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)

The biochemical properties of cyclic nucleotide phosphodiesterases in a nonmetastasizing and a spontaneously metastasizing rat mammary carcinoma were compared. The phosphooiesterases in both tumors had a pH optimum of around 8.0 and preferentially hydrolysed cyclic purine nucleotides. The rate of hydrolysis of purine nucleotides in the nonmetastasizing tumor was two times higher than in the metastasizing tumor, but the rate of pyrimidine nucleotide hydrolysis was equal in both tumors. Theophylline, caffeine, and D,L-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro20-1724) inhibited the enzyme activity in both tumors; the percent inhibition was the same by each inhibitor. The cyclic nucleotie phosphodiesterase activity in either tumor was stimulated by Mg++, Mn++, and Co++ and suppressed by Ca++, Zn,++, and Ni++. EDTA inhibited the activity below the basal level (activity in the absence of added cation), an this inhibition could be recovered up to the basal level by an equimolar quantity of either Mn++ or Mg++. Further stimulation of the enzyme activity with increasing concentrations of divalent cations was observed only with Mn++. Similar effects were observe with ethylene glycol bis(beta-aminoethyl ether)-tn,n-tetraacetic acid. The stimulatory cations affected both the low and high Michaelis constant (tkm) enzymes in these tumors by increasing the maximum velocity. In the low Km enzyme, the Km was also slightly increased. Neither guanosine 3',5'-cyclic monophosphate nor adenosine 3',5'-cyclic monophosphate had any effect on the hydrolysis of the other at physiologic levels.
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PMID:Biochemical properties of cyclic nucleotide phosphodiesterase in metastasizing and nonmetastasizing rat mammary carcinomas. 0 60

Adenylate cyclase activity as well as intracellular content of sAMP were decreased 2.5-4-fold, as compared with normal state, in plasmatic membranes (PM) of hepatoma 22 and of Ehrlich ascites carcinoma--the tumors characterized by high level- of malignancy. Activity of cAMP phosphodiesterase exceeded distinctly the normal value in all the tumors studied. In less malignant hepatoma 48 the adenylate cyclase activity and content of cAMP were similar to those found in normal liver cells. The guanylate cyclase activity did not differ markedly from values found in normal liver cells in PM of all the tumors studied and in liver tissue of the tumor-bearing animals. Distinct alterations were not found in content of cGMP in the tumors, except of hepatomas 60 and 22, in which the nucleotide level exceeded 2-fold the normal value. The ratio cAMP/cGMP was decreased in the most malignant tumors. At the same time, the ratio was distinctly elevated in tumors with the middle level of malignancy (hepatomas 60 and 61).
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PMID:[Concentration of cyclic nucleotides, activity of adenylate cyclase, 3',5'-AMP phosphodiesterase and guanylate cyclase in plasma membranes from liver and hepatomas of different degrees of malignancy]. 3 Feb 12

Data from cultured cells have suggested that cyclic AMP and cyclic GMP may be important determinants of cell growth and transformation. However, few studies have examined cyclic nucleotide content and metabolism in naturally occurring tumors of man. Accordingly, in the present study we compared cAMP and cGMP levels and metabolism in carcinomas of the human colon to those of the adjacent uninvolved mucosa after therapeutic resection of these tissues. The cAMP content of the tumors, determined in samples frozen 30 min after excision, was significantly lower than that of the adjacent mucosa, when expressed on the basis of tissue wet weight, protein, or DNA content. By contrast, the cGMP content of the tumors was higher than that of the surrounding mucosa if calculated on the basis of tissue wet weight, but this difference did not persist when correction was made for the higher protein or DNA content of the tumors. Incubation of slices of mucosa or tumor with or without theophylline in vitro increased tissue cAMP and cGMP content above levels observed in frozen samples of the same tissue. However, after such incubations cAMP levels in the tumors remained clearly below that of the mucosa, while cGMP content of the two tissues did not differ. The failure of theophylline to abolish differences in cAMP content and the comparable activities of high and low Km cAMP-phosphodiesterase in homogenates of the two tissues suggested that the lower cAMP content of the tumors was a consequence of diminished cAMP synthesis rather than enhanced degradation. This possibility was supported by the reduction in basal and maximal prostaglandin E1 (PGE1)-responsive adenylate cyclase activity found in tumor homogenates relative to those of mucosa, and the lower levels of cAMP in tumor slices after incubation of the tissues with a maximal dose of PGE1 and theophylline. Since NaF-responsive adenylate cyclase activity was not significantly reduced in the tumors, the lower basal and PGE1 activities may not be related to a deficiency of the catalytic unit of the cyclase complex in this tissue. The role of reduced activity of the adenylate cyclase-cAMP system and/or reduced tissue cAMP-to-cGMP ratios in the pathogenesis of colonic carcinoma is uncertain, but these changes might favor unregulated cellular proliferation.
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PMID:The content and metabolism of cyclic adenosine 3', 5'-monophosphate and cyclic guanosine 3', 5'-monophosphate in adenocarcinoma of the human colon. 17 89

Cyclic AMP and cyclic GMP phosphodiesterase activities (3',5'-cyclic AMP 5'-nucleotidohydrolase, EC 3.1.4.17) were investigated in the human thyroid gland from patients with hyperthyroidism. Low substrate concentration (0.4 muM) was used. About 60% of the cyclic-AMP and 80% of the cyclic-GMP hydrolytic activities in the homogenate were obtained in the soluble fraction (105 000 X g supernatant). The thyroid gland contains two forms of cyclic-AMP phosphodiesterase, one with a Km of 1.3-10(-5) M and the second with a Km of 2-10(-6) M. Cyclic-AMP and cyclic-GMP phosphodiesterase were purified by gel filtration on a Sepharose-6B column. Cyclic-AMP phosphodiesterase activities were found in a broad area corresponding to molecular weights ranging from approx. 200 000 to 250 000 and cyclic-GMP phosphodiesterase activity was found in a single area corresponding to a molecular weight of 260 000. Cyclis-AMP phosphodiesterase activities were stimulated by the protein activator which was found in human thyroid and this stimulation was dependent on Ca2+. Stimulation of cyclic-AMP phosphodiesterase by the activator was not significant even in the presence of enough Ca2+. The effect of D,L-triiodothyronine, D,L-thyroxine, L-diiodotyrosine, L-monoiodotyrosine, L-thyronine, L-diiodothyronine, thyrotropin, hydrocortisone, adrenocorticotropin, cyclic-AMP and cyclic-GMP on the phosphodiesterase activities was studied. Cyclic-AMP, cyclic-GMP, D,L-triiosothyronine, D,L-thyroxine, adrenocorticotropin and hydrocortisone where found to inhibit the phophodiesterase. Triiodothyronine and thyroxine inhibited cyclic-AMP phosphodiesterase more effectively than cyclic-GMP phosphodiesterase. Thyroxine was a more potent inhibitor than triiodothyronine. The concentration of cyclic AMP producing a 50% inhibition of cyclic-GMP phosphodiesterase activity was 5-10(-5) M, while the concentration of cyclic GMP producing a 50% inhibition of cyclic-AMP phosphodiesterase was 3-10(-3) M. Both cyclic-AMP and cyclic-GMP phosphodiesterase activities in the homogenate of hyperthyroidism, thyroid carcinoma and adenoma were higher than in normal thyroid tissue, when assayed with a low concentration of the substrate (0.4 muM). When a higher concentration (1 mM) of cyclic nucleotides was used as the substrate, cyclic-AMP hydrolytic activity in adenoma tissue was similar to that of normal tissue, while the other activities were higher than normal.
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PMID:Human thyroid cyclic nucleotide phosphodiesterase. Its characterization and the effect of several hormones on the activity. 18 33

3':5'-Cyclic-AMP phosphodiesterase (EC 3.1.4.17) and the activating factor of cyclic nucleotide phosphodiesterase were detected in cultured human cell lines from patients with lymphoblastic leukemia and retinoblastoma and in the Brown-Pearce (rabbit) carcinoma. The homogenate of lymphoblasts contained levels of the activating factor in excess of that required to produce maximal activation of the endogenous phosphodiesterase. The activating factor found in these malignant cells appears to be similar to the calcium-binding protein activator of bovine brain phosphodiesterase on the basis of the molecular weight obtained from gel filtration, electrophoretic patterns, calcium requirement for the activity, and the effect of calcium on the proteolysis. In addition, the tumor-derived activator was able to restore the activity of activator-deficient phosphodiesterase from the bovine brain.
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PMID:Cyclic nucleotide phosphodiesterase and protein activator in human cancer cell lines and Brown-Pearce carcinoma. 20 Jul 56

The adenylate cyclase-cyclic AMP-phosphodiesterase system of human thyroid tissues adjacent to cold nodules (control), two follicular adenomas, one hyperplastic thyroid and one hyperfunctioning follicular carcinoma have been compared. In the hyperfunctional follicular carcinoma the basal adenylate cyclase is much higher than in control tissue, carcinoma adenylate cyclase does not respond to TSH and prostaglandin E1, whereas it responds normally to fluoride. In the hyperplastic, but hypofunctional thyroid the basal adenylate cyclase is higher than in normal tissue whereas the response to TSH, PGE1, and fluoride is normal. No difference between the follicular adenomas and normal thyroid stimulated and unstimulated adenylate cyclase was observed. Furthermore in various thyroid tissues no changes in the level of cyclic AMP phosphodiesterase was found. Our data indicate a greater change in the synthesis rather than in degradation of cyclic AMP in the human pathological thyroids studied.
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PMID:The adenylate cyclase-cyclic AMP-phosphodiesterase system in pathological human thyroid. 22 51

Transplantable Brown-Pearce carcinoma was adapted successfully in the rabbit anterior chamber. Regression of tumor growth was attained on tri-weekly perfusion of the AC with 10 micromolar of methotrexate. Tumor cyclic nucleotide phosphodiesterase (PDE) and protein activator were found to be markedly depressed during the course of chemotherapy and the PDE cAMP/cGMP ratio was similarly altered. Corroborative light and electron-microscopic studies showed specific alterations of intracellular organelles in relation to MTX and tumor cell death. These findings suggest that metabolic pathways of cyclic nucleotides are important biochemical modulators of neoplastic cells. The method of intraocular perfusion precludes systemic toxic effects and avoids compromising the animals' immunocompetence.
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PMID:Experimental intraocular malignancy: the effect of intracameral perfusion. 23 85

Walker carcinoma cell lines sensitive or resistant to bifunctional alkylating agents have been found to contain multiple forms of cyclic AMP phosphodiesterase (3':5'-cyclic AMP 5'-nucleotidohydrolase, EC 3.1.4.17). These activities have been resolved using Sepharose 6B gel filtration and their apparent molecular weights have been estimated. The enzyme appears to occur in four active forms of apparent mol. wts of greater than 1 000 000, 430 000, 350 000 and 225 000, when assayed at low substrate concentrations. Evidence has been obtained which suggests that all four forms of the enzyme are composed of subunits of mol. wt of approximately 15 000 and are interconvertible. While the ionic strength of the buffer affected the predominance of the different forms, the presence of cyclic AMP at 10(-6) M had no effect on aggregation or dissociation of the enzyme. An activity shift from high molecular weight forms of the enzyme to low molecular weight forms has been found in the resistant tumour at low substrate concentration. No change in elution profile between sensitive and resistant tumours was observed for the low affinity form of the enzyme. The pH optima of the enzymes with both high and low affinity for the substrate was found to be pH 8.0 in the sensitive line. In the resistant tumour the pH optima of the high affinity form is shifted to pH 8.4 while the low affinity form remains at pH 8.0. The high affinity forms of the phosphodiesterase in the sensitive and resistant tumour also differed in their inhibition by theophylline. In both cases inhibition was of the competitive type with Ki values for the sensitive and resistant lines being 2.35 and 0.32 mM, respectively. There was no significant difference in the inhibition of the low affinity form between the sensitive and resistant tumour.
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PMID:Characterisation of cyclic adenosine 3':5'-monophosphate phospodiesterase from Walker carcinoma sensitive and resistant to bifunctional alkylating agents. 23 30

Human papillary thyroid carcinoma (PTC) has a relatively benign prognosis despite a high frequency of lymphatic metastasis. This suggests that local anticancer factors, generated in lymph nodes, control PTC progression. The cytokine, tumor necrosis factor-alpha (TNF-alpha), may be one such factor. We have previously shown that a human PTC cell line (NP-PTC) has high affinity TNF-alpha receptors. We now report on the action of TNF-alpha in these cells. TNF-alpha decreased [3H]thymidine incorporation as well as cellular DNA content and cell number in a dose-dependent manner. The abundance of phosphodiesterase and manganous superoxide dismutase mRNA species was increased in a time- and dose-dependent manner in the NP-PTC cells after TNF-alpha treatment. TNF-alpha activated NF-kappa B, a nuclear factor thought to mediate multiple actions of TNF-alpha, in these cells with a maximum effect observed after 30 min of treatment. Thus, TNF-alpha has an antiproliferative action on NP-PTC cells, despite its ability to induce the accumulation of mRNA that encodes an enzyme (manganous superoxide dismutase), thought to be cytoprotective. The net antiproliferative effect must therefore be explained by a balance of protective and tumoricidal or static effects that ultimately result in control of tumor spread. These antiproliferative effects may be in part mediated by NF-kappa B and PDE.
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PMID:Tumor necrosis factor-alpha activates nuclear factor kappa B and induces manganous superoxide dismutase and phosphodiesterase mRNA in human papillary thyroid carcinoma cells. 132 6

We examined the effect of protein kinase C (PKC) activation on the cyclic GMP response to heat-stable enterotoxin (STa) in a colonic carcinoma intestinal epithelial cell line, T84 cells. Our results demonstrate that the active phorbol ester analog, phorbol dibutyrate, but not the inactive alpha-phorbol dibutyrate, acts synergistically with STa to elevate cyclic GMP in intact T84 cells. The effect is observed in the absence or presence of the phosphodiesterase inhibitor, isobutylmethylxanthine, which suggests that phorbol dibutyrate modifies cyclic GMP synthesis rather than cyclic GMP degradation. In contrast to several systems in which prolonged treatment with phorbol ester desensitizes PKC-mediated responses, the cyclic GMP response in T84 cells is not diminished by prolonged treatment of T84 cells with phorbol dibutyrate. Also, transient treatment of T84 cells with phorbol dibutyrate enhances subsequent STa-stimulated cyclic GMP accumulation. These observations suggest that PKC activation produces a long-lived signal in T84 cells which enhances cyclic GMP accumulation in response to STa. Second messenger "cross talk" [T. Yoshimasa, D. R. Sibley, M. Bouvier, R. J. Lefkowitz, and M. G. Caron, Nature (London) 327:67-70, 1987] may be important in the pathogenesis of diarrheal disease.
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PMID:Phorbol esters enhance the cyclic GMP response of T84 cells to the heat-stable enterotoxin of Escherichia coli (STa). 196 50


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