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)

Diabetes mellitus is associated with an increased risk of cardiovascular disease. In order to elucidate the association between hyperglycemia and vascular complications, the growth patterns of vascular smooth muscle cells were studied under high glucose conditions. We examined the effect of culturing porcine aortic smooth muscle cells (PVSMC) in high glucose (25 mM, HG) on total cell protein, cell volume, DNA synthesis and cell number. We observed that cells cultured in HG had higher total cell protein content which was associated with increased cell volume as compared to the cells cultured under normoglycemic conditions (5.5 mM glucose, NG). PVSMC cultured in HG also had 1.4 fold increased growth rate and a greater fetal calf serum-induced DNA synthesis rate compared to cells cultured in NG. These observations suggest for the first time that elevated glucose could lead to both hypertrophic and hyperplastic effects in PVSMC. We also examined protein kinase C (PKC) activities as well as the cellular levels of the 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid (12-HETE) in NG and HG as possible mechanisms for the enhanced growth effects in HG. The results show that PVSMC cultured in HG have increased PKC activity as well as increased levels of 12-HETE. Therefore hyperglycemia may be linked to accelerated vascular disease by increasing smooth muscle cell growth and proliferation.
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PMID:Vascular smooth muscle cells exhibit increased growth in response to elevated glucose. 152 Mar 46

We have shown earlier that the 12-lipoxygenase product of arachidonic acid (AA), 12-hydroxyeicosatetraenoic acid (12-HETE), plays an important role in mediating angiotensin II (AII)-induced aldosterone secretion (J. Clin. Invest. (1987) 80, 1763). In the present study, we have evaluated whether diacylglycerol (DG) is the source of arachidonic acid giving rise to this 12-HETE. Treatment of rat adrenal glomerulosa cells with a DG lipase inhibitor, RHC 80267, which prevents conversion of DG to AA and HETEs, blocked AII-induced aldosterone and 12-HETE formation. In contrast, a DG kinase inhibitor, R59022, which prevents conversion of DG to phosphatidic acid, potentiated AII-induced aldosterone and 12-HETE formation. These two inhibitors block DG metabolism which would be expected to lead to increased DG levels and protein kinase C activity and AII-induced steroidogenesis. However, only R59022 potentiated AII action while RHC 80267 was inhibitory. This suggests that conversion of DG to AA and 12-HETE is important for AII action. Further proof for this was obtained by measuring [3H]AA-labeled DG levels. The combination of the inhibitors significantly potentiated AII-induced DG formation even though this same combination was inhibitory on AII-induced aldosterone and 12-HETE. Thus, the inhibitory effect of RHC 80267 is due to blockade of AA release and not of DG formation. These results suggest that DG plays a dual role in AII action, both as an activator of protein kinase C and as a source of AA for 12-HETE formation.
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PMID:Key role of diacylglycerol-mediated 12-lipoxygenase product formation in angiotensin II-induced aldosterone synthesis. 217 2

A variety of evidence indicates that activation of Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) in nerve terminals leads to enhanced neurotransmitter release. Arachidonic acid and its 12-lipoxygenase metabolite, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), have been suggested to act as second messengers mediating presynaptic inhibition of neurotransmitter release. In the present study it was found that CaM-kinase II, purified from rat brain cortex, was inhibited both by arachidonic acid (IC50 = 24 microM) and by 12-HPETE (IC50 = 0.7 microM). Neither substance inhibited CaM-kinase I or III, protein kinase C, or the catalytic subunit of cAMP-dependent protein kinase. Specific inhibition of Ca2+/calmodulin-dependent protein phosphorylation by arachidonic acid was also demonstrated in intact synaptic terminals (synaptosomes) isolated from rat forebrain. These results suggest that arachidonate and its metabolites may modulate synaptic function through the inhibition of CaM-kinase II-dependent protein phosphorylation.
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PMID:Inhibition of Ca2+/calmodulin-dependent protein kinase II by arachidonic acid and its metabolites. 255 19

To evaluate the regulation and effects of pancreatic islet lipoxygenase, adult rat islets were permeabilized, using digitonin or staphylococcal alpha-toxin, and then were studied in a medium simulating an intracellular milieu at fixed ambient concentrations of Ca2+. Permeabilized islets retained 12-lipoxygenase activity, as indicated by conversion of tritiated arachidonic acid to a predominant peak of [3H]12-hydroxyeicosatetraenoic acid (12-HETE); this activity was inhibited (89-98%) by the lipoxygenase blockers nordihydroguaiaretic acid (35 microM), BW755c (250 microM) or ETYA (35 microM). Lesser amounts of compounds coeluting with 15- and 11-HETE (but little or no 5-HETE) were formed; however, 11-HETE (and possibly some 15-HETE) was probably synthesized (at least in part) via cyclooxygenase, as suggested by the partial synthesis blockade induced by 50 microM ibuprofen. The production of 12-HETE did not require the presence of Ca2+, Mg2+ or ATP; it also was not stimulated by addition of cyclic AMP, a phorbol ester, or calmodulin. However, it was augmented modestly by provision of a basal cytosolic free Ca2+ concentration of 60-80 nM, with no further increase at physiologically elevated levels of 260-530 nM. Elevations in cytosolic free Ca2+ concentrations induced insulin release which was inhibited by cooling, epinephrine or protein kinase inhibitors and, therefore, was exocytotic in nature. Lipoxygenase inhibitors blocked this insulinotropic effect of calcium at submaximal or saturating Ca2+ concentrations (with or without its potentiation by 12-O-tetradecanoylphorbol-13-acetate, an activator of protein kinase C) by 53-82%. However, they did not reduce the Ca2+-independent secretory effects (at subnanomolar Ca2+ concentrations) of the phorbol ester alone. Similar results were seen using dibutyryl cyclic AMP to activate protein kinase A. The alpha 2-adrenergic agonists epinephrine or clonidine inhibited Ca2+-, TPA- or cyclic AMP-induced insulin release without reducing HETE formation. We conclude that (1) islet lipoxygenase is constitutively expressed and is not physiologically regulated by alpha 2-adrenergic agonism, Ca2+ or protein kinases; (2) lipoxygenase modulates insulin release; HETE production is not merely an epiphenomenon reflecting the activation (or inhibition) of exocytotic secretion; (3) islet lipoxygenase inhibitors reduce insulin secretion, at least in part, by blocking the direct effects of Ca2+ on exocytosis and/or its synergism with Ca2+-binding proteins such as protein kinase C; and (4) these same inhibitors do not directly poison protein kinase C or A, or the exocytotic apparatus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Blockade by lipoxygenase inhibitors of Ca2+-dependent insulin secretion from permeabilized rat islets. A molecular mechanism distinct from that of alpha 2-adrenergic agonists. 256 95

The lipoxygenase products of arachidonic acid metabolism have been shown to be important mediators of stimulus secretion coupling in various endocrine tissues. We have recently shown that the 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid plays a key role as a new specific mediator of angiotensin II-induced aldosterone secretion in the adrenal. In view of the several pathways by which cellular arachidonate can be generated and the important role of diacylglycerol in angiotensin II-responses, we studied the role of diacylglycerol as the source of arachidonic acid for 12-hydroxyeicosatetraenoic formation. Treatment of normal human adrenal glomerulosa cells with the selective diacylglycerol-lipase inhibitor, RHC 80267, resulted in a dose-dependent inhibition of angiotensin II-induced aldosterone as well as 12-hydroxyeicosatetraenoic formation. These results suggest that AA derived from diacylglycerol is the precursor of 12-hydroxyeicosatetraenoic involved in angiotensin II-induced aldosterone secretion. These results reveal a new second messenger role for diacylglycerol in addition to activation of protein kinase C.
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PMID:Diacylglycerol provides arachidonic acid for lipoxygenase products that mediate angiotensin II-induced aldosterone synthesis. 284 16

Phospholipase A2 inhibitors and lipoxygenase inhibitors markedly suppressed mouse skin ODC (ornithine decarboxylase) induction and promotion of papilloma by TPA. The inhibitory potency was related to the inhibition of epidermal 12-lipoxygenase. Lipoxygenase inhibitors, such as AA 861 and tetrahydrochalcone were lacking in the inhibitory action on protein kinase C. Moreover, palmitoylcarnitin, a protein kinase C inhibitor, inhibited TPA-induced differention of HL 60 cells and TPA-induced epidermal ODC induction and tumor promotion in mouse skin. Intraperitoneal injection of TPA also induced ODC in liver, kidney and spleen, but not in the skin of mice. In isolated mouse epidermal cells, TPA and diacylglycerol induced ODC. The induction of ODC was inhibited by phospholipase A2 inhibitors, lipoxygenase inhibitors, anticalmodulines, Ca++ entry blockers and Ca++ antagonists. These results indicate that intracellular Ca++ is involved in TPA induction of ODC.
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PMID:[Factors controlling tumor promotion induced by TPA]. 308 83

Both 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) and 3,4,2',4'-tetrahydroxychalcone inhibited 12-lipoxygenase of mouse epidermis. The IC50 of AA861 and 3,4,2',4'-tetrahydroxychalcone for epidermal 12-lipoxygenase were 1.9 and 0.2 microM, respectively. These agents showed very weak inhibitory actions on epidermal cyclooxygenase, with the potency of inhibition for cyclooxygenase less than 1/50 of that for lipoxygenase. Induction of epidermal ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate (TPA; 10 nmol/mouse) was potently inhibited by these agents in a dose-dependent manner (1-30 mumol/mouse). TPA (5 nmol/mouse)-induced skin tumor formation was also strongly suppressed by these agents (15 mumol/mouse). Both AA861 and 3,4,2',4'-tetrahydroxychalcone failed to inhibit partially purified epidermal protein kinase C activity. These results support the proposed involvement of lipoxygenase product(s) of arachidonic acid in TPA-induced skin tumor promotion.
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PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-mediated epidermal ornithine decarboxylase induction and skin tumor promotion by new lipoxygenase inhibitors lacking protein kinase C inhibitory effects. 309 75

12(S)-Hydroxyeicosatetraenoic acid [12(S)-HETE] is the 12-lipoxygenase metabolite of arachidonic acid. Previously, we have demonstrated that exogenous 12(S)-HETE can activate protein kinase C, increase cell surface expression of integrins, enhance adhesion, induce endothelial cell retraction, and increase experimental metastasis of tumor cells. Because of these prominent effects of exogenous 12(S)-HETE on tumor cell metastatic potential, it is important to determine whether there is endogenous 12(S)-HETE production by tumor cells. In the present study, mRNAs from human, rat, and mouse platelets as well as human colon carcinoma (Clone A), rat Walker carcinoma (W256), and mouse melanoma (B16a) and lung carcinoma (3LL) were reverse transcribed and amplified by polymerase chain reaction with platelet 12-lipoxygenase specific primers. Identity of the polymerase chain reaction fragments was confirmed by sequencing. 12-Lipoxygenase protein was detected by Western blotting. Tumor cell-derived 12-HETE was determined by reverse phase-high performance liquid chromatography analysis. In addition, the effect of endogenous 12(S)-HETE on tumor cells was studied by using a platelet-type 12-lipoxygenase selective inhibitor (N-benzyl-N-hydroxy-5-phenylpentanamide). Our results suggest that some tumor cells express platelet-type 12-lipoxygenase mRNA, protein and metabolize arachidonic acid to 12(S)-HETE and that endogenous 12(S)-HETE, like the exogenous 12(S)-HETE, may play an important role in tumor cell adhesion to matrix in vitro and lung colonization in vivo.
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PMID:Endogenous 12(S)-HETE production by tumor cells and its role in metastasis. 751 Oct 46

The process of tumor cell invasion of the basement membrane is proposed to consist of three steps: attachment, local proteolysis and migration. 12-(S)-HETE, a 12-lipoxygenase metabolite of arachidonic acid, upregulates surface expression of integrin cytoadhesins and an autocrine motility factor receptor, suggesting that this metabolite may play an important regulatory function in tumor cell invasion. In the present study, we determined whether 12-(S)-HETE affects surface expression and/or release of cathepsin B, a cysteine protease that has been implicated in focal degradation of basement membrane. Secretion and distribution of cathepsin B was evaluated in two model systems for various stages of neoplastic progression: (i) murine B16 melanoma lines of low (B16-F1) and high (B16a) lung colonization potential, and (ii) immortalized and ras-transfected MCF-10 human breast epithelial cells that differ in their invasive capacities in vitro. In the B16a cells, 12-(S)-HETE induced release of native and latent cathepsin B activity and concomitantly reduced cell-associated cathepsin B immunoreactivity. In contrast, 12-(S)-HETE did not induce the release of cathepsin B from B16-F1 cells, suggesting that there may be an enhanced response to 12-(S)-HETE in more malignant cells. This was confirmed in the MCF-10 system, in which 12-(S)-HETE was able to induce the release of cathepsin B from the ras-transfected cells, but not from the immortal cells. A simultaneous reduction in staining for cathepsin B was observed in the ras-transfected cells, but not in their immortal counterparts. The release of cathepsin B may be mediated by PKC as pretreatment of B16a cells with the selective PKC inhibitor calphostin C, but not with the PKA inhibitor H8, prevented the stimulated release of cathepsin B. In B16a cells, the release of cathepsin B was accompanied by a translocation toward the cell periphery of vesicles staining for cathepsin B, resulting in focal areas of accumulation of cathepsin B. After 12-(S)-HETE stimulation of the ras-transfected MCF-10 cells, cathepsin B was distributed homogeneously on the apical surface. Thus, 12-(S)-HETE can upregulate the surface expression on tumor cells of proteins able to mediate each of the three steps of tumor cell invasion: adhesion, degradation, and migration.
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PMID:A lipoxygenase metabolite, 12-(S)-HETE, stimulates protein kinase C-mediated release of cathepsin B from malignant cells. 752 40

Epidermal growth factor (EGF) increases 12-lipoxygenase mRNA by about 2-fold with a lag period of 4 to 8 hr, which precedes the increase in 12-lipoxygenase activity by 2 to 4 hr in human epidermoid carcinoma A431 cells. Induction of 12-lipoxygenase expression in human erythroleukemia cells by phorbol 12-myristate 13-acetate (PMA) has been reported previously. The present report describes a study of the involvement of protein kinase C (PKC) in EGF-induced 12-lipoxygenase expression in A431 cells. EGF-induced 12-lipoxygenase expression was inhibited by methyl 2,5-dihydroxycinnamate, a tyrosine kinase inhibitor. Staurosporine and calphostin C, which are two PKC inhibitors, inhibited EGF-induced enzyme activity and mRNA expression of 12-lipoxygenase. 1,2-Dioctanoyl-sn-glycerol (a membrane-permeant diacylglycerol) and PMA significantly induced enzyme activity and mRNA expression. Simultaneous treatment of cells with EGF and PMA did not exhibit an additive effect, suggesting that EGF and PMA share a common biochemical pathway in 12-lipoxygenase induction. Expression of mRNA for PKC alpha, delta and zeta was detected in A431 cells, whereas no mRNA expression for PKC beta 1, gamma and epsilon was observed. Taken together, these results suggest that EGF-induced 12-lipoxygenase expression is at least in part mediated by the PKC signal transduction pathway.
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PMID:Induction of 12-lipoxygenase expression by epidermal growth factor is mediated by protein kinase C in A431 cells. 752 31


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