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)

The phenobarbital-induced activation of cytochrome P4502H1 (CYP2H1) and 5-aminolevulinate synthase (ALAS-1) genes in chick embryo hepatocytes occurs at the level of gene transcription, but the molecular mechanism underlying this induction is not understood in detail. In the present study, we report that the protein kinase inhibitor 2-aminopurine markedly inhibits the phenobarbital-induced activation of CYP2H1 and ALAS-1 genes as measured by Northern blot analysis, but does not alter the basal expression of these genes in the absence of drug. Transient expression studies confirmed these findings. The construct pCATBg4.8 contains a 4.8-kb drug-responsive domain of the CYP2H1 gene fused to the enhancerless SV40 promoter and the drug-induced expression of this construct in chick embryo hepatocytes was inhibited by 2-aminopurine. Another construct pCAT, with the first 547 bp of 5' flanking region of the CYP2H1 gene, is not responsive to drug and basal expression of this construct was not altered by the addition of 2-aminopurine. The evidence presented here demonstrates that the inhibitory action of 2-aminopurine on drug-induction is not due to a toxic effect on the cells. The induction of the CYP2H1 gene by phenobarbital was not altered by treating cells with the specific inhibitors for protein kinase C (GF 109203X and Ro 31-8220) or prolonged exposure to 12-O-tetradecanoyl-phorbol 13-acetate (TPA) or treatment with the specific inhibitors for tyrosine kinase (genistein and tyrphostin A25). Overall, the data indicate that a 2-amino-purine-sensitive protein kinase activity is required for the phenobarbital-induction mechanism but this is unlikely to be a protein kinase C or tyrosine kinase. It can be postulated that phosphorylation of a drug receptor protein may be an important step in the drug-induction process.
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PMID:Phenobarbital-induced activation of CYP2H1 and 5-aminolevulinate synthase genes in chick embryo hepatocytes is blocked by an inhibitor of protein phosphorylation. 861 14

The rod photoreceptors of teleost retinas elongate in the light. To characterize the role of protein kinases in elongation, pharmacological studies were carried out with rod fragments consisting of the motile inner segment and photosensory outer segment (RIS-ROS). Isolated RIS-ROS were cultured in the presence of membrane-permeant inhibitors that exhibit selective activity toward specific serine/threonine protein kinases. We report that three distinct classes of protein kinase inhibitors stimulated elongation in darkness: (1) cyclic-AMP-dependent protein kinase (PKA)-selective inhibitors (H-89 and KT5720), (2) a protein kinase C (PKC)-selective inhibitor (GF 109203X) that affects most PKC isoforms, and (3) a kinase inhibitor (H-85) that does not affect PKC and PKA in vitro. Other kinase inhibitors tested neither stimulated elongation in darkness nor inhibited light-induced elongation; these include the myosin light chain kinase inhibitors ML-7 and ML-9, the calcium-calmodulin kinase II inhibitor KN-62, and inhibitors or activators of diacylglycerol-dependent PKCs (sphingosine, calphostin C, chelerythrine, and phorbol esters). The myosin light chain kinase inhibitors as well as the PKA and PKC inhibitors H-89 and GF 109203X all enhanced light-induced elongation. These observations suggest that light-induced RIS-ROS elongation is inhibited by both PKA and an unidentified kinase or kinases, possibly a diacylglycerol-independent form of PKC.
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PMID:Stimulation of cell elongation in teleost rod photoreceptors by distinct protein kinase inhibitors. 863 53

The hypothesis that the increase in Ca2+ sensitivity on norepinephrine-induced contraction of smooth muscles and also the decrease of the norepinephrine-induced sustained level of intracellular Ca2+ concentration are produced by the activation of protein kinase C was tested. Phorbol 12,13-dibutyrate (PDB; 10(-6) M) relaxed the norepinephrine-induced sustained contraction in a concentration-dependent manner. On pretreatment with PDB a transient contraction was produced by the application of norepinephrine, but the sustained contraction was significantly reduced. The sustained elevations of intracellular Ca2+ concentration ([Ca2+]i) and the contraction induced by norepinephrine in fura-2-loaded preparations were decreased by the application of PDB. These inhibitory effects were antagonized by potent protein kinase inhibitors, 2-(1-(3-dimethylaminopropyl)-indol-3-yl)-3-(-indol-3-yl)-maleimide (GF 109203X) (10 (-6) M) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) (10 (-6) M), but were not affected by a protein kinase A/G inhibitor, N-(2-cinnamylaminoethyl)-5-isoquinolinesulfonamide (H-88) (10(-6) M). The slope of the regression line for norepinephrine for [Ca2+]i and tension was significantly steeper than those obtained with high K+. Also, on pretreatment with PDB the Ca2+ sensitivity of the K(+)-induced contraction was decreased, but the Ca2+ sensitivity of norepinephrine-induced contraction tended to be increased. These observations indicate that PDB induces a decrease of [Ca2+]i on Ca2+ mobility and an increase of Ca2+ sensitivity on contraction of smooth muscle through the activation of protein kinase C.
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PMID:Inhibitory effect of phorbol 12,13-dibutyrate on norepinephrine-induced contraction in rabbit iris dilator muscle. 884 Jan 25

The effects of vasoconstrictor-receptor (neuropeptide Y, alpha-adrenergic, serotonergic, histaminergic) stimulation on currents through ATP-sensitive potassium (KATP) channels in arterial smooth muscle cells were examined. Whole-cell KATP currents, activated by the synthetic KATP channel opener pinacidil or by the endogenous vasodilator, calcitonin gene-related peptide, which acts through protein kinase A, were measured in smooth muscle cells isolated from mesenteric arteries of rabbit. Stimulation of NPY-, alpha 1-, serotonin (5-HT2)-, and histamine (H1)-receptors inhibited KATP currents by 40-56%. The signal transduction pathway that links these receptors to KATP channels was investigated. An inhibitor of phospholipase C (D609) and of protein kinase C (GF 109203X) reduced the inhibitory effect of these vasoconstrictors on KATP currents from 40-56% to 11-23%. Activators of protein kinase C, a diacylglycerol analogue and phorbol 12-myristate 13-acetate (PMA), inhibited KATP currents by 87.3 and 84.2%, respectively. KATP currents, activated by calcitonin gene-related peptide, were also inhibited (47-87%) by serotonin, phenylephrine, and PMA. We propose that KATP channels in these arterial myocytes are subject to dual modulation by protein kinase C (inhibition) and protein kinase A (activation).
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PMID:Vasoconstrictors inhibit ATP-sensitive K+ channels in arterial smooth muscle through protein kinase C. 889 79

Addition of phorbol 12,13-dibutyrate (PDB) to H 69, H 345, and H 510 small cell lung cancer (SCLC) cells led to a rapid concentration- and time-dependent increase in p42mapk activity. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one], a selective inhibitor of mitogen activated protein kinase (MAPK) kinase 1, prevented activation of p42mapk by PDB in SCLC cells. PDB also stimulated the activation of p90rsk, a major downstream target of p42mapk. The effect of PDB on both p42mapk and p90rsk activation could be prevented by down-regulation of protein kinase C (PKC) by prolonged pretreatment with 800 nM PDB or treatment of SCLC cells with the PKC inhibitor bisindolylmaleimide (GF 109203X), demonstrating the involvement of phorbol ester-sensitive PKCs in the signaling pathway leading to p42mapk activation. Various neuropeptides, such as bradykinin, vasopressin, bombesin, neurotensin, and galanin, which promote clonal growth in SCLC cells, also induced activation of p42mapk in these cells. In particular, galanin and neurotensin stimulated p42mapk activation in SCLC cells by a pathway that was dependent on the activity of PKC. Furthermore, galanin-stimulated clonal growth of SCLC cells in semisolid medium could be prevented by the PKC inhibitor GF 109203X and by PD 098059. Thus, our results suggest that activation of p42mapk plays an important role in neuropeptide-induced growth of SCLC.
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PMID:Galanin, neurotensin, and phorbol esters rapidly stimulate activation of mitogen-activated protein kinase in small cell lung cancer cells. 897 Nov 88

Prolactin induces milk protein gene expression in rabbit primary mammary cells without any concomitant cell multiplication. Prolactin or other lactogenic hormones is the major inducer of cell division in the rat lymphoid Nb2 cells. In Nb2 cells, prolactin also rapidly induces the expression of the c-myc gene, and beta-actin and stathmin gene expression is induced more slowly. The possible involvement of casein kinase II (CKII), mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) in these process is not well known. The present work was undertaken to evaluate the effect of prolactin on these protein kinases and to determine the possible involvement of these enzymes in the activity of several genes under the control of the hormone. In rabbit mammary cells, prolactin did not alter CKII activity but did transiently stimulate MAP kinase activity. Prolactin also stimulated Ca(2+)-independent PKC. This effect was visible after 10 min and was maintained for at least 24 hr. Staurosporine, an inhibitor of PKC and of several tyrosine kinases altered Ca(2+)-independent PKC only moderately. In contrast, GF 109203X, a potent and specific inhibitor of PKC, abrogated almost all PKC activity. Staurosporine, but not GF 109203X, prevented the induction of the casein gene by prolactin. In Nb2 cells, prolactin induced a slow stimulation of CKII activity. The hormone did not induce MAP kinase activity. Prolactin stimulated Ca(2+)-independent PKC over periods of 24 hr. GF 109203X, but not staurosporine, inhibited PKC activity, whereas staurosporine but not GF 109203X, inhibited the induction of Nb2 cell multiplication and the accumulation of c-myc, beta-actin and stathmin mRNAs. From these data, it can be concluded that (1) the stimulation of CKII by prolactin in Nb2 cells is concomitant with cell multiplication: (2) MAPK stimulation is not necessary for prolactin to induce Nb2 cell multiplication; and (3) PKC is stimulated in mammary and Nb2 cells, but this stimulation is not required for prolactin to stimulate casein, c-myc, beta-actin and stathmin gene expression and Nb2 cell division.
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PMID:The effect of prolactin on casein kinase II, MAP kinase and PKC in rabbit mammary cells and Nb2 rat lymphoid cells. 898 34

Thromboxane A2 (TxA2) is a potent vasoconstrictor and platelet agonist. Its biological function is tightly regulated. G protein-coupled membrane receptors transduce the effects of TxA2. However, although a single thromboxane receptor (TP) gene has been identified, two splice variants have been cloned from human placenta and megakaryocytic lines (TPalpha) and from human endothelial cells (TPbeta). These differ in the length of their carboxyl-terminal extensions (15 versus 79 residues), which contain multiple potential sites for receptor phosphorylation. Given that TP agonists activate protein kinase C (PKC), it would seem possible that PKC-dependent phosphorylation of TPs might play a central role in homologous desensitization of these receptors. To determine if the TP isoforms were differentially phosphorylated in response to agonist in vivo, human embryonic kidney (HEK) 293 cells were stably transfected with TPalpha and TPbeta. Isoform-specific anti-peptide antibodies were developed and used to immunoprecipitate the phosphorylated receptors. U46619, a PGH2/TxA2 mimetic, induced specific phosphorylation of both isoforms. Phosphorylation of the two isoforms was similar in dose and time dependence, reaching a plateau at around 100 nM U46619. Inhibition of PKC with either GF 109203X (5 microM) or RO 31-8220 (5 microM) or of protein kinase A with H-89 (50 microM) marginally influenced agonist-dependent phosphorylation of either isoform and failed to modulate homologous desensitization of agonist-induced stimulation of inositol phosphate formation. Similar results were obtained when PKC was down-regulated by long term incubation with the phorbol ester, phorbol myristate acetate. Although short term stimulation with phorbol myristate acetate caused PKC-dependent phosphorylation of TPs in vivo, thrombin stimulation of the TP-transfected HEK cells in vivo failed to phosphorylate either of the TP isoforms. Thus, despite the capacity of PKC to phosphorylate TPs in HEK 293 cells and the likely activation of PKC by TP stimulation, this enzyme, like protein kinase A, contributes marginally to rapid, agonist-induced phosphorylation of either TP isoform.
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PMID:Rapid, agonist-dependent phosphorylation in vivo of human thromboxane receptor isoforms. Minimal involvement of protein kinase C. 905 15

The mechanism of mitogen-activated protein kinase (MAPK, ERK) stimulation by the GnRH analog [D-Trp6]GnRH (GnRH-a) was investigated in the gonadotroph-derived alphaT3-1 cell line. GnRH-a as well as the protein kinase C (PKC) activator 12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulated a sustained response of MAPK activity, whereas epidermal growth factor (EGF) stimulated a transient response. MAPK kinase (MEK) is also activated by GnRH-a, but in a transient manner. GnRH-a and TPA apparently activated mainly the MAPK isoform ERK1, as revealed by Mono-Q fast protein liquid chromatography followed by Western blotting as well as by gel kinase assay. GnRH-a and TPA stimulated the tyrosine phosphorylation of several proteins, and this effect as well as the stimulation of MAPK activity were inhibited by the PKC inhibitor GF 109203X. Similarly, down-regulation of TPA-sensitive PKC subspecies nearly abolished the effect of GnRH-a and TPA on MAPK activity. Furthermore, the protein tyrosine kinase (PTK) inhibitor genistein inhibited protein tyrosine phosphorylation and reduced GnRH-a-stimulated MAPK activity by 50%, suggesting the participation of genistein-sensitive and insensitive pathways in GnRH-a action. Although Ca2+ ionophores have only a marginal stimulatory effect, the removal of Ca2+ markedly reduced MAPK activation by GnRH-a and TPA, but had no effect on GnRH-a and TPA stimulation of protein tyrosine phosphorylation. Interestingly, the removal of Ca2+ also partly inhibited the activation of MAPK by EGF and vanadate/H2O2. Thus, a calcium-dependent component(s) downstream of PKC and PTK might also participate in MAPK activation. Elevation of cAMP by forskolin exerted partial inhibition on EGF, but not on TPA or GnRH-a action, suggesting that MEK activators other than Raf-1 might be involved in GnRH action. We conclude that Ca2+, PTK, and PKC participate in the activation of MAPK by GnRH-a, with Ca2+ being necessary downstream to PKC and PTK.
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PMID:Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary of alphaT3-1 cell line: differential roles of calcium and protein kinase C. 907 30

Annexin 2 phosphorylated in vitro by protein kinase C has been shown to restore partially catecholamine secretion in streptolysin O-permeabilized chromaffin cells depleted of their protein kinase C activity. This result suggested a phosphorylation of annexin 2 in stimulated cells. Nicotine stimulation induced an increase of 32P incorporation in annexin 2 heavy chain concomitant with catecholamine release. This incorporation results from phosphorylation by protein kinase C because (a) serine was the only phosphorylated residue, (b) 32P incorporation was inhibited by the protein kinase inhibitors H7, GF 109203X, and staurosporine, and (c) activators of this enzyme, 12-O-tetradecanoylphorbol 13-acetate and 1,2-dioctanoylglycerate, increased the incorporation of radioactivity. The phosphorylated heavy chain had an electrophoretic mobility lower than that of the unmodified one, thus allowing determination of the fraction of phosphorylated protein. In the resting state, a significant fraction of annexin 2 heavy chain was phosphorylated, and nicotine stimulation resulted in an activation of both phosphorylation and dephosphorylation. Phosphorylation was largely increased in the presence of okadaic acid, indicating the involvement of type 1 and 2A phosphatases.
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PMID:Phosphorylation by protein kinase C of annexin 2 in chromaffin cells stimulated by nicotine. 908 46

PGF2alpha stimulates the proliferation of clonal osteoblastic MC3T3-E1 cells via PGF2alpha receptor linked to phospholipase C activation. To elucidate intracellular events elicited by this receptor, we examined the effects of PGF2alpha on tyrosine phosphorylation and mitogen-activated protein kinase (MAPK) activity in MC3T3-E1 cells. PGF2alpha rapidly raised the level of phosphotyrosine of cellular proteins with Mr values of 62, 68, 72, 76, 82, 125, and 150 kDa. This PGF2alpha-induced tyrosine phosphorylation of proteins (except for pp62) was blocked by down-regulating protein kinase C (PKC) by 12-O-tetradecanoylphorbol 13-acetate pretreatment and by GF 109203X, a potent specific PKC inhibitor. The addition of PGF2alpha also transiently activated MAPK in the same range of concentrations that stimulated tyrosine phosphorylation. In addition, PGF2alpha augmented the MAPK kinase kinase activity of Raf-1, whereas basal activity of MAPK/extracellular signal-regulated protein kinase kinase was less than that of Raf-1 and was little affected by PGF2alpha. Like the tyrosine phosphorylation, these activations of Raf-1 and MAPK activities were reduced by inhibition and down-regulation of PKC. Genistein, a potent inhibitor of tyrosine kinases, did not block the Raf-1 induced by PGF2alpha, indicating a tyrosine kinase-independent pathway for Raf-1 activation. However, the tyrosine kinase inhibitor partially inhibited the MAPK activity, suggesting an involvement of another Raf-1-independent kinase cascade for activation of MAPK by PGF2alpha. Fluprostenol, a specific agonist of PGF2alpha receptor, mimicked the actions of PGF2alpha consistent with a PGF2alpha receptor pathway. Thus, the action of PGF2alpha on osteoblastic MC3T3-E1 cells appears to involve a single receptor that uses diverse interacting signal transduction systems.
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PMID:Prostaglandin F2alpha stimulates tyrosine phosphorylation and mitogen-activated protein kinase in osteoblastic MC3T3-E1 cells via protein kinase C activation. 911 74


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