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:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

8-Cl-cAMP and 8-NH2-cAMP induced MCF-7 cell death. The type(s) of cell death were studied in more detail and compared with the cell death type (apoptosis) induced by okadaic acid, an inhibitor of serine/threonine phosphatases. By morphological criteria dying cells showed loss of cell-cell interactions and microvilli, condensation of nuclear chromatin and segregation of cytoplasmic organelles. By in situ nick end-labelling, using digoxigenin-conjugated dUTP as probe, a large fraction of 8-Cl-cAMP, 8-NH2-cAMP and 8-Cl-adenosine-exposed cells stained positively in the advanced stages of death. In the early phase of chromatin condensation the cells stained negatively. Specific (internucleosomal) DNA fragmentation was not observed. The MCF-7 cell death induced by 8-Cl-cAMP and 8-NH2-cAMP was not mediated by activation of the cAMP kinase since more stable cAMP analogues (8-CPT-cAMP and N6-benzoyl-cAMP) or forskolin failed to induce death. Furthermore, 8-Cl-cAMP action was counteracted by adenosine deaminase and 3-isobutyl-1-methylxanthine, and mimicked by 8-Cl-adenosine, a major metabolite of 8-Cl-cAMP. It is concluded that 8-Cl- and 8-NH2-cAMP can induce morphological and biochemical effects resembling apoptotic cell death in MCF-7 cells through their conversion into potent cytotoxic metabolite(s).
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PMID:8-Chloro-cAMP induces apoptotic cell death in a human mammary carcinoma cell (MCF-7) line. 757 61

The olfactory epithelium (OE) of the mouse provides a unique system for understanding how cell birth and cell death interact to regulate neuron number during development and regeneration. We have examined cell death in the OE in normal adult mice; in adult mice subjected to unilateral olfactory bulbectomy (surgical removal of one olfactory bulb, the synaptic target of olfactory receptor neurons (ORNs) of the OE); and in primary cell cultures derived from embryonic mouse OE. In vivo, cells at all stages in the neuronal lineage--proliferating neuronal precursors, immature ORNs, and mature ORNs--displayed signs of apoptotic cell death; nonneuronal cells did not. Bulbectomy dramatically increased the number of apoptotic cells in the OE on the bulbectomized side. Shortly following bulbectomy, increased cell death involved neuronal cells of all stages. Later, cell death remained persistently elevated, but this was due to increased apoptosis by mature ORNs alone. In vitro, apoptotic death of both ORNs and their precursors could be inhibited by agents that prevent apoptosis in other cells: aurintricarboxylic acid (ATA), a membrane-permeant anlog of cyclic AMP (CPT-cAMP), and certain members of the neurotrophin family of growth factors (brain-derived neurotrophic factor, neurotrophin 3, and neurotrophin 5), although no neurotrophin was as effective at promoting survival as ATA or CPT-cAMP. Consistent with observed effects of neurotrophins, immunohistochemistry localized the neurotrophin receptors trkB and trkC to fractions of ORNs scattered throughout neonatal OE. These results suggest that apoptosis may regulate neuronal number in the OE at multiple stages in the neuronal lineage and that multiple factors-potentially including certain neurotrophins--may be involved in this process.
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PMID:Apoptosis in the neuronal lineage of the mouse olfactory epithelium: regulation in vivo and in vitro. 758 10

Pretreating confluent T84 cells with the phorbol ester phorbol 12-myristate 13-acetate (PMA) inhibits adenosine 3',5'-cyclic monophosphate (cAMP)- and carbachol-induced Cl secretion. Both a sustained short-circuit current (Isc), seen after the addition of 50 microM 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPT-cAMP) and 100 microM 3-isobutyl-1-methylxanthine (IBMX), and a transient current, seen after the subsequent addition of 100 microM carbachol, are inhibited by 80% following pretreatment with 100 nM PMA for 2 h. Pretreatment with PMA has no effect on the level of cystic fibrosis transmembrane conductance regulator protein or apical cAMP-dependent Cl conductance. Carbachol does not induce an increase in apical Cl conductance. Basolateral K conductance was measured in monolayers treated with apical nystatin and exposed to a K gradient. Agonist-independent K conductance is 10-fold greater in Cl media than in gluconate media. Pretreatment with PMA inhibits agonist-independent K conductance by 57% in Cl media but stimulates K conductance by 1.9-fold in gluconate media. The addition of carbachol induces a transient increase in basolateral K conductance, and pretreatment with PMA inhibits the agonist-dependent K conductance by 66% in Cl media and by 92% in gluconate media. In Cl media, serosal barium, at 3 mM, inhibits agonist-independent K conductance but has no significant effect on the carbachol-induced conductance. In nonpermeabilized monolayers, serosal barium inhibits the cAMP-dependent Isc by 56% but has no effect on the carbachol-induced Isc. These results demonstrate that the primary effect of PMA on Cl secretion is not inhibition of apical Cl channels but inhibition of basolateral K channels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of cAMP- and Ca-dependent Cl- secretion by phorbol esters: inhibition of basolateral K+ channels. 767 50

We have investigated the effects of cAMP-enhancing agents on depolarization-induced membrane capacitance increases (delta Cm) in single rat pancreatic B-cells. Concentrations of IBMX, 8-CPT cAMP and forskolin, which enhance cAMP and insulin release, all enhance depolarization-induced delta Cm's seen in response to single voltage-clamp pulses and reduce the depression of delta Cm responses often seen with trains of pulses. These effects often occur in the absence of changes in peak Ca2+ current or the total Ca2+ charge entry during the depolarizing pulse. These data suggest that cAMP-modulating maneuvers may directly affect the mechanism of insulin granule mobilization into a readily releasible store or fusion at a discharge site.
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PMID:Enhancers of cytosolic cAMP augment depolarization-induced exocytosis from pancreatic B-cells: evidence for effects distal to Ca2+ entry. 769 89

Cyclic AMP-mediated desensitization of D1 dopamine receptor-coupled adenylyl cyclase was investigated using NS20Y neuroblastoma cells. Pretreatment of the cells for 24 h with 8-(4-chlorophenylthio)-adenosine-3':5'-cyclic monophosphate (CPT-cAMP), a membrane-permeable analog of cAMP, resulted in an approximately 90% reduction of the maximum dopamine-stimulated adenylyl cyclase activity. In addition, there was a twofold reduction in the potency of dopamine for stimulating cAMP production that was not dependent on the concentration of Mg2+ in the assay. These effects of CPT-cAMP pretreatment were time dependent, showing a t1/2 of about 3 h and a maximum reduction after about 8 h. Receptor-binding activity, as measured using the D1-selective antagonist [3H]SCH-23390, also declined following CPT-cAMP pretreatment with a t1/2 of about 5 h and a maximum reduction of about 70% after 20 h. Saturation analysis indicated that the loss in radioligand binding was due to a reduction in maximum binding capacity (Bmax) with no alteration in receptor affinity (KD). The EC50 of CPT-cAMP for producing enzyme desensitization and D1 receptor downregulation was determined to be about 30 microM with a maximal response occurring at 1 mM. These regulatory effects of CPT-cAMP were pharmacologically specific as other analogs of cAMP, such as dibutryl-cAMP, 8-bromo-cAMP, and Sp-cAMPS, were capable of inducing D1 receptor desensitization and downregulation, whereas treatment of the cells with the cAMP antagonist Rp-cAMPS had no effect. Conversely, Rp-cAMPS was capable of blocking the regulatory effects of CPT-cAMP but was apparently without effect in blocking dopamine-induced desensitization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic AMP-mediated desensitization of D1 dopamine receptor-coupled adenylyl cyclase in NS20Y neuroblastoma cells. 770 30

LPS, a bacterial endotoxin, induces the expression of many genes in macrophages. We report the cloning of a novel 3.3-kb cDNA that is a member of the thymidylate kinase family of genes. This clone, which we have designated TYKi, was obtained by screening a cDNA library prepared from RNA isolated from the murine cell line RAW264.7 after bacterial LPS treatment. TYKi is quite similar to all thymidylate kinases for which there are sequence data. It conserves two very important domains in these kinases, namely, the catalytic domain or P-loop and the nucleotide binding domain. After LPS exposure, the TYKi message appears at 2 h, peaks at 6 h, and declines at 8 h. LPS induction of TYKi is dependent on de novo protein synthesis. Increasing cytosolic cAMP with forskolin attenuates the LPS induction of TYKi. However, treatment with 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) or dibutyryl-cAMP did not affect the LPS induction of TYKi. In contrast, activation of protein kinase C with phorbol ester augmented the LPS response, whereas inhibiting protein kinase C with 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) suppressed the LPS response. Removing extracellular Ca2+ with EGTA inhibited LPS induction of TYKi, whereas increasing intracellular calcium with the calcium ionophore A23187 had little effect on the levels of the TYKi transcript. Inhibiting tyrosine kinase with genistein suppressed the induction of TYKi by LPS.
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PMID:A unique member of the thymidylate kinase family that is induced during macrophage activation. 775 51

We have previously observed that chronic cocaine administration increases levels of adenylyl cyclase and cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc). In the present work we directly examined the involvement of the cAMP system at the level of the NAc in cocaine-induced locomotor activity and sensitization. Groups of rats were pretreated on 3 consecutive days with cocaine (10 mg/kg, i.p.) concurrently with intraacumbens infusion saline, 8-bromo-cAMP (2 micrograms/side; a membrane permanent analogue of cAMP which activates PKA), or RP-CPT-cAMP (20 nmol/side; which inhibits PKA). In a separate experiment, control animals received total infusion of either 8-bromo-cAMP or saline plus i.p. saline. All animals were tested for locomotor activity on pretreatment days, and following an additional cocaine challenge ona subsequent day. Over pretreatment days, animals given 8-bromo-cAMP showed greater cocaine-induced activity, while animals given RP-CPT-cAMP tended to be less active, compared to saline infused animals. When subsequently challenged with cocaine, animals pretreated with intraaccumbens 8-bromo-cAMP showed greater locomotor activity during the last 30 min of the 60 min test session than animals pretreated with saline or RP-CRT-cAMP. No differences in locomotor activity were evident between the two control groups on pretreatment or challenge days. These data suggest that PKA activation at the level of the NAc may have a facilitative role with respect to acute and long-term stimulant-induced locomotor activity.
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PMID:Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens. 779 10

Protein phosphorylation plays important roles in the mechanisms underlying serotonin (5-HT)-induced presynaptic facilitation of Aplysia sensory neurons. To study mechanisms involved in facilitation, we investigated the pattern of protein phosphorylation in sensory neurons as a function of different durations of 5-HT. Two minutes and 1.5 hr treatments with 5-HT altered the phosphorylation of 5 and 10 proteins, respectively. These different duration treatments with 5-HT produced unique effects on the phosphorylation of different sets of proteins. This result suggests that cells may encode and measure the duration of a stimulus by the pattern of specific proteins that are phosphorylated or dephosphorylated. In addition, because the changes in phosphorylation produced by 2 min treatments with 5-HT were not observed after 25 min treatments with 5-HT, mechanisms must exist for the transient phosphorylation of some proteins even when the 5-HT treatment persists. Anisomycin, an inhibitor of protein synthesis, blocked the effect of 1.5 hr treatments with 5-HT on the phosphorylation of six proteins but had no effect on the phosphorylation change of four other proteins. Both CPT-cAMP (an activator of protein kinase A) and PDAc (an activator of protein kinase C) mimicked the effects of 5-HT on four proteins. Interestingly, the effect of 5-HT on these four proteins did not require protein synthesis. CPT-cAMP, but not PDAc, mimicked the effect of 5-HT on one protein (L55) and, the effect of 5-HT on this protein appeared to require protein synthesis. Because both activation of PKA and protein synthesis are involved in the induction of long-term facilitation, protein L55 is a good candidate for a protein that might play a key role in long-term facilitation. Finally, the effects of 5-HT on four proteins were not mimicked by either CPT-cAMP or PDAc. This finding raises the interesting possibility that some effects of 5-HT are mediated by second-messenger systems other than PKA or PKC.
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PMID:Dynamics of protein phosphorylation in sensory neurons of Aplysia. 782 47

The enzyme phosphoenolpyruvate carboxykinase (PEPCK) plays a key role in gluconeogenesis in liver and in glyceroneogenesis in adipose tissue. These processes, and PEPCK, are regulated by a number of hormones, some of which have different effects on the enzyme in liver and adipose tissue. To explore this phenomenon, PEPCK gene expression was studied in 3T3-F442A adipocytes maintained in a serum-free medium. The beta-adrenergic agonist isoprenaline (isoproterenol) and a cyclic AMP analogue (8-CPT-cAMP) increased PEPCK mRNA. A maximal 3-fold induction occurred in 2 h. Dexamethasone decreased PEPCK mRNA by 80% in 4 h. Dexamethasone also counteracted the inductive effects of isoprenaline and 8-CPT-cAMP. Run-on transcription experiments showed that the isoprenaline and dexamethasone actions were, at least in part, exerted at the level of PEPCK gene transcription. These effects were further analysed by using transient and stable transfection of adipocytes with a plasmid containing bp -2100 to 69 of the PEPCK gene promoter fused to the chloramphenicol acetyltransferase (CAT) gene. In such cells isoprenaline stimulated CAT expression, an effect that was prevented if the cells were also exposed to dexamethasone.
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PMID:Expression of the phosphoenolpyruvate carboxykinase gene in 3T3-F442A adipose cells: opposite effects of dexamethasone and isoprenaline on transcription. 782 55

In PC12 cells, cAMP stimulates the MAP kinase pathway by an unknown mechanism. Firstly, we examined the role of calcium ion mobilization and of protein kinase C in cAMP-stimulated MAP kinase activation. We show that cAMP stimulates p44mapk independently of these events. Secondly, we studied the role of B-Raf in this process. We observed that NGF, PMA and cAMP induce the phosphorylation of B-Raf as well as an upward shift in its electrophoretic mobility. We show that B-Raf is activated following NGF and PMA treatment of PC12 cells, and that it can phosphorylate and activate MEK-1. However, cAMP inhibits B-Raf autokinase activity as well as its ability to phosphorylate and activate MEK-1. This inhibition is likely to be due to a direct effect since we found that PKA phosphorylates B-Raf in vitro. Further, we show that B-Raf binds to p21ras, but more important, this binding to p21ras is virtually abolished with B-Raf from PC12 cells treated with CPT-cAMP. Hence, these data indicate that the PKA-mediated phosphorylation of B-Raf hampers its interaction with p21ras, which is responsible for the PKA-mediated decrease in B-Raf activity. Finally, our work suggests that in PC12 cells, cAMP stimulates MAP kinase through the activation of an unidentified MEK kinase and/or the inhibition of a MEK phosphatase.
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PMID:Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP. 783 30


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