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)

Stimulation of human monocytes by lipopolysaccharide or phorbol ester resulted in an increase in thromboxane-B2 and prostaglandin-E2 production, whereas interleukin 1, tumour necrosis factor alpha and leukotriene C4 exerted no effects. Inhibitors of protein kinase C suppressed these increases. The activity of cyclooxygenase was induced 3.2-fold by an 8-h stimulation, whereas thromboxane-synthase and prostaglandin-E-isomerase activities remained unchanged. A glucocorticoid, dexamethasone, blocked both basal and induced prostanoid release, as well as cyclooxygenase activity. By immunoprecipitation, we were able to demonstrate an enhanced de novo synthesis of cyclooxygenase protein induced by lipopolysaccharide and phorbol ester. Dexamethasone suppressed cyclooxygenase synthesis, whereas thromboxane synthase was induced. For cyclooxygenase, we calculated a half-life of 3.2 h in human monocytes, and for thromboxane synthase, a half-life of 28 h. These results suggest that the regulation of differential prostanoid production mainly occurs by up and down regulation of cyclooxygenase.
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PMID:Regulation of cyclooxygenase and thromboxane synthase in human monocytes. 158 65

To investigate the mechanisms by which endothelin 1 (ET-1) causes pulmonary vasoconstriction, we studied the effect of synthetic ET-1 on pulmonary vascular tone in the buffer-perfused isolated rabbit lung. In nanomolar concentrations (1.2-8 nM), ET-1 causes a dose-dependent increase in pulmonary arterial pressure that persists for greater than or equal to 1 h (increase in pressure 19 +/- 2 mmHg with ET-1 vs. 2 +/- 1 with vehicle, P less than 0.0001). Reduction of calcium availability with verapamil, cadmium, or a calcium-free buffer significantly blunts the increase in pressure caused by ET-1. Pretreatment with a calcium-free buffer plus the chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N', N'-tetraacetic acid (EGTA) completely eliminates the vasoconstriction. Three different inhibitors of protein kinase C, phloretin, staurosporine, and dihydrosphingosine, significantly diminish the response to ET-1. Indomethacin and a thromboxane synthase inhibitor partially decrease the response to the highest concentration of ET-1. Isoproterenol and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) are significantly more effective in preventing the vasoconstriction caused by ET-1 than are nitroprusside and guanosine 5'-cyclic monophosphate (cGMP) analogues. ET-1 in doses of 1.2-8 nM is a potent pulmonary vasoconstrictor in the isolated rabbit lung. ET-1 appears to cause pulmonary vasoconstriction by increasing calcium entry and by activating protein kinase C. Vasodilators that increase cAMP are substantially more effective in preventing the increase in pressure than are drugs that increase cGMP.
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PMID:Mechanisms by which endothelin 1 induces pulmonary vasoconstriction in the rabbit. 165 58

Platelet eicosanoid metabolism resulting from tumor-cell-induced platelet aggregation (TCIPA) was examined in a homologous in vitro system. Rat Walker 256 carcinosarcoma cells induced the aggregation of rat platelets via a thrombin-dependent mechanism with concomitant production of eicosanoid metabolites (e.g., 12-HETE, TXA2). TCIPA was dependent on the concentration of tumor cells inducing aggregation, as well as cyclooxygenase and lipoxygenase products. Cyclooxygenase inhibitors, but not lipoxygenase inhibitors, blocked platelet aggregation induced in vitro by a low concentration of agonist. At a high agonist concentration, neither cyclooxygenase nor lipoxygenase inhibitors alone affected platelet aggregation; however, the combined inhibition of both the cyclooxygenase and lipoxygenase pathways resulted in subsequent inhibition of platelet aggregation regardless of agonist concentration. The extent of platelet TXA2 and 12-HETE biosynthesis was likewise dependent on and correlated with agonist concentration. The inhibitors used in this study did not significantly inhibit protein kinase C activity at the doses tested. Platelet surface glycoprotein alpha IIb beta 3 play an important role in platelet aggregation. The effect of platelet cyclooxygenase and lipoxygenase inhibition in regulating alpha IIb beta 3 surface expression was examined by flow cytometric analysis. Thrombin stimulation of washed rat platelets resulted in significantly increased surface expression of platelet alpha IIb beta 3 integrin complex. The enhanced surface expression was not inhibited by a cyclooxygenase inhibitor (aspirin), a thromboxane synthase inhibitor (CGS-14854) or a thromboxane receptor antagonist (SQ 29,548), nor was it stimulated by a thromboxane A2 mimic (pinane-thromboxane A2). However, alpha IIb beta 3 expression was blocked by lipoxygenase inhibition and stereospecifically increased by the platelet lipoxygenase metabolite 12(S)-HETE. These results suggest that both the platelet lipoxygenase and cyclooxygenase pathways are important for TCIPA but that different mechanisms of action are involved.
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PMID:Studies on the role of platelet eicosanoid metabolism and integrin alpha IIb beta 3 in tumor-cell-induced platelet aggregation. 847 51

We have previously shown that superoxide anion (O2-) stimulates the release of vasoconstrictor prostanoids and induces a prolonged rise in coronary perfusion pressure (CPP) that persists even after removal of O2-. In this study, we tested the hypothesis that the increased CPP is mediated by activation of TxA2/ PGH2 (TP) receptors and protein kinase C (PKC)-dependent mechanisms. In Langendorff perfused rat hearts, O2- was applied for 15 min and then washed out over a period of 20 min. Application of O2- increased the release of vasoconstrictive (TxA2 and PGF2alpha) and decreased vasodilating (PGI2 and PGE2) prostanoids. Although indomethacin (10 microM), a cyclooxygenase inhibitor, attenuated the rise in CPP during O2- perfusion, the increase was not completely blocked. OKY 046Na (10 microM), a thromboxane synthase inhibitor, had no effect on O2--induced increases in CPP, whereas ONO 3708 (10 microM), a TP receptor antagonist, suppressed this effect. PKC activity was also elevated by more than 50% by O2- perfusion. CPP typically increased throughout the O2- wash-out. This post-O2- vasoconstriction was not inhibited by indomethacin, nitroglycerin or nitrendipine. In contrast, ONO 3708 (10 microM) and two PKC inhibitors, staurosporine (10 nM) and calphostin C (100 nM), completely blocked the rise in CPP, and even elicited vasodilation. PDBu enhanced the post-O2- vasoconstriction. We conclude that O2--induced coronary vasoconstriction is initially mediated by TP receptors, but activation of PKC sustains the response.
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PMID:Activation of TxA2/PGH2 receptors and protein kinase C contribute to coronary dysfunction in superoxide treated rat hearts. 1088 48

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