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)

1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation were measured simultaneously in strips from the body of rat urinary bladder. 2. [3H]NA and [14C]ACh release was greater during continuous stimulation (CS; 10 Hz, 100 shocks) or in the presence of eserine than during intermittent train stimulation (IS; 10 Hz, 10 shocks every 5 s, 10 times). Atropine (1 microM) or pirenzepine (0.05-0.1 microM) blocked the CS- or eserine-facilitated release. 3. The protein kinase C (PKC) activator phorbol dibutyrate (PDB; 0.05 and 0.5 microM) increased the release of both [3H]NA and [14C]ACh in a concentration-dependent manner. Atropine blocked the PDB-induced facilitation of ACh release but not the facilitation of NA release. 4. The protein kinase A (PKA) activator 8-Br-cAMP did not affect ACh release but enhanced NA release. 5. The PKC inhibitor H-7 (50-100 microM) inhibited the CS- or eserine-facilitated release of both ACh and NA, but did not affect the non-facilitated release evoked by IS. H-7 also inhibited 0.5 microM PDB-induced facilitation of ACh release but not NA release. 6. Down-regulating PKC by pretreatment for 30 min with 5 microM PDB decreased the facilitated release of ACh and the eserine-induced facilitation of NA release. 7. Electrically evoked contractions of the bladder strips exhibited a biphasic response to PDB (2.5 microM), which consisted of an initial enhancement of the peak amplitude and area followed after 20 min by an inhibition of contractions. H-7 inhibited the electrically evoked contractions in a dose-dependent fashion. 8. It is concluded that a phospholipase C-PKC signal transduction pathway is essential for muscarinic receptor-induced facilitation of ACh and NA release but is not involved in the non-facilitated release of transmitters in the rat urinary bladder.
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PMID:M1 muscarinic receptor-induced facilitation of ACh and noradrenaline release in the rat bladder is mediated by protein kinase C. 891 Feb 12

Protein kinase D (PKD) is a serine/threonine protein kinase that is directly stimulated in vitro by phorbol esters and diacylglycerol in the presence of phospholipids. Here, we examine the regulation of PKD in living cells. Our results demonstrate that tumour-promoting phorbol esters, membrane-permeant diacylglycerol and serum growth factors rapidly induced PKD activation in immortalized cell lines (e.g. Swiss 3T3 and Rat-1 cells), in secondary cultures of mouse embryo fibroblasts and in COS-7 cells transiently transfected with a PKD expression construct. PKD activation was maintained during cell disruption and immunopurification and was associated with an electrophoretic mobility shift and enhanced 32P incorporation into the enzyme, but was reversed by treatment with alkaline phosphatase. PKD was activated, deactivated and reactivated in response to consecutive cycles of addition and removal of PDB. PKD activation was completely abrogated by exposure of the cells to the protein kinase C inhibitors GF I and Ro 31-8220. In contrast, these compounds did not inhibit PKD activity when added directly in vitro. Co-transfection of PKD with constitutively activated mutants of PKCs showed that PKCepsilon and eta but not PKCzeta strongly induced PKD activation in COS-7 cells. Thus, our results indicate that PKD is activated in living cells through a PKC-dependent signal transduction pathway.
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PMID:Protein kinase D (PKD) activation in intact cells through a protein kinase C-dependent signal transduction pathway. 894 45

Cycloheterophyllin, a prenylflavone, inhibited the superoxide anion (O2-) generation from formylmethionyl-leucyl-phenylalanine (fMLP)- and phorbol 12-myristate 13-acetate (PMA)-stimulated rat neutrophils in a concentration-dependent manner with IC50 values of 47.0 +/- 5.0 and 1.7 +/- 0.4 microM, respectively. Cycloheterophyllin had no effect on O2- generation in xanthine-xanthine oxidase system and during dihydroxyfumaric acid (DHF) autoxidation. Cycloheterophyllin exerted a concentration-dependent inhibition of neutrophil cytosolic protein kinase C (PKC) and rat brain PKC, but had no effect on porcine heart protein kinase A (PKA). Unlike staurosporine, cycloheterophyllin did not affect the trypsin-treated rat brain PKC. [3H]Phorbol 12,13-dibutyrate ([3H]PDB) binding to neutrophil cytosolic PKC was significantly suppressed by cycloheterophyllin. However, cycloheterophyllin had negligible effect on the PMA-induced membrane translocation of PKC-beta and PKC-delta in neutrophils. Moreover, the fMLP-induced [Ca2+]i elevation and inositol trisphosphate (IP3) formation of neutrophils were not affected by cycloheterophyllin at concentrations which significantly suppressed the O2- generation. In cell-free system, addition of arachidonate (AA) into the mixture of cytosol and membrane fractions of the resting neutrophils to make NADPH oxidase assembly and activation. Cycloheterophyllin had no effect on O2- generation in AA-activated cell-free system. These results suggest that the suppression of PKC activity through the interaction with the regulatory region of PKC is involved in the inhibition by cycloheterophyllin of the O2- generation in rat neutrophils.
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PMID:Blockade of protein kinase C is involved in the inhibition by cycloheterophyllin of neutrophil superoxide anion generation. 915 Dec 91

We compared the effects of guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS, an activator of G-protein), phorbol 12,13-dibutylate (PDB, an activator of protein kinase C) and pimobendan (an inotropic agent with Ca2+-sensitizing action) on the Ca2+ sensitivity of the contractile proteins in beta-escin-skinned muscle preparations obtained from rabbit left ventricles and mesenteric arteries. After the skinning procedure, when GTPgammaS (100 microM) or PDB (1 microM) was added to the Ca2+ solutions, pCa50 were significantly increased in preparations obtained from vascular smooth muscle, but not from cardiac muscle, indicating that G-protein- and protein kinase C-mediated direct Ca2+ sensitization may occur only in smooth muscle, but not in cardiac muscle. In contrast, pimobendan (50 microM) increased the Ca2+ responsiveness only in cardiac muscle. Therefore, we conclude that, in addition to the common regulatory factors affecting Ca2+ sensitivity such as intracellular pH and phosphorylation by protein kinase A, there are other means of regulation of Ca2+ sensitivity working differently in cardiac and in vascular smooth muscles.
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PMID:Different regulation of myofilament Ca2+ sensitivity in beta-escin-skinned cardiac and vascular smooth muscles. 919 68

We have analyzed the differentiation program of growth factor-dependent TF-1 erythroleukemia cells as well as clones with inducible expression of the APL-specific PML/RARalpha protein. We have shown that TF-1 cells may be induced to megakaryocytic differentiation by phorbol ester (phorbol dibutyrate, PDB) addition, particularly when combined with thrombopoietin (Tpo). RT-PCR studies showed that Tpo induces Tpo receptor (TpoR or c-mpl), whose expression was further potentiated by PDB addition. When the cells are induced with both PDB and Tpo erythropoietin receptor (EpoR) expression was inhibited. In the absence of Zn2+-induced PML/RARalpha expression, PDB and Tpo induced megakaryocytic differentiation of TF-1 MTPR clones as observed in 'wild-type' TF-1 cells. Conversely, when PML/RARalpha expression was induced by Zn2+, PDB and Tpo treatment of these clones caused only a reduced level of megakaryocytic differentiation. These observations indicate that: (1) TF-1 cells as well as other erythroleukemic cells, possess the capacity to differentiate to megakaryocytic cells when grown in the presence of protein kinase (PKC) activators and more efficiently when combined with Tpo; (2) the PML/RARalpha gene has a wide capacity to interfere with the program of hematopoietic differentiation, including megakaryocytic differentiation. Finally, we also observed that PML/RARalpha expression in TF-1 cells induces an up-modulation of interleukin-3 receptor, c-kit and c-mpl, a phenomenon which may offer these cells a growth advantage.
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PMID:Terminal megakaryocytic differentiation of TF-1 cells is induced by phorbol esters and thrombopoietin and is blocked by expression of PML/RARalpha fusion protein. 955 15

Protein kinase D (PKD) is a protein serine kinase that is directly stimulated in vitro by phorbol esters and diacylglycerol in the presence of phospholipids, and activated by phorbol esters, neuropeptides, and platelet-derived growth factor via protein kinase C (PKC) in intact cells. Recently, oxidative stress was shown to activate transfected PKC isoforms via tyrosine phosphorylation, but PKD activation was not demonstrated. Here, we report that oxidative stress initiated by addition of H(2)O(2) (0.15-10 mm) to quiescent Swiss 3T3 fibroblasts activates PKD in a dose- and time- dependent manner, as measured by autophosphorylation and phosphorylation of an exogenous substrate, syntide-2. Oxidative stress also activated transfected PKD in COS-7 cells but not a kinase-deficient mutant PKD form or a PKD mutant with critical activating serine residues 744 and 748 mutated to alanines. Genistein, or the specific Src inhibitors PP-1 and PP-2 (1-10 micrometer) inhibited H(2)O(2)-mediated PKD activation by 45%, indicating that Src contributes to this signaling pathway. PKD activation by H(2)O(2) was also selectively potentiated by cotransfection of PKD together with an active form of Src (v-Src) in COS-7 cells, as compared with PDB-mediated activation. The specific phospholipase C inhibitor, partly blocked H(2)O(2)-mediated but not PDB-mediated PKD activation. In contrast, PKC inhibitors blocked H(2)O(2) or PDB-mediated PKD activation essentially completely, suggesting that whereas Src mediates part of its effects via phospholipase C activation, PKC acts more proximally as an upstream activator of PKD. Together, these studies reveal that oxidative stress activates PKD by initiating distinct Src-dependent and -independent pathways involving PKC.
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PMID:Oxidative stress induces protein kinase D activation in intact cells. Involvement of Src and dependence on protein kinase C. 1074 11

A DNA fragment containing 1.5 kb of the 5'-flanking region of the human ubiquitous PFKFB3 gene, coding for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, was cloned and its promoter activity was examined. The 5' flanking region contains a TATA box-like and GC-rich sequences, yielding several potential Specific protein (Sp-1) and activator protein (AP)-2 binding sites. Putative regulatory motifs for E-box, nuclear factor (NF)-1 and progesterone response element were also found by computer assisted analysis. Transient expression assays of truncated promoter-reporter constructs in HeLa cells showed that this gene is induced by phorbol esters (PDB) and cyclic-AMP-dependent protein kinase signal activation. Furthermore, the genomic organization of the PFKFB3 gene is reported. This gene spans more than 26 kb containing at least 16 exons that accounts for the two reported isoforms, inducible and ubiquitous, generated through alternative splicing of exon 15.
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PMID:The human ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene (PFKFB3): promoter characterization and genomic structure. 1124 87

Sodium fluoride (NaF) has previously been reported to induce a strong IL-8 response in human epithelial lung cells (A549) via mechanisms that seem to involve the activation of G proteins. In the present study the signal pathways downstream of the G proteins have been examined. NaF induced a weak, but sustained increase in PKC activity. In contrast, the PKC activator TPA induced a relatively strong, but transient effect and augmented the NaF-induced PKC activity. TPA induced a marked IL-8 response compared to NaF. PDB, another PKC activator, was less effective, but augmented the IL-8 response to NaF. Pretreatment with TPA for 20 h, or the PKC inhibitor GF109203X for 1 h, abolished the basal and NaF-induced PKC activities and partially prevented the NaF-induced IL-8 response. Inhibition of the MAP kinase p38 by SB202190 partially reduced the IL-8 response to NaF, whereas a reduction in ERK activity by PD98059 led to an increased response. The NaF-induced IL-8 response was weakly augmented by the PKA stimulator forskolin and the G(i) inhibitor pertussis toxin. The PKA inhibitor H89 seemed to reduce the NaF-induced IL-8 response, but the measured effect was not statistically significant. BAPTA-AM, KN93 and W7, that inhibit Ca(2+)-linked effects, did not affect the IL-8 response. Furthermore, the tyrosine kinase inhibitor genestein, the PI-3 kinase inhibitor wortmannin and phosphatase inhibition were without effects. In conclusion, the data suggest that NaF-induced increase of IL-8 in A549 cells involved PKC- and p38-linked pathways, whereas an ERK-dependent pathway counteracted the response. Tyrosine kinases, Ca(2+)-linked pathways, PI-3 kinase, PKA and phosphatase inhibition seem to play no or minor roles in the fluoride-induced IL-8 response.
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PMID:Mechanisms in fluoride-induced interleukin-8 synthesis in human lung epithelial cells. 1156 78

Cyclic-GMP-dependent protein kinase (PKG) is widely appreciated as having diverse roles in a variety of cell types. Many reports have indicated that PKG might regulate cell function by activating members of the mitogen-activated protein kinase (MAPK) family of signaling proteins. In this study, stimulation of HEK-293 cells with nitric oxide (NO) was found to induce a rapid accumulation of phosphorylated p38 MAPK. The involvement of PKG in this process was confirmed by cotransfection of a dominant negative PKG construct (G1alphaR-GFP), which was able to block cGMP-induced p38 MAPK activation. Transfection of cells to express dominant negative Rac1(T17N) was also able to dose-dependently block cGMP-stimulated activation of p38 MAPK, thus indicating the importance of this pathway downstream of PKG. GST-PDB affinity-precipitation experiments revealed that stimulation of HEK293 cells with either nitric oxide or 8-Br-cGMP resulted in a rapid and transient activation of Rac1 with similar kinetics to p38 MAPK phosphorylation. Moreover, using in vitro kinase assays it was found that cGMP also stimulated the activity of the Rac1 effector Pak1. The activation of both Rac1 and Pak1 by 8-Br-cGMP was completely abolished by transfection of the cells with G1alphaR-GFP. Expression of the Rac1(T17N) mutant inhibited PKG-dependent activation of PAK1 indicating that Rac1 functions upstream of PAK1 in this pathway. Immunofluorescence experiments demonstrated clear colocalization of PKG and Rac1 in membrane ruffles and dynamic membrane regions supporting a functional interaction. However, in vitro kinase assays demonstrated that Rac1 is not a substrate for PKG suggesting an indirect activation mechanism. Taken together these data demonstrate a novel PKG-dependent pathway by which the Rac1/Pak1 pathway is activated. Furthermore, we demonstrate that this pathway is central to the activation of p38 MAPK by PKG in these cells.
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PMID:Activation of the small GTPase Rac1 by cGMP-dependent protein kinase. 1521 66

Since Calcitonin (CT) inhibits osteoclastic bone resorption, it has been widely used to treat metabolic bone disorders, such as Paget's disease of bone, malignancy-associated hypercalcemia, and osteoporosis. It is recognized, however, that continuous treatment with CT causes a loss of its inhibitory effects on bone resorption. We and other investigators have studied the mechanism and the results indicated that desensitization to CT was closely associated with the down regulation of the CT receptor (CTR). This down regulation was due not only to internalization of the receptor but also to reduced cell surface receptor concentration through inhibition of de novo CTR synthesis. An essential signal for osteoclast differentiation from its precursor cells, which was termed as ODF, was also found identical to tumor necrosis factor (TNF) related activation induced cytokine (TRANCE) and receptor activator of nuclear factor-kappa B ligand (RANKL). Using soluble RANKL and macrophage colony stimulating factor, we recently studied the mechanisms of the biological responses to CT in cells of human osteoclast lineage. The signaling pathway responsible for CTR down regulation in human osteoclasts is different from that observed in mouse osteoclasts: the activation of protein kinase A pathway is primarily responsible for CTR regulation in mouse osteoclasts, while the activation of protein kinase C was predominant in humans. Treatment with CT reduced concentration of cellular surface CTR and CTR mRNA expression also in human osteoclasts. The reduced specific binding, CTR mRNA levels and CT-sensitive adenylate cyclase responsiveness returned to the control levels by 96h after removal of CT. These results may suggest that intermittent administration of CT would be effective for the treatment of osteoporosis, resulting in reduced desensitization in CT target cells.
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PMID:[Appropriate clinical usage of calcitonin escape phenomenon and intermittent v.s. daily administration of calcitonin]. 1577 28


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