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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the effects of endogenous lipoxygenase products on basal progesterone (P4) production by cultured bovine mid-luteal cells. The involvement of lipoxygenase products in the stimulatory effect of LH on luteal cAMP accumulation and P4 production was also examined. Bovine luteal cells from mid-cycle corpora lutea (CL) were exposed for 16 h to a lipoxygenase inhibitor (nordihydroguaiaretic acid: NDGA; 0.33-33 microM). For the last 4 h of incubation, the cells were exposed to LH and/or three different lipoxygenase products, 5-, 12- and 15-hydroxyeicosatetraenoic acid (HETE). NDGA inhibited P4 production by the cells in a dose-dependent manner (P < 0.05). NDGA-reduced P4 production was reversed by the addition of 12-HETE, but not 5- or 15-HETE, whereas 5-, 12- and 15-HETE alone showed no significant effect on P4 production in the intact cells. Furthermore, NDGA (33 microM) blocked the stimulatory action of LH on P4 production (P < 0.05), without changing cAMP accumulation (P > 0.1). When the cells were exposed to 5-, 12- or 15-HETE with LH and NDGA, only 15-HETE maintained the stimulatory effect of LH on P4 production in the cells (P < 0.05). These results suggest that endogenous lipoxygenase products play important roles in P4 production by bovine CL, i.e. basal P4 production is supported by 12-HETE, and LH-stimulated P4 production is partially mediated via the activation of lipoxygenase and subsequent 15-HETE formation downstream of the LH-activated cAMP-PKA-phosphorylation pathway.
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PMID:The lipoxygenase pathways are involved in LH-stimulated progesterone production in bovine corpus luteum. 1178 97

Histamine and arachidonic acid (AA) release was measured using the P2-purinoceptor antagonists, phospholipase A2 (PLA2) and cyclooxygenase (COX)/lipoxygenase (LOX) inhibitors to determine whether or not ATP-induced histamine release is associated with arachidonic acid (AA) release in rat peritoneal mast cells. ATP increased histamine release in a dose dependent manner, whereas adenosine did not. PPADS (a selective P2X-purinoceptor antagonist) and suramin (a nonselective P2X,2Y-purinoceptor antagonist) inhibited ATP-induced histamine release in a dose dependent manner. However, RB-2 (a P2Y-purinoceptor antagonist) did not block ATP-induced histamine release. Manoalide and oleyloxyethyl phosphorylcholine (OPC), secretory PLA2 inhibitors, also inhibited ATP-induced histamine release dose-dependently. Both COX inhibitors (ibuprofen and indomethacin) and LOX inhibitors (baicalein and caffeic acid) inhibited ATP-induced histamine in a dose dependent manner. ATP significantly increased [3H]AA release by 54%. PPADS and suramin significantly inhibited ATP-induced [3H]AA release by 81% and 39%, respectively. ATP-induced histamine release was significantly inhibited by a variety of protein kinase inhibitors, such as bisindolmaleimide, genistein, methyl 2,5-dihydroxycinnamate, W-7 and trifluoperazine. Overall, the results suggest that ATP-induced histamine release is in part related to the PLA2-mediated AA metabolism and P2X-purinoceptors.
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PMID:ATP-induced histamine release is in part related to phospholipase A2-mediated arachidonic acid metabolism in rat peritoneal mast cells. 1179 34

Cell adhesion to the extracellular matrix via integrins is a primary regulatory mechanism for numerous aspects of normal cellular function. However, disruption of this interaction can result in pathology. For example, one characteristic of transformed cells is loss of adhesion dependence for viability. Adhesion also is a necessary step in tumor metastasis. It has been shown previously, in HeLa cells, that cell attachment to a gelatin-coated substrate results in the release of arachidonic acid, which is metabolized by lipoxygenase. A subsequent cascade of lipid second messengers activates protein kinase C, which triggers actin polymerization leading to cell spreading. We now demonstrate by inhibitor studies and biochemical analysis, a parallel branch of arachidonic acid signaling that reorganizes the actin cytoskeleton into small bundles. This branch of the pathway is initiated by cyclooxygenase, which generates prostaglandins and causes the downstream activation of cyclic AMP-dependent protein kinase. This work elucidates a system of interacting signals in which arachidonic acid functions at a branch point in cytoskeletal signaling. The lipoxygenase branch provides polymerized actin; these actin filaments act as a substrate for the cylooxygenase branch to generate actin bundles.
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PMID:Arachidonic acid signaling to the cytoskeleton: the role of cyclooxygenase and cyclic AMP-dependent protein kinase in actin bundling. 1221 Nov 5

A series of inhibitors were tested to determine the participation of de novo protein synthesis, protein kinase activity, extracellular Ca2+, and lipoxygenase activity in arachidonic acid elicitation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) gene expression and sesquiterpene phytoalexin biosynthesis in potato (Solanum tuberosum L. cv Kennebec). Gene-specific probes were used to discriminate effects on the expression of two HMGR genes (hmg1 and hmg2) that respond differentially in tuber tissue following wounding or elicitor treatment. Inhibition of protein synthesis with cycloheximide completely blocked arachidonate-induced hypersensitive necrosis and browning, including HMGR gene induction and phytoalexin accumulation. This suggests that proteins necessary for coupling arachidonic acid reception to HMGR mRNA accumulation are either rapidly turned over or not present constitutively and are induced following elicitor treatment. Staurosporin, a potent inhibitor of protein kinases, and ethyleneglycol-bis([beta]-aminoethyl ether)-N,N[prime]-tetraacetic acid, a Ca2+ chelator, inhibited arachidonate-induction of hmg2 gene expression and phytoalexin accumulation but did not inhibit the wound-induced expression of hmg1. However, staurosporin inhibited arachidonate's suppression of hmg1 gene expression. Eicosatetraynoic acid, a lipoxygenase inhibitor that suppresses elicitor-induced phytoalexin accumulation, also inhibited arachidonate's suppression of hmg1 and induction of hmg2. The results indicate that arachidonate's suppression of hmg1 and activation of hmg2 depend on a common intermediate or set of intermediates whose generation is sensitive to the inhibitors tested.
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PMID:Involvement of de Novo Protein Synthesis, Protein Kinase, Extracellular Ca2+, and Lipoxygenase in Arachidonic Acid Induction of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Genes and Isoprenoid Accumulation in Potato (Solanum tuberosum L.). 1223 62

We evaluated the role of lipoxygenase products of arachidonic acid metabolism in mechanical hyperalgesia induced by epinephrine, an agent that directly sensitizes nociceptors to produce mechanical hyperalgesia via three second messenger signaling pathways, protein kinase A (PKA), protein kinase C epsilon (PKCepsilon), and mitogen activated protein kinase (MAPK). Epinephrine hyperalgesia and that induced by a selective activator of PKCepsilon, psiepsilonRACK, were inhibited by nordihydroguaretic acid (NDGA, non-selective lipoxygenase inhibitor), baicalein (BAIC, 12-lipoxygenase inhibitor) and 5, 6-dehydroarachidonic acid (5, 6-dhAA, 5-lipoxygenase inhibitor). NDGA and 5, 6-dhAA inhibited the hyperalgesia associated with activation of the protein kinase A pathway, elicited by the direct-acting hyperalgesic agent prostaglandin E(2) or by the catalytic subunit of protein kinase A. The hyperalgesia produced by active MAPK was not blocked by any of the lipoxygenase inhibitors. Injection of 5- and 12-lipoxygenase produced hyperalgesia that was not antagonized by inhibitors of PKA, PKCepsilon or MAPK. These findings suggest that: (1). lipoxygenase products of arachidonic acid function as second messengers in the peripheral hyperalgesia induced by agents that act directly on primary afferent nociceptors (epinephrine and prostaglandin E(2)), (2). products of the 5-lipoxygenase and 12-lipoxygenase pathway are involved in this function, and (3). these lipoxygenase products contribute to hyperalgesia at or downstream of protein kinase A and PKCepsilon.
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PMID:Contribution of 5- and 12-lipoxygenase products to mechanical hyperalgesia induced by prostaglandin E(2) and epinephrine in the rat. 1258 31

The arachidonic acid metabolite of 12 lipoxygenase, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) promotes metastatic behavior of tumor cells (1). In this study we set out to identify 12(S)-HETE stimulated signaling pathways, and their contribution to cellular functions in A431 epidermoid carcinoma. 1) 12(S)-HETE signaling involves extracellular-regulated protein kinase (ERK1/2), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3 kinase) and Src kinase. 2) 12(S)-HETE stimulates cell migration on laminin, which is eliminated by PKC and PI3 kinase inhibitors, reduced by 50% with Src inhibitor, but unaffected by inhibition of ERK1/2. 3) 12(S)-HETE stimulated spreading on fibronectin relies on ERK1/2 and PI3 kinase activities, but not on PKC or Src. 4) Focal adhesion kinase, a key organizer of focal adhesions, is tyrosine phosphorylated in response of 12(S)-HETE treatment, which requires Src, but not PKC, PI3 kinase or ERK1/2 activity. 5) Inhibition of 12 lipoxygenase leads to apoptosis in serum starved A431 cells. 12(S)-HETE stimulated p90Rsk and Akt, key players in an ERK and a PI3 kinase (respectively) dependent anti apoptotic pathways.
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PMID:12(S)-HETE, pleiotropic functions, multiple signaling pathways. 1266 33

The adhesion of a cell to its surrounding matrix is a key determinant in many aspects of cell behavior. Adhesion consists of distinct stages : attachment, cell spreading, motility, and/or immobilization. Interrelated signaling pathways regulate these stages, and many adhesion-related signals control the architecture of the cytoskeleton. The various cytoskeletal organizations then give rise to the specific stages of adhesion. It has been shown that arachidonic acid acts at a signaling branch point during cell attachment. Arachidonic acid is metabolized via lipoxygenase to activate actin polymerization and cell spreading. It is also metabolized by cyclooxygenase to generate small actin bundles. We have used confocal microscopy and indirect immunofluorescence to investigate the structure of these cyclooxygenase dependent actin bundles in HeLa cells. We have also employed cell migration assays and pharmacological modulation of cyclooxygenase and downstream signals. The results indicate that cyclooxygenase and PKA stimulate the formation of actin bundles that contain myosin II and associate with small focal adhesions. In addition, we demonstrate that this cytoskeletal organization correlates with increased cell motility.
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PMID:Cyclooxygenase and cAMP-dependent protein kinase reorganize the actin cytoskeleton for motility in HeLa cells. 1284

Angiotensin (Ang) peptides play a critical role in regulating vascular reactivity and structure. We showed that Ang-(1-7) reduced smooth muscle growth after vascular injury and attenuated the proliferation of vascular smooth muscle cells (VSMCs). This study investigated the molecular mechanisms of the antiproliferative effects of Ang-(1-7) in cultured rat aortic VSMCs. Ang-(1-7) caused a dose-dependent release of prostacyclin from VSMCs, with a maximal release of 277.9+/-25.2% of basal values (P<0.05) by 100 nmol/L Ang-(1-7). The cyclooxygenase inhibitor indomethacin significantly attenuated growth inhibition by Ang-(1-7). In contrast, neither a lipoxygenase inhibitor nor a cytochrome p450 epoxygenase inhibitor prevented the antiproliferative effects of Ang-(1-7). These results suggest that Ang-(1-7) inhibits vascular growth by releasing prostacyclin. Ang-(1-7) caused a dose-dependent release of cAMP, which might result from prostacyclin-mediated activation of adenylate cyclase. The cAMP-dependent protein kinase inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate attenuated the Ang-(1-7)-mediated inhibition of serum-stimulated thymidine incorporation. Finally, Ang-(1-7) inhibited Ang II stimulation of mitogen-activated protein kinase activities (ERK1/2). Incubation of VSMCs with concentrations of Ang-(1-7) up to 1 micromol/L had no effect on ERK1/2 activation. However, preincubation with increasing concentrations of Ang-(1-7) caused a dose-dependent reduction in Ang II-stimulated ERK1/2 activities. Ang-(1-7) (1 micromol/L) reduced 100 nmol/L Ang II-stimulated ERK1 and ERK2 activation by 42.3+/-6.2% and 41.2+/-4.2%, respectively (P<0.01). These results suggest that Ang-(1-7) inhibits vascular growth through the release of prostacyclin, through the prostacyclin-mediated production of cAMP and activation of cAMP-dependent protein kinase, and by attenuation of mitogen-activated protein kinase activation.
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PMID:Molecular mechanisms of inhibition of vascular growth by angiotensin-(1-7). 1295 14

The mechanism by which the tumour product proteolysis-inducing factor (PIF) induced increased expression of the ubiquitin-proteasome proteolytic pathway was studied in C2C12 murine myotubes. PIF directly increased total protein breakdown at concentrations between 4 and 16 nM, and the effect was attenuated by eicosapentaenoic acid (EPA) and the 12/15-lipoxygenase inhibitor 2,3,5-trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504). PIF induced an increased expression of mRNA for proteasome alpha (C2) and beta (C5) subunits over the same concentration range as that inducing protein degradation and with a maximal effect 4 h after PIF addition. The effect was attenuated by both EPA and CV-6504, suggesting the role of a lipoxygenase metabolite in the increased gene transcription. 15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE], an intermediate in intracellular signalling by PIF was shown to activate protein kinase Calpha(PKC) over the same concentration range as that inducing proteasome expression and both effects were attenuated by calphostin C, a highly specific inhibitor of PKC. 15(S)-HETE induced phosphorylation and degradation of IkappaBalpha at the same concentrations as those inducing 20S proteasome expression, and this effect was attenuated by calphostin C, suggesting the mediation of PKC. These results suggest potential control points in proteasome activation that could be useful for therapeutic intervention.
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PMID:Signalling pathways in the induction of proteasome expression by proteolysis-inducing factor in murine myotubes. 1545 Oct 26

The dietary cis-polyunsaturated fatty acid, arachidonic acid, stimulates adhesion of metastatic human breast carcinoma cells (MDA-MB-435) to the extracellular matrix, but the molecular mechanisms by which fatty acids modify the behavior of these cells are unclear. Exposure to arachidonic acid activates multiple signaling pathways. Activation of p38 mitogen-activated protein kinase (p38 MAPK) is required for increased cell adhesion to type IV collagen, and this activation is sensitive to inhibitors of lipoxygenases, suggesting a requirement for arachidonic acid metabolism. The goals of the current study were to identify the one or more key metabolites of arachidonic acid that are responsible for activation of p38 MAPK and to elucidate the upstream kinases that lead to p38 MAPK activation. High performance liquid chromatographic analysis revealed that MDA-MB-435 cells metabolize exogenous arachidonic acid predominantly to 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE). Immunoblot analysis with antibodies specific to 15(S)-lipoxygenase-1 (LOX-1) and 15(S)-lipoxygenase-2 (LOX-2) demonstrated the expression of 15-LOX-2, but not 15-LOX-1, in these tumor cells. A LOX inhibitor, nordihydroguaiaretic acid, attenuated production of 15(S)-HETE and inhibited the phosphorylation of p38 MAPK following exposure to arachidonic acid. In contrast, overexpression of LOX-2 sensitized the cells to the addition of arachidonic acid, leading to increased activation of p38 MAPK. Addition of exogenous 15(S)-HETE to MDA-MB-435 cells stimulated cell adhesion to type IV collagen and activated the p38 MAPK pathway, including the upstream kinases transforming growth factor-beta1-activated protein kinase-1 (TAK1) and MAPK kinase 6. Transfection of these cells with a dominant negative form of TAK1 blocked arachidonic acid-stimulated p38 MAPK phosphorylation. These data demonstrate that 15(S)-LOX-2 generation of 15(S)-HETE activates specific growth factor receptor-related signaling pathways, thereby initiating signal transduction events leading to increased cell adhesion to the extracellular matrix.
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PMID:15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. 1600 Mar 13


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