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Results for “Cyclic CMP”

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PubMed2007

Immediate early gene IEX-1 induces astrocytic differentiation of U87-MG human glioma cells.

The immediate early response gene IEX-1 is involved in the regulation of apoptosis and cell growth. In order to increase the apoptotic sensitivity to chemotherapeutic drugs and gamma-ray, we attempted to establish U87-MG human glioma cell line expressing IEX-1. Unexpectedly, however, transfection of IEX-1 into U87-MG glioma cells resulted in morphological changes to astrocytic phenotype and increase in glial differentiation marker proteins, S-100 and glial fibrillary acidic protein (GFAP). Glial cell differentiation was used to examine in rat C6 glioma cell line, since this cell line express astrocytic phenotypes by increase in intracellular cAMP concentration. Stimulation of human U87-MG glioma cells by membrane-permeable dibutyryl cAMP (dbcAMP) not only elicited their morphological changes but also induced expression of IEX-1 as well as S-100 and GFAP. H89, an inhibitor of protein kinase A (PKA), blocked dbcAMP-induced morphological changes of U87-MG cells and expression of IEX-1. In contrast, morphological changes and expression of S-100 and GFAP induced by IEX-1 were not affected by H89. Morphological changes induced by dbcAMP were totally abolished by functional disruption of IEX-1 expression by anti-sense RNA. These results indicate that IEX-1 plays an important role in astrocytic differentiation of human glioma cells and that IEX-1 functions at downstream of PKA.

Animals↗
PubMed1992

Quantitation by fast-atom bombardment mass spectrometry: assay of cytidine 3',5'-cyclic monophosphate-responsive protein kinase.

A protein kinase, stimulated by cytidine 3',5'-cyclic monophosphate, is conventionally assayed by monitoring the incorporation of radiolabelled phosphate from adenosine triphosphate into a histone substrate. Here the assay of the protein kinase is carried out by positive-ion fast-atom bombardment mass spectrometric analysis of the enzyme incubation mixture after the reaction has been terminated. The data so obtained show good agreement with data obtained by the conventional radiometric assay: the intrinsic advantage of the mass spectrometric assay is the capacity for multiple component monitoring; the ability of the kinase to bind competing cyclic nucleotides together with integral adenosine triphosphatase (ATPase) and phosphodiesterase activity can also be assessed.

Adenosine Triphosphate↗
PubMed2001

An isothermal titration calorimetric method to determine the kinetic parameters of enzyme catalytic reaction by employing the product inhibition as probe.

An isothermal titration calorimetric (ITC) method was developed to measure the kinetic parameters of ribonuclease A catalytic hydrolysis of cytidine 2',3'-cyclic monophosphate. Employing the inhibition of product as a probe, the K(m), K(i), k(c), and DeltaH(m) can be determined by two simple calorimetric measurements. First, the substrate was titrated into the cell containing high concentration of enzyme. The molar reaction heat was calculated from the titration peak area divided by substrate moles per titration, and the initial catalytic reaction rate in the presence of various concentrations of product can be calculated from the peak height and the molar reaction heat. From Michaelis-Menten function in the presence of inhibitors, the relationship between K(m) and K(i) can be obtained. Then, the dissociation constant, which is equal to K(i), was measured by a regular ITC experiment. Thus, K(m) and k(c) can be calculated. The method developed here can be applied in other enzyme catalytic systems with inhibitive products.

Binding Sites↗
PubMed1983

The effects of probenecid on cyclic adenosine 3',5'-monophosphate levels in cerebrospinal fluid and on brain phosphodiesterase activity in the rat.

In rats, probenecid exhibits a dose-dependent increase in the concentration of cyclic adenosine 3',5'-monophosphate (cAMP) in cisternal cerebrospinal fluid (CSF). Maximal accumulation is reached 2 h after IP administration at a dosage of 150 mg/kg body weight. Serum levels of cAMP are unchanged after 200 mg/kg probenecid. In vitro investigations show an inhibitory effect of probenecid on the uptake of cAMP into the isolated choroid plexus of the rabbit. A non-competitive inhibition of probenecid on a high affinity fraction of cyclic nucleotide phosphodiesterase from rat brain homogenates is demonstrated with an inhibitor constant of 3.4 X 10(-3M. The results appear to validate the "probenecid test" for cAMP in clinical diagnostics.

Animals↗
PubMed2006

Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells.

Bioscavenger prophylactic therapy using purified human acetylcholinesterase (AChE) or butylcholinesterase (BChE) is a promising treatment for future protection against chemical warfare nerve agent exposure. Potential immune response due to the complex structure of cholinesterases, mutations, post-translational modifications, and genetic variation is a limiting factor against purified enzyme therapy. We investigated an alternative bioscavenger approach using forskolin, an inducer of intracellular cyclic AMP (cAMP), which activates AChE promoter and up-regulates its expression. A mouse neuronal cell line, Neuro 2A, was treated with various doses of forskolin and analysis of the expressed enzyme indicates that the AChE activity was significantly increased in cells exposed to repeated administration of the drug every other day for 7-10 days. Cholinesterase enzyme assays showed that the enzyme activity was increased approximately 2-fold for the extracellular enzyme and 3-fold for the intracellular enzyme. The optimal dose found for extracellular enzyme production was 12-24 microM forskolin, while the optimal dose for intracellular was 12 microM. In parallel with the rise in the AChE level, the morphology of forskolin-treated cells showed neurite growth with increasing doses. Forskolin treatment protects Neuro 2A cells from diisopropylflurophophate (DFP), a surrogate of the organophosphate chemical warfare agents soman and sarin, induced toxicity in Neuro 2A cells. These results indicate that transcriptional inducers, such as forskolin, can sufficiently up-regulate cellular AChE production and protect cells against organophosphate toxicity.

Acetylcholinesterase↗
PubMed1979

Regulation of the intracellular calcium level in human blood platelets: cyclic adenosine 3',5'-monophosphate dependent phosphorylation of a 22,000 dalton component in isolated Ca2+-accumulating vesicles.

Two protein kinase activities have been separated from the supernatants of homogenized human blood platelets by DEAE cellulose chromatography. One of them (peak I enzyme) is an efficient stimulator of the uptake of Ca2+ into isolated membrane vesicles in the presence of cyclic AMP and ATP. The second (peak II enzyme), although equally active towards histone, exerts only about one third of the activity of the peak I enzyme. The stimulation of Ca2+ uptake is accompanied by the phosphorylation of a membrane protein with an apparent molecular weight of 22 000, which appears to play an essential role in the regulation of the intracellular Ca2+ level and hence of platelet activity.

Biological Transport↗
PubMed1979

1H NMR study on the interaction of cupric ion with ribonuclease A.

The reassignment of the 1H NMR C-2 histidine signals of the bovine pancreatic ribonuclease A has required a revision of the 1H NMR data on the role of the different histidines in their interaction with the Cu2+. The results of our measurements carried out at p2H 5.5 and 7.0 reduce the importance of His-12 as main site of interaction. At p2H 5.5 a very strong binding site involves His-119, while a weaker one contains certainly His-105. On the contrary, at p2H 7.0 the histidines 105 and 119 seem to possess binding constants of the same order of magnitude and in addition they provide stronger ligands for the Cu2+ than His-12. The comparison with X-ray data in the crystal shows numerous analogies. Finally, preliminary results on the competitive inhibition effect between the Cu2+ and 2',3'-cytidine monophosphoric acid are discussed.

Animals↗
PubMed1989

Interaction of rat brain cytidylate cyclase with phospholipids.

The interaction of rat brain cytidylate cyclase with some phospholipids such as L-alpha-phosphatidylcholine (PC), L-alpha-phosphatidylserine (PS), L-alpha-phosphatidylethanolamine (PE) and L-alpha-phosphatidic acid (PA) was studied. Cytidylate cyclase activity of Triton X-100 - solubilized fraction was inhibited by PS, PE and PA, but not with PC. The addition of PC to the incubation mixture containing PS, PE or PA dose - dependently reversed the inhibition of enzyme activity by these phospholipids. Phospholipids showed similar effect on the intact membrane - bound enzyme. PC could reactivate the enzyme which was inactivated by deoxycholate treatment, suggesting that PC may be an important factor to reconstitute an active conformation of the enzyme. These findings indicate that cytidylate cyclase could be regulated by phospholipids constituting its microenvironment of the membrane.

Animals↗
PubMed1991

Differential modulation by N4, 2'-O-dibutyryl cytidine 3':5'-cyclic monophosphate of neutrophil activation.

The cyclic pyrimidine nucleotide, cCMP, is an endogenous substance in mammalian cells but little is known on its functional role. We studied the effects of cCMP, its cell-permeant analogue, N4,2'-O-dibutyryl cytidine 3':5'-cyclic monophosphate (Bt2cCMP), and of butyrate on superoxide (O2-) formation and cytosolic Ca2+ [( Ca2+]i) in human neutrophils. Bt2cCMP inhibited O2- formation and the rise in [Ca2+]i induced by a chemotactic peptide at submaximally effective concentrations. O2- formation induced by platelet-activating factor was potentiated by Bt2cCMP, whereas the cyclic nucleotide had no effect on the rise in [Ca2+]i induced by this agonist. Bt2cCMP enhanced O2- formation induced by tau-hexachlorocyclohexane at a submaximally effective concentration. O2- formation stimulated by complement C5a, concanavalin A, NaF, A 23187, phorbol myristate acetate and arachidonic acid was not affected by Bt2cCMP. cCMP was less effective than Bt2cCMP to inhibit fMet-Leu-Phe-induced O2- formation, and butyrate was without effect on any of the functional parameters studied. Our data show that a cell-permeant analogue of cCMP differentially inhibits and potentiates activation of human neutrophils.

Butyrates↗
PubMed1991

Signal transduction pathways in the induction of HLA class I antigen expression on Huh 6 cells by interferon-gamma.

This study investigated the intracellular signal transduction regulating the appearance of HLA class I antigens on Huh 6 cells induced by interferon-gamma. The expression was blocked by a protein kinase C inhibitor, H-7, but not by a calmodulin antagonist, W-7, nor by a protein kinase A inhibitor, H-8, at low dose. The antigen expression was induced by a direct activator of protein kinase C, phorbol myristate acetate, but not by calcium ionophore A23187 nor an analog of cAMP, dbcAMP. Therefore, we concluded that protein kinase C is involved in the expression of HLA class I antigens on Huh 6 cells induced by interferon-gamma but Ca(2+)-calmodulin and cAMP are not.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Studies on the enzymatic and physicochemical behaviour of the trichloroacetic acid-treated and untreated bovine pancreatic ribonuclease.

Exposure of ribonuclease A to 5% trichloroacetic acid inactivates the enzyme partially. One of the possible reasons for such inactivation might be the exposure of one of the buried tyrosyl groups to the outside surface of the molecule (Sagar and Pandit (1983) Biochim. Biophys. Acta 743, 303-309). The trichloroacetic acid-treated enzyme hydrolysed 2':3'-cCMP with an efficiency of about 60%; while with rRNA as substrate, it is about 45%. Results indicate that apart from the reduction in the activity on trichloroacetic acid treatment, the enzyme possesses a reduced ability to break down the secondary structures of substrates such as rRNA in the first phase of the reaction. Thermal unfolding of ribonuclease A was followed by various physicochemical techniques such as UV absorbance, CD-spectroscopy and differential scanning microcalorimetry. The results indicate that the enzyme, after trichloroacetic acid-treatment, has a less ordered structure when compared to that of untreated enzyme. Thermal unfolding profiles reveal that trichloroacetic acid-treated ribonuclease A, like the untreated enzyme, follows a one-step transition with relatively lower transition temperature (Tm). NMR-spectral data suggests perturbations in the histidyl environment at the active site.

Binding Sites↗
PubMed1990

Dibutyrylcytidine 3',5'-cyclic monophosphate stimulates neurite outgrowth in rat pheochromocytoma PC12.

Dibutyrylcytidine 3',5'-cyclic monophosphate (Bt2cCMP) stimulated neurite outgrowth in rat pheochromocytoma PC12 cells in a dose-dependent manner at the dose range from 0.5 mM to 6 mM. About 25% of the cells had neurites in response to 6 mM Bt2cCMP. In contrast with the effect of nerve growth factor (NGF) which increased the percentage of cells with neurites gradually during a 6-day culture period, the stimulating effect of Bt2cCMP reached a plateau 2 days after plating. Staurosporine inhibited the neurite outgrowth induced by NGF, but not that by Bt2cCMP. These results suggest that Bt2cCMP stimulates neuronal differentiation by a mechanism different from that by NGF.

Adrenal Gland Neoplasms↗
PubMed1989

Inhibition of DNA synthesis of adult rat hepatocytes in primary culture by dibutyrylcytidine 3', 5'-cyclic monophosphate.

The effect of dibutyrylcytidine 3',5'-cyclic monophosphate (Bt2cCMP) on DNA synthesis of adult rat hepatocytes in primary culture was examined. Bt2cCMP caused dose-dependent inhibition of the DNA syntheses stimulated by various growth factors including human hepatocyte growth factor (hHGF). Dibutyryladenosine 3',5'-cyclic monophosphate (Bt2cAMP) inhibited the DNA synthesis more effectively than Bt2cCMP, but dibutyrylguanosine 3',5'-cyclic monophosphate (Bt2cGMP) and n-butyrate had a slight or null inhibitory effect. When added at the onset of DNA synthesis, Bt2cAMP was much less effective, but Bt2cCMP was still effective. Thus Bt2cCMP is able to inhibit growth factor-stimulated hepatocyte proliferation.

1-Methyl-3-isobutylxanthine↗