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

Phorbol esters, potent activators of protein kinase C (PKC), greatly enhance the release of arachidonic acid and its metabolites (TXA2, HETES, HHT) by Ca2+ ionophores in human platelets. In this paper, we report the relationship between intracellular Ca2+ mobilization and external calcium influx into platelets and the ability of PMA plus A23187 to promote thromboxane A2 (TXA2) synthesis. The enhanced levels of TXA2 due to the synergistic stimulation of the platelets with A23187 and phorbol esters are not affected significantly by the presence of external Ca2+ or the calcium-chelator EGTA. PKC inhibitors, staurosporine and sphingosine, abolished phorbol myristate acetate (PMA) potentiation of TXA2 production which strongly supports the role of PKC in the synergism. Platelet aggregation is more sensitive to PMA and external calcium than TXA2 formation. PMA increased TXA2 production as much as 4-fold at low ionophore concentrations. The A23187-induced rise in [Ca2+]i was reduced by pretreatment of human platelets with phorbol esters, both in the presence and absence of EGTA, and staurosporine reversed this inhibitory effect. These results indicate that the synergistic stimulation of TXA2 production by A23187 and phorbol esters is promoted by intracellular Ca2+ mobilization and not by external calcium influx. Our data also suggest that PKC is involved in the regulation of Ca2+ mobilization from some specific intracellular stores and that PKC may also stimulate the Ca(2+)-dependent phospholipase A2 at suboptimal Ca2+i concentrations.
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PMID:Intracellular Ca2+ mobilization and not calcium influx promotes phorbol ester-stimulated thromboxane A2 synthesis in human platelets. 160 22

Both 12-hydroxyheptadecatrienoic acid (12-HHT) and thromboxane A2 (TXA2) are products derived from prostaglandin H2 (PGH2) catalyzed by thromboxane synthase. Whether or not they exhibit similar actions remains to be determined. While TXA2-induced activation of extracellular signal-regulated kinases (ERKs) has been extensively studied, 12-HHT-induced activation of ERKs has not been explored. We reported for the first time that 12-HHT induced activation of ERKs in human prostate cancer cell line, PC3. We also compared the mechanisms of 12-HHT- and I-BOP-, a TXA2 mimetic, mediated ERK activation in PC3 cells. The activation of ERKs induced by either agent was shown to involve protein kinase C (PKC)-, protein kinase A (PKA)-, Src kinase and phosphoinositide-3 kinase (PI-3K)-dependent mechanisms in addition to the transactivation of the EGF receptor (EGFR) and the involvement of matrix metalloproteinases (MMPs) based on the sensitivity of the activation to their respective inhibitors. JNK/SAPK and p38 MAPK pathways were responsive to I-BOP but not to 12-HHT stimulation. Both 12-HHT- and I-BOP-induced activations of ERKs were also examined in other human prostate cancer cells, human lung cancer cells, and human lung fibroblast. I-BOP appeared to induce activation of ERKs in most cell lines, whereas 12-HHT induced activation of ERKs only in lung fibroblast in addition to PC3 cells. It appears that TPs are more generally expressed and the potential 12-HHT receptor (s) is expressed in limited specific cell types. Our results suggest that increased expression of thromboxane synthase as seen in prostate tumor may stimulate tumorigenesis as a consequence of concurrent increased synthesis of two fatty acids capable of activating ERKs.
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PMID:Activation of extracellular signal-regulated kinase by 12-hydroxyheptadecatrienoic acid in prostate cancer PC3 cells. 1788 Sep 8