 30 previously sequenced peptides and comprised a protein of 915 amino acids. Data base analysis of the ATX sequence revealed a 45% amino acid identity (including 30 out of 33 cysteines) with PC-1, a pyrophosphatase/type I phosphodiesterase expressed on the surface of activated B cells and plasma cells. ATX, like PC-1, was found to hydrolyze the type I phosphodiesterase substrate p-nitrophenyl thymidine-5'-monophosphate. Autotaxin now defines a novel motility-regulating function for this class of ecto/exo-enzymes.
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PMID:cDNA cloning of the human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases. 798 64

The standard patch-clamp technique was employed on enzymatically digested acinar cells of submucosal glands isolated from feline trachea. ATP (-10(-3) M) evoked bidirectional current responses and an initial inward current at -80 mV (Cl- current) was followed by an outward current at 0 mV of membrane potential (K+ current). Isoproterenol (ISO) alone did not evoke any significant current responses. However, ISO augmented the ATP-induced inward and outward currents. A phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, mimicked the augmentation by ISO. [Ca2+]i of acinar cells in isolated gland was measured using a fluorescent dye, fura 2. ATP (-10(-3) M) induced an immediate increase in [Ca2+]i followed by a prolonged plateau, and Ca2+ removal resulted in an initial increase alone without the prolonged phase. ISO also augmented the ATP-evoked increases in [Ca2+]i mainly in the plateau phases. Mucus glycoprotein (MGP) secretion was estimated by measuring trichloroacetic acid-precipitable [3H]glycoconjugates from isolated glands. ATP (-10(-3) M) evoked significant MGP secretion and ISO enhanced the ATP-induced MGP secretion. In contrast, adenosine (-10(-3) M) produced no significant responses in current, MGP secretion, or [Ca2+]i. These findings suggest that 1) P2-receptor stimulation and the resultant [Ca2+]i rise induced both electrolyte and MGP secretions and 2) ATP-induced secretion is enhanced by an adenosine 3',5'-cyclic monophosphate intracellular concentration [cAMP]i-rise after beta-receptor stimulation in airway submucosal glands.
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PMID:Extracellular ATP regulation of feline tracheal submucosal gland secretion. 807 38

Preservation of platelet integrity and responsiveness was examined in platelet concentrates prepared in the presence of various formulations and combinations of platelet-activation inhibitors affecting intracellular levels of cyclic 3'-5' adenosine monophosphate (cAMP). Platelet concentrates were prepared and stored in an artificial medium for two weeks at 22 degrees C. Markers of metabolic activity (pH, lactate, pO2, pCO2 in the medium), aggregation response, hypotonic shock response, and glycoprotein Ib (GPIb) expression were assessed along with direct measurements of cAMP in platelet pellets and thromboxane B2 (TxB2) in the supernate. The platelet concentrates prepared with only adenylate-cyclase stimulators (prostaglandin E-1 or forskolin) showed less maintenance of the integrity and responsiveness markers and greater loss of GPIb than concentrates prepared with phosphodiesterase inhibitors (theophylline or caffeine) or combinations with the above. These results were correlated with the ability of these compounds to sustain elevation of cAMP above basal level during the entire extended-storage period. The strong correlation (rs = -0.67) between elevation of cAMP levels and suppression of TxB2 production suggests that the phosphodiesterase inhibitors provided better protection than stimulators of adenylate cyclase alone through a reduction in platelet activation and its deleterious effects on preservation of platelets during storage.
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PMID:Sustained elevation of intracellular cyclic 3'-5' adenosine monophosphate is necessary for preservation of platelet integrity during long-term storage at 22 degrees C. 811 27

Exposure of endothelial cells (ECs) to thrombin or cytokines leads to major changes in their biochemical properties, which confer procoagulant activities. Stimulated ECs express the procoagulant glycoprotein tissue factor (TF). Although some TF is expressed on the apical surface of the cells, most is deposited as a cryptic pool in the subendothelial matrix. This matrix-associated TF may play a role in thromboembolic complications associated with alterations in the integrity of the EC monolayer. We have measured TF activity on the surface and in the subcellular matrix of human saphenous vein ECs in culture, by assaying the TF-dependent formation of activated factor X in the presence of factor VII. The subcellular matrix was prepared by exposure of ECs to ammonium hydroxide. Incubation of ECs for 4 h with 1 U/ml human thrombin induced TF expression on the apical cell surface and in the matrix. Activity in the matrix was 4.1 +/- 0.5 times greater than on the cell surface. Pentoxifylline inhibited the expression of TF both on the cell surface and in the matrix. The EC50 was on the order of 3.9 mM in both cases. No signs of cell toxicity were observed at this concentration of pentoxifylline. Similar effects were obtained with trequinsin (HL 725), a phosphodiesterase inhibitor, with an EC50 of 40 microM. This suggests that an increase in cAMP may be involved in the mechanism of action of pentoxifylline. Inhibition of TF deposition in the matrix may be important in the prevention of thromboembolic episodes in conditions where ECs either retract or are removed by major injury.
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PMID:Inhibitors of phosphodiesterase (pentoxifylline, trequinsin) inhibit apical and subcellular matrix expression of tissue factor in cultured human endothelial cells. 869 70

Autotaxin (ATX) is an extracellular enzyme and an autocrine motility factor that stimulates pertussis toxin-sensitive chemotaxis in human melanoma cells at picomolar to nanomolar concentrations. This 125-kDa glycoprotein contains a peptide sequence identified as the catalytic site in type I alkaline phosphodiesterases (PDEs), and it possesses 5'-nucleotide PDE (EC 3.1.4.1) activity (Stracke, M. L., Krutzsch, H. C., Unsworth, E. J., Arestad, A., Cioce, V., Schiffmann, E., and Liotta, L. (1992) J. Biol. Chem. 267, 2524-2529; Murata, J., Lee, H. Y., Clair, T., Krutsch, H. C., Arestad, A. A., Sobel, M. E., Liotta, L. A., and Stracke, M. L. (1994) J. Biol. Chem. 269, 30479-30484). ATX binds ATP and is phosphorylated only on threonine. Thr210 at the PDE active site of ATX is required for phosphorylation, 5'-nucleotide PDE, and motility-stimulating activities (Lee, H. Y., Clair, T., Mulvaney, P. T., Woodhouse, E. C., Aznavoorian, S., Liotta, L. A., and Stracke, M. L. (1996) J. Biol. Chem. 271, 24408-24412). In this article we report that the phosphorylation of ATX is a transient event, being stable at 0 degrees C but unstable at 37 degrees C, and that ATX has adenosine-5'-triphosphatase (ATPase; EC 3.6.1.3) and ATP pyrophosphatase (EC 3.6.1.8) activities. Thus ATX catalyzes the hydrolysis of the phosphodiester bond on either side of the beta-phosphate of ATP. ATX also catalyzes the hydrolysis of GTP to GDP and GMP, of either AMP or PPi to Pi, and the hydrolysis of NAD to AMP, and each of these substrates can serve as a phosphate donor in the phosphorylation of ATX. ATX possesses no detectable protein kinase activity toward histone, myelin basic protein, or casein. These results lead to the proposal that ATX is capable of at least two alternative reaction mechanisms, threonine (T-type) ATPase and 5'-nucleotide PDE/ATP pyrophosphatase, with a common site (Thr210) for the formation of covalently bound reaction intermediates threonine phosphate and threonine adenylate, respectively.
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PMID:Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities. 899 94

Phosphodiesterase inhibitors have been shown to modulate cell differentiation. We have previously shown that a series of imidazo[1,2-a]pyrazine derivatives displayed inhibitory effects on phosphodiesterase isoenzymes types III. IV and V isolated from Dami cells and on Dami cell growth. In the present study we have investigated the effect of these derivatives on the expression of two differentiation markers, glycoproteins Ib and IIb/IIIa of the human megakaryoblastic leukaemic Dami cell line in comparison to those elicited by 3-isobutyl-1-methylxanthine and selective phosphodiesterase inhibitors of types 1 (8-methoxymetyl-1-methyl-3-(2-methylpropyl) xanthine), III (Milrinone), IV (RO-201724) and V (Zaprinast). Imidazo[1,2-a]pyrazine derivatives, 3-isobutyl-1-methylxanthine and selective phosphodiesterase inhibitors, except 8-methoxymethyl-1-methyl-3-(2-methylpropyl) xanthine, decreased glycoprotein Ib expression. SCA40, SCA41, SCA44 and 3-isobutyl-1-methylxanthine-but not the other compounds affected the expression of glycoprotein IIb/IIIa in a positive manner. The effects of imidazo[1,2-a]pyrazine derivatives on glycoprotein expression appeared to be related to their phosphodiesterase inhibitory potency.
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PMID:Modulation of the megakaryoblastic Dami cell line differentiation by phosphodiesterase inhibitors and imidazo[1,2-a]pyrazine derivatives. 922 65

Autotaxin (ATX) is a 125 kDa glycoprotein motility factor and exoenzyme which can catalyze the hydrolysis of either the alpha-beta or at the beta-gamma phosphodiester bond in ATP. Its motility stimulating activity requires an intact 5'-nucleotide phosphodiesterase (PDE) active site. Photolysis-dependent labeling of ATX with alpha-[32P]-8-N3-ATP, lysC digestion, and peptide HPLC resolved two radioactive fractions containing single peptides whose amino-terminal sequences were determined. Peptide A (T210FPNLYTLATG. . .) was derived from the PDE active site and peptide B (Y318GPFGPEMTNP. . .) was not previously known to be involved in any of the activities of ATX. The differential effect of NaCl concentration on the labeling of these two peptides, as well as on the two reaction types catalyzed by ATX, allows a classification of activities which predicts both the position of preferential peptide labeling by bound ATP and also the position of phosphodiester bond hydrolysis.
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PMID:Nucleotide binding to autotaxin: crosslinking of bound substrate followed by lysC digestion identifies two labeled peptides. 924 Apr 59


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