Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transduction in glycosaminoglycan (GAG) synthesis by chondrocytes has been studied. The activity of various subspecies of protein kinase C (PKC) in chondrocytes derived from rodent costal cartilage and bovine articular cartilage has been determined and the role of PKC in GAG synthesis as well as the possible interactions of PKC with calcium- or cyclic AMP (cAMP)-dependent systems in the synthesis of GAG. To investigate GAG synthesis in inflammatory conditions, the effects of hydrogen peroxide on PKC activity of the chondrocytes and PKC-mediated GAG synthesis have been studied. 12-O-Tetradecanoylphorbol-13-acetate (TPA), an activator of PKC, increased GAG synthesis in a dose-dependent fashion. This suggests that PKC up-regulates the synthesis of GAG in cultured chondrocytes. This increase was not significantly affected by simultaneous addition of the calcium ionophore, ionomycin, or dibutyryl cAMP (db-cAMP), a cAMP analogue. Ionomycin and db-cAMP, when used alone, did not significantly alter GAG synthesis by chondrocytes. Thus there appears to be no interaction between PKC and calcium- or cAMP-mediated systems in GAG synthesis. The increase in GAG synthesis induced by TPA was significantly (P less than 0.01) reduced by simultaneous addition of hydrogen peroxide (10(-6) M), without affecting cell viability. The activity of PKC in chondrocytes pretreated with 10(-6) M hydrogen peroxide was also significantly inhibited. Thus hydrogen peroxide which is generated by inflammatory cells may be important in suppression of GAG synthesis in inflammatory conditions.
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PMID:Signal transduction in glycosaminoglycan (GAG) synthesis by cultured chondrocytes and its inhibition by inflammatory cell-derived hydrogen peroxide. 131 22

We investigated the effect of agents which raise intracellular cyclic AMP (cAMP) and protein kinase C activators on the production of plasminogen activator inhibitor type-2 (PAI-2) by cultured human promyelocytic leukemia cell line, PL-21. As previously reported, PMA, a protein kinase C activator, showed a strong stimulating effect on the PAI-2 production. 1-oleoyl-2-acetyl-sn-glycerol (OAG), another synthetic protein kinase C activator, also showed a stimulating effect, which was, however, much less than that of PMA. The agents which raise intracellular cAMP, dibutyryl cAMP, 8-bromo cAMP, prostaglandin E1, and 3-isobutyl-1-methyl-xanthine, little increased the PAI-2 production when tested alone, but showed significant synergistic effects with PMA or OAG. The synergistic effect between PMA and dibutyryl cAMP was further verified by SDS-PAGE followed by immunoblotting using a monoclonal antibody against the PAI-2. It is interesting that the up-regulation of PAI-2 by cAMP and the synergistic effect with PKC activators forms a contrast to the previous reported bi-directional regulation of endothelial PAI-1 secretion by PKC activator and cAMP.
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PMID:Synergistic stimulating effect between cyclic AMP and phorbol ester on plasminogen activator inhibitor type 2 production in human promyelocytic leukemia cell line PL-21. 131 98

The activities of Ca2+/calmodulin (CaM)-dependent, Ca2+/phospholipid-dependent, and cyclic AMP-dependent protein kinases (CaM-KII, PKC, and PKA, respectively) were determined in rat brains after global ischemia. Both CaM-KII and PKC activities were significantly depressed in both hippocampal and cerebral cortical regions of ischemic animals, whereas no change was detected in PKA activity. The loss of CaM-KII activity was more dramatic and more sustained than the loss of PKC activity and correlated with the duration of ischemia. These decreases in enzyme activity were found in both supernatant and pellet fractions from crude homogenates. When the supernatant and pellet were analyzed for the amount of CaM-KII 50-kDa protein, a significant decrease was detected in supernatant fractions that paralleled a gain in the amount of CaM-KII in the pellet. Thus, the loss of CaM-KII activity in the supernatant can be explained by translocation of the enzyme to the pellet. Whether inactivation of CaM-KII occurs during or after the enzyme translocates from the supernatant to the pellet is unknown. Our results indicate that loss in CaM-KII activity parallels neuronal damage associated with ischemia; down-regulation of CaM-KII activity coincided with translocation of the enzyme to the particulate fraction, and it is proposed that this may be, in fact, a mechanism for controlling excessive CaM-KII phosphorylation.
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PMID:Ischemia-induced translocation of Ca2+/calmodulin-dependent protein kinase II: potential role in neuronal damage. 131 52

Activation of protein kinase C (PKC) in Aplysia bag cell neurons causes the recruitment of voltage-dependent calcium channels. Using imaging techniques on isolated cells, we have now found that an activator of PKC, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), promotes the rapid appearance of new sites of calcium influx associated with a change in the morphology of neurite endings. In untreated cells, calcium influx triggered by action potentials occurs along neurites and in the central region of growth cones, but does not usually occur at the leading edge of lamellipodia. TPA produces extension of the lamellipodium, and action potentials now trigger calcium influx at the distal edge of the newly extended endings. Cotreatment with TPA and a cyclic AMP analog promotes movement of secretory organelles toward the new sites of calcium influx. Our results suggest that these second messenger systems promote the rapid formation of morphological structures that contribute to the potentiation of peptide release.
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PMID:Recruitment of Ca2+ channels by protein kinase C during rapid formation of putative neuropeptide release sites in isolated Aplysia neurons. 131 64

We have recently shown that mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the reproductive toxicant di-(ethylhexyl) phthalate (DEHP), inhibited FSH- but not forskolin-, isoproterenol-, or cholera toxin-stimulated granulosa cell cAMP accumulation in vitro. In addition, MEHP also inhibited FSH-stimulated progesterone production, a cAMP-dependent process. Similar to MEHP, the protein kinase C (PKC) activator, 12-0-tetradecanoyl-phorbol 13-acetate (TPA) has been shown to inhibit rat granulosa cell cAMP accumulation in a FSH-specific manner, and decrease FSH-stimulated progesterone production. Due to the similarity with respect to inhibition of cAMP accumulation, we conducted studies to determine if the inhibitory actions of MEHP on granulosa cell function are mediated via activation of PKC. Treatment of granulosa cells for 48 h with 100 microM MEHP produced no effect on forskolin- or isoproterenol-stimulated progesterone production, indicating that MEHP does not have a post-cyclic AMP site of action with respect to progesterone inhibition. Unlike the FSH-specific effect seen with MEHP, treatment with 10 nM TPA inhibited FSH-, forskolin-, and isoproterenol-stimulated progesterone production. In addition, maximally inhibitory concentrations of TPA and MEHP caused significantly greater inhibition of FSH-stimulated cAMP accumulation than either compound alone. Finally, addition of the progesterone precursor, pregnenolone, reversed the FSH-stimulated progesterone production inhibition by MEHP, but not that by TPA. Taken together, these data indicate that the inhibitory effects of MEHP on granulosa cell function are independent of phorbol ester-sensitive PKC activation.
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PMID:Evidence that MEHP inhibits rat granulosa cell function by a protein kinase C-independent mechanism. 131 32

1. Voltage-activated currents through calcium channels in primary cultures of murine dorsal root ganglion cells (DRG) were studied with the whole-cell and cell-attached patch recording techniques. 2. The chemical phosphatase 2,3-butanedione monoxime (BDM) reversibly reduced the amplitude of L-type calcium current (ICa) in a dose-dependent manner; at a concentration of 20 mM, BDM caused a 47% suppression of ICa. 3. Application of 10 mM-8-bromo-cyclic AMP or 50 microM-isoprenaline onto DRG treated with BDM completely restored ICa to the pre-BDM level. 4. In striking contrast, bath application of Bay K 8644 (0.5-5 microM) had no effect on the BDM-suppressed ICa. As expected, Bay K 8644 alone caused a two- to threefold increase of the maximal ICa and shifted its I-V relationship to the left. Interestingly, if a cell was first exposed to Bay K 8644 further treatment with 20 mM-BDM resulted in 100% suppression of ICa. This suggests that Bay K 8644 changes the conformation of the calcium channel to one which is more sensitive or more accessible to the action of the phosphatase. 5. Pre-treatment of DRG with an activator of protein kinase C, 12-O-tetradecanoyl-phorbol-13-acetate, did not antagonize BDM's effect on ICa. 6. The depressant action of BDM on ICa was distinct from that of nifedipine in that it did not exhibit use dependence. 7. When single calcium channel currents were recorded in cell-attached patches (barium as the charge carrier), bath application of BDM reduced the percentage of time that the channel spent in the open state. 8. Superfusion with 8-bromo-cyclic AMP restored the ensemble macroscopic 'ICa' to the pre-BDM amplitude. This was due to a dramatic enhancement of the frequency of channel openings. 9. We suggest that BDM acts through the cytoplasm to alter cyclic AMP-dependent protein kinase modulation of neuronal L-type calcium channels. The brief, high-frequency openings which 8-bromo-cyclic AMP activates in the presence of BDM may reflect a rapid phosphorylation-dephosphorylation sequence which controls channel gating.
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PMID:Novel suppression of an L-type calcium channel in neurones of murine dorsal root ganglia by 2,3-butanedione monoxime. 131 30

In human D384 astrocytoma cells, cyclic AMP accumulation can be conveniently studied after labelling of the adenosine triphosphate pool (15 fmol cell-1) with [3H]adenine. In this study, adenosine had a biphasic effect on cyclic AMP accumulation, which was scarcely altered by blocking adenosine uptake and metabolism. Low concentrations of adenosine led to an inhibition of cyclic AMP accumulation, and higher concentrations led to stimulation. No effect of adenosine on cyclic AMP was observed unless phosphodiesterase was inhibited by rolipram. The A1 receptor antagonist DPCPX attenuated the inhibitory phase of adenosine response, and enhanced the cyclic AMP accumulation induced by adenosine analogues. The cyclic AMP accumulation was stimulated by NECA greater than ADO greater than CGS 21680 greater than CV 1808 greater than CPA greater than or equal to CHA, indicating mediation by A2 receptors. The stimulatory effect of NECA was much more effectively blocked by the combined A1 and A2 receptor antagonist CGS 15943 (KB 4 nmol l-1) than by the A1 antagonist DPCPX (KB 110 nmol l-1). Treatment of the cells with pertussis toxin (0.2 microgram ml-1 for 2.5 h) potentiated the cyclic AMP response to adenosine analogues significantly. The cyclic AMP response to NECA was enhanced by the protein kinase C activator phorbol dibutyrate even after pertussis toxin treatment. By contrast, nanomolar concentrations of bradykinin, which increases Ca(2+)-levels and protein kinase C activity in D384 cells, reduced NECA-induced cyclic AMP accumulation in control and pertussis toxin-treated cells. Thus, D384 cells possess both A1 and A2 adenosine receptors influencing cyclic AMP in opposite directions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptor-induced cAMP changes in D384 astrocytoma cells and the effect of bradykinin thereon. 131 54

Simultaneous treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) and dibutyryl cyclic AMP (diBu-cAMP) for 72 h induced neurites in NG108-15 cells significantly longer than treatment with each alone. Treatment for 72 h with both drugs induced irreversible neurite extension and a decline in protein kinase C activity, although neurites extended by diBu-cAMP alone disappeared after the withdrawal of the drug. The expression of growth-associated protein-43 (GAP-43) mRNA was also observed by a combined application of TPA and diBu-cAMP. The increased level of GAP-43 mRNA induced by treatment with both drugs for 72 h was maintained at least 24 h after withdrawal of the drugs. In cells transfected with GAP-43 cDNA, neurites induced by treatment with diBu-cAMP alone for 72 h were maintained at least 48 h after removal of the drugs. These results suggest that GAP-43 could be involved in the maintenance of elongated neurites and that a decline in protein kinase C activity may be involved in the accumulation of GAP-43.
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PMID:Involvement of growth-associated protein-43 with irreversible neurite outgrowth by dibutyryl cyclic AMP and phorbol ester in NG108-15 cells. 131 72

We investigated the effect of phorbol myristate acetate (PMA), dexamethasone (Dex) and reagents which raise intracellular cyclic AMP, on the production of plasminogen activator inhibitor type-2 (PAI-2) in human promyelocytic leukemia cell line, PL-21 and on the production of urinary type plasminogen activator (u-PA) in human pre-B cell lymphoma cell line, RC-K8. Cells were cultured in fetal bovine serum free RPMI-1640 containing the test-reagents for 48 hours. PAI-2 and u-PA antigens were measured by ELISA kits. PMA, an activator of protein kinase C (PKC), markedly increased both PAI-2 and u-PA production in each cell line. On the other hand, cAMP increased PAI-2 production in PL-21 cells, but decreased u-PA synthesis in RC-K8 cells. Similar to cAMP, Dex also increased PAI-2 production but decreased u-PA production in RC-K8 cells. Moreover, PMA and cAMP synergistically increased the PAI-2 production. This was verified by Western blot, using a monoclonal antibody against the PAI-2. These two cell lines are, therefore, useful for clarifying the role of A kinase and C kinase on PAI-2 and u-PA synthesis in human hemopoietic cells.
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PMID:[Effect of cyclic AMP and phorbol ester on PAI-2 synthesis in a leukemic cell line PL-21 and on u-PA secretion in a pre-B cell lymphoma cell line RC-K8]. 131 13

The ability of cyclic AMP (cAMP) to modulate human B cell proliferative responses and the possible role of cAMP-dependent kinases (PKA) in cAMP modulation of proliferative responses were investigated. The addition of dibutyl cAMP (Bt2 cAMP) or the cAMP-elevating agent forskolin to B cells stimulated by crosslinking surface immunoglobulins (sIg) resulted in a concentration-dependent inhibition of proliferative responses. By contrast, Bt2 cAMP or forskolin enhanced the proliferative responses of B cells after direct stimulation by phorbol myristate acetate (PMA) and the calcium ionophore ionomycin. The inhibition and enhancement of B cell proliferative responses by Bt2 cAMP were observed at different incubation intervals and were not due to temporal shifts of optimal responses. Also, Bt2 cAMP caused only small changes in B cell RNA synthesis compared to modulation of proliferative responses. Exposure of B cells to Bt2 cAMP rapidly activated PKA. Blocking Bt2 cAMP activation of PKA with the kinase inhibitor HA1004 prevented Bt2 cAMP enhancement of B cell responses after direct stimulation by PMA and ionomycin. In reciprocal experiments, the kinase inhibitor H7 resulted in some inhibition of PKC activation but did not inhibit Bt2 cAMP activation of PKA or Bt2 cAMP enhancement of proliferative responses. Other experiments demonstrated that B cells treated with Bt2 cAMP had selective increases in the de novo phosphorylations of two endogenous substrates which reflected PKA activation. Furthermore, concentrations of HA1004 or H8 which inhibited Bt2 cAMP enhancement of proliferative responses also inhibited PKA phosphorylations of these substrates whereas H7 did not. Thus, elevations of cAMP can enhance or inhibit human B cell proliferative responses to different stimuli and the activation of PKA is important for cAMP enhancement of certain responses.
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PMID:Cyclic AMP modulation of human B cell proliferative responses: role of cAMP-dependent protein kinases in enhancing B cell responses to phorbol diesters and ionomycin. 132 Apr 64


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