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)

To determine whether the 2-5A system has a role in the regulation of cell growth we have examined all constituents of the 2-5A pathway in mouse embryo fibroblasts undergoing one cycle of division at the tertiary stage under conditions where a high degree of uniformity is maintained within each stage of the cycle. Levels of the 2-5A synthetase increased up to tenfold late in S phase and declined as cells moved through G2. A similar but smaller increase in the 2-5A-dependent ribonuclease was observed, whereas activity of the 2'5' phosphodiesterase was highest in quiescent cells. At the time of maximum synthetase levels no phosphorylated 2-5A could be detected in the intact cell. Endogenous interferon (IFN) was found in the culture supernatants in increasing concentration with cell cycle progression and addition of antibodies to IFN reduced the increase in synthetase seen in late S. Treatment of cells with a growth inhibitor that cells produce also affected synthetase activity.
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PMID:Expression of the 2-5A system during the cell cycle. 402 67

In order to study interrelationships between the components of the interferon enzyme system and the cyclic AMP system, NIH 3T3 cells were incubated in the presence of theophylline or adrenaline that cause a rise of intracellular cAMP, respectively, through inhibition of phosphodiesterase of cAMP and activation of adenylate cyclase. In doses that caused a transient, 2-to 3-fold elevation of the cAMP level, theophylline and adrenaline elicited about 2.5-fold elevation of 2',5'-oligoadenylate synthetase (2-5A synthetase) activity. This increase could be prevented by actinomycin D. This suggests that the elevation of the enzyme activity in the cells was due to a transcription-dependent induction process. Theophylline and adrenaline treatment of the cell cultures also led to a 2-to 3-fold fall of the activity of the phosphodiesterase of 2',5'-oligoadenylate (2'-phosphodiesterase). This effect of adrenaline was prevented by propanolol but not by actinomycin D. In the case of adrenaline, the fall of 2'-phosphodiesterase activity was accompanied by at least 5-fold increase in the enzyme activity which did not occur if actinomycin D was present in the culture. Similarities and differences between these effects and those induced by interferon are discussed. It is concluded that cAMP is an important regulator of the enzyme system of the 2',5'-oligoadenylate metabolism. 2',5'-Oligoadenylate, in turn, was found to act on the activity of phosphodiesterase of cyclic AMP. The cAMP phosphodiesterase activity in the NIH 3T3 cell lysates was activated 2- to 2.5-fold at physiological concentrations (10(-9) to 10(-7) M) of both the phosphorylated form of oligoisoadenylate, ppp(5'A2'p)n5'A2'OH, and the dephosphorylated form, HO(5'A2'p)25'A2'OH. The phosphorylated form of oligoisoadenylate also activated partially purified preparations of cAMP phosphodiesterase. The data obtained in this study allow us to consider cAMP and 2',5'-oligoadenylate as the key metabolites that may be used in the cells to form a complex, interconnected, multifunctional circuit that involves the interferon enzyme system and the system of cyclic AMP metabolism and governs essential cell functions, as regulation of RNA metabolism and protein synthesis, cell growth and differentiation.
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PMID:A study on the relationship between the interferon enzyme system and the system of cyclic nucleotide metabolism. 608 24

Theophylline, an inhibitor of cAMP phosphodiesterase, induces in human ovary carcinoma cells (CaOv) a 2-2.5-fold elevation of intracellular cAMP. This rise in the cAMP level is followed by an increase of the activity of 2',5'-oligo(A) synthetase in CaOv cells -insignificant (1.5-fold) after 16 hr incubation, and substantial (3.7-fold) after 30 hr incubation, as well as the development of antiviral resistance. Once CaOv cells have been incubated with the mixtures containing theophylline (2 mM) and lambda-, beta-, and gamma-interferon preparations (0.5-13 IU/ml), the total antiviral effect of the mixtures exceeds that generated by interferon or theophylline separately; the action of the above agents being additive. These data agree with the previously obtained results and support the suggestion that cAMP phosphodiesterase inhibitors partially mimic the antiviral action of interferon.
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PMID:Antiviral activity of lambda-, beta-, and gamma-interferons in the presence of theophylline: involvement of 2',5'-oligo(A) synthetase. 608 14

Daudi cells, a human lymphoblastoid line, are exceptionally sensitive to the growth inhibitory effects of interferon, 1 unit/ml being sufficient to inhibit cell growth. In addition, interferon treatment of these cells severely inhibits the incorporation of exogenous thymidine into DNA and causes cells to accumulate in the G1(G0) at the expense of the S phase of the cell cycle. The possible involvement of ppp(A2'p)nA(n = 2 to less than or equal to 4) in these effects has been investigated. No (less than 1 nM) ppp(A2'p)nA or (A2'p)nA or alternative products of the ppp(A2'p)nA synthetase [e.g. NAD (2'pA)2] were detected in interferon-treated cells. In addition no evidence was obtained for the occurrence of ppp(A2'p)nA-mediated ribosomal RNA cleavage in these cells even after several days of treatment with relatively high doses of interferon. A line of Daudi cells which is resistant to all three of the above effects of interferon was selected. The wild type and resistant lines were compared with respect to the ppp(A2'p)nA and interferon and double-stranded RNA (dsRNA)-mediated protein kinase systems. The resistant line was not receptor-negative as it responded to interferon by the production of elevated levels of the ppp(A2'p)nA synthetase similar to those observed in extracts from wild-type cells. There was no detectable difference between the lines in the levels of the (2'-5')phosphodiesterase responsible for the degradation of ppp(A2'p)nA. There was, however, about a twofold increase in the ppp(A2'p)nA-dependent endoribonuclease activity in response to interferon with extracts from the wild-type but not the resistant cells. In addition, although the dsRNA-dependent protein kinase activity increased in both types of cell there was a striking reduction in the level of protein phosphorylation in general in response to interferon with material from the wild-type but not the resistant cells.
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PMID:The ppp(A2'p)nA and protein kinase systems in wild-type and interferon-resistant Daudi cells. 618 93

Induction of cyclic AMP (cAMP) depresses natural killer (NK) cell activity. The present results demonstrate that this is dependent on a decreased capacity of the effector cells to conjugate to target cells. This was found either if dibutyryl-cAMP was used or if cAMP was induced by adenylate cyclase stimulation with prostaglandin E1 (PGE1) or by inhibition of phosphodiesterase activity with the inhibitor ZK 62711. The sites of action for cAMP-induced NK suppression and interferon (IFN)-induced NK enhancement are demonstrated to be distinct, since IFN acts by increasing the lytic efficiency and the recycling capacity without influencing target binding. Sequential treatment with cAMP/IFN and IFN/cAMP shows that IFN can neither restore target binding when added after cAMP nor protect against the cAMP-induced target binding inhibition when added before cAMP. The results are discussed in view of earlier data on cAMP in relation to cell membrane functions and cellular recognition, the mechanism underlying the cAMP-induced target binding inhibition, and the potential of the NK system as an indicator for immunosuppression. The present work also demonstrates the particular subpopulation in peripheral blood which mediates most NK activity, to respond strongly to PGE1 stimulation with regard to cAMP induction.
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PMID:Inhibition of human NK cell cytotoxicity by induction of cyclic AMP depends on impaired target cell recognition. 618 4

The antiproliferative effect of human fibroblast interferon (IFN-beta), human recombinant leukocyte interferon (IFN-alpha A), and polyinosinic . polycytidylic acid [poly(I) . poly(C)] was investigated in human colon carcinoma cell line HT-29. Exposure of HT-29 cells for 1 to 3 days with 100 to 2000 units of either interferon preparation resulted in a 30 to 50% inhibition of growth after 3 days. Similar treatment of cells with 100 micrograms per ml poly(I) . poly(C) resulted in progressive inhibition of growth by 50 to 60% in 2 to 3 days. The inhibitory effects of combination of either IFN-beta or IFN-alpha A with poly(I) . poly(C) were additive with up to 80 to 90% inhibition of cell growth after 3 days of exposure. None of the treatment regimens was markedly cytocidal, and only 25 to 30% reduction in colony formation was noted under optimal treatment conditions following 2 to 3 days of drug exposure. Measurements of DNA, RNA, and protein synthesis following interferon treatment indicated a dose-dependent reduction in all three parameters, particularly when interferon was administered with poly(I) . poly(C). The associated changes in the (2',5')oligoadenylate [(2',5')oligo(A)] pathway produced by IFN-beta and IFL-alpha A were measured under growth-inhibitory conditions. A concentration-dependent induction of (2',5')oligo(A) synthetase was produced by IFN-beta or IFL-alpha A with a concomitant decrease in (2',5')oligo(A) phosphodiesterase. Poly(I) . poly(C) alone induced (2',5')oligo(A) synthetase activity but had no effect on the associated activity of phosphodiesterase. The combination of either IFN-beta or IFL-alpha A and poly(I) . poly(C) further reduced (2',5')oligo(A) phosphodiesterase activity. There was no general dose-response correlation between the induction of (2',5')oligo(A) synthetase and the cytostatic activity of interferon treatment alone or in combination with double-stranded RNA.
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PMID:Effects of fibroblast and recombinant leukocyte interferons and double-stranded RNA on ppp(2'-5')An synthesis and cell proliferation in human colon carcinoma cells in vitro. 618 84

Wheezing episodes often accompany viral respiratory infections. Viral pathogens are also known to induce interferon production. Cyclic AMP (cAMP) levels affect bronchial reactivity; therefore, we analyzed cAMP accumulation in human lymphocytes as a model to determine if interferon might influence the accumulation of this important intracellular mediator. After an overnight exposure to interferon in whole blood, a reduction in agonist-stimulated cAMP accumulation was demonstrated. Basal cAMP concentrations were equivalent in control and interferon-exposed lymphocytes from the same donor, but the response to isoproterenol and prostaglandin E1 was significantly reduced by 61 and 30%, respectively. The decreased responsiveness persisted in the presence of RO 20-1724, a phosphodiesterase inhibitor, indicating that the effect was in part due to a decrease in cAMP synthesis in intact cells. These results suggest that interferon may play a role in inducing or potentiating bronchospasm.
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PMID:Interferon inhibits agonist-induced cyclic AMP accumulation in human lymphocytes. 620 16

Mechanisms whereby prostaglandins and other cyclic adenosine 3',5'-monophosphate (cAMP) modulators might enhance the growth of herpes simplex virus (HSV) in human skin fibroblasts were explored. Prostaglandins A1, B1, E1, E2, and F2 alpha, as well as isoproterenol, imidazole, carbamylcholine, and dibutyryl cAMP had no effect on HSV growth. On the other hand, the phosphodiesterase inhibitors 1-methyl-3-isobutylxanthine and theophylline delayed the growth, suppressed the cell-to-cell spread, but inhibited neither the adsorption nor the penetration of the virus. Although none of the cAMP-elevating reagents directly enhanced HSV growth, they were found to inhibit dose dependently the antiviral action of both type I and HSV antigen-induced human interferon preparations. Furthermore, these reagents suppressed the production of HSV antigen-induced interferon by immune human mononuclear leukocytes. These data support the hypothesis that prostaglandin elaboration in vivo could contribute to exacerbations of HSV infections by compromising the host's interferon defense system.
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PMID:Effect of prostaglandins and cyclic adenosine 3',5'-monophosphate modulators on herpes simplex virus growth and interferon response in human cells. 624 26

The levels of two dsRNA-dependent enzyme activities, the pppA(2'p5'A)n synthetase (2-5A synthetase) and protein kinase were investigated in control and interferon-treated murine cells: L-929, K/Balb and NIH/3T3. Treatment of these cells with interferon resulted both in the establishment of the antiviral response and the development of anticellular effects. This latter was observed 3 days after treatment with interferon. The levels of 2-5A synthetase and protein kinase in control and interferon-treated cells seemed to vary from one cell type to the other. In L-929 cells, both the 2-5A synthetase and protein kinase were induced by interferon as has been shown previously. On the other hand, treatment of NIH/3T3 cells with interferon resulted in the induction of 2-5A synthetase in the absence of any enhanced protein kinase activity. This lack of protein kinase in interferon-treated NIH/3T3 cells was not due to the presence of high levels of protein phosphatases. A third type of mouse cells, K/Balb cells, contained very high levels of 2-5A synthetase in the absence of any apparent resistance to virus infection. On treatment with interferon the level of 2-5A synthetase in K/Balb cells remained constant while the protein kinase activity was enhanced by several fold. Both control and interferon-treated K/Balb cells showed similar sensitivity to the action of exogenous 2-5A thus suggesting that the 2-5A system (the 2-5A dependent nuclease and the phosphodiesterase which degrades 2-5A) was not altered on treatment with interferon. The significance of these results in relation to the mechanism of action of interferon is discussed.
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PMID:Lack of systematic correlation between the interferon mediated antiviral state and the levels of 2-5A synthetase and protein kinase in three different types of murine cells. 628 3

A rapid and convenient assay for adenylyl(2' leads to 5')adenosine(A2'p5'A) or adenylyl(3' leads to 5')adenosine(A3'p5'A) phosphodiesterase activities is described. The dinucleotides A3'p5'A and A2'p5'A were labeled to a high specific activity by means of a catalytic-exchange procedure. Degradation studies of each of these labeled dinucleotides showed an asymmetrical distribution of label between the two adenine bases. Enzymatic degradation of [3H]A3'p5'A or [3H]A2'p5'A could be quantitated by first digesting the reaction products with bacterial alkaline phosphatase and then adding a slurry of DEAE-Sephadex. Under conditions described, adenosine did not adsorb to the resin, whereas dinucleotides as well as AMP did adsorb. As a consequence, when liquid scintillation fluid was added to the DEAE-Sephadex reaction mixture slurry, the radioactivity of the dinucleotides and AMP was severely quenched. This permitted a direct estimation of the amount of adenosine liberated during the phosphodiesterase degradation and subsequent alkaline phosphatase digestion. This method was applied to the measurement of A2'p5'A degrading activities in extracts of mouse L cells. Extracts from control mouse L cells were as active in degrading A2'p5'A as extracts from interferon pretreated cells.
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PMID:Assay of 2',5'-oligoadenylate phosphodiesterase activity in mouse L-cell extracts. 630 30


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