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)

Interleukin-1 beta (IL-1 beta) induces a dose-dependent increase in the release of corticotropin-releasing factor-41 (CRF) from dispersed rat fetal hypothalamic cells in culture. This release of CRF could be inhibited by the protein kinase C inhibitor H-7, and by the protein kinase A inhibitor IP-20. This suggests that both protein kinase C and protein kinase A-dependent pathways are involved in the response of CRF to IL-1 beta. Dexamethasone also blocked the CRF response to IL-1 beta, indicating that activated glucocorticoid receptors can inhibit the response of CRF to IL-1 beta.
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PMID:Interleukin-1 beta induces corticotropin-releasing factor-41 release from cultured hypothalamic cells through protein kinase C and cAMP-dependent protein kinase pathways. 151 98

ETR103 cDNA was cloned as an immediate early gene in the course of macrophagic differentiation of HL-60 cells stimulated by TPA (12-O-tetradecanoylphorbol-13-acetate). The induction by TPA was immediate-early (within 30 min) and transient. This gene was not induced by vitamin D3 or by retinoic acid, which stimulates differentiation of HL-60 cells to the monocytic or granulocytic lineage, respectively. The ETR103 mRNA was induced by TPA in lymphoid or myeloid leukemia cell lines of several maturation stages. The induction by TPA seems to proceed by a protein kinase C-mediated mechanism, on the basis of the results obtained by using protein kinase C inhibitor (H-7), protein kinase C activator (diC8), and an activator of protein kinase A (dibutyryl cAMP). Okadaic acid, an inhibitor of protein phosphatases, also induced the ETR103 mRNA expression. The nucleotide sequence of the ETR103 cDNA reveals that ETR103 encodes a human zinc finger-containing transcription factor identical to Egr-1 and 225, which is homologous to mouse Egr-1, Zif/268, Krox-24, and TIS8, or to rat NGFI-A.
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PMID:A gene coding for a zinc finger protein is induced during 12-O-tetradecanoylphorbol-13-acetate-stimulated HL-60 cell differentiation. 156 51

The mRNA level of the type-1 angiotensin II receptor (AT1) was down-regulated by angiotensin II in cultured rat glomerular mesangial cells. The effect was maximum with 1 microM AII at 6 h, sensitive to cycloheximide, and specific to AT1 since this phenomenon was blocked by DuP753, an AT1 antagonist, but not by type-2 antagonist PD123319. Dibutyryl cAMP, forskolin, and cholera toxin also caused AT1 down-regulation. These effects were not altered by either the protein kinase A inhibitor H-8 or cycloheximide. Calcium ionophore A23187, pertussis toxin, protein kinase C inhibitor staurosporine, or prolonged incubation with phorbol ester were without effect. These results suggest that there are at least two pathways to down-regulate AT1 mRNA; one way is an angiotensin II-induced, protein kinase C-independent, and cycloheximide-sensitive pathway and the other is an angiotensin II-independent, cAMP-induced, and cycloheximide-insensitive pathway.
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PMID:Two distinct pathways in the down-regulation of type-1 angiotension II receptor gene in rat glomerular mesangial cells. 159 49

The effect of activation of calcium- and phospholipid-dependent protein kinase (protein kinase C) on human chorionic gonadotropin (hCG) release by cultured trophoblast cells was studied and a role of protein kinase C in the GnRH-mediated hCG release was also evaluated. Both GnRH and 1-oleoyl-2-acetylglycerol (OAG), a protein kinase C activator, stimulated hCG release after 3 h incubation in a dose-dependent manner with ED50 of 55 nmol/l and 4.0 nmol/l, respectively. A tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) also stimulated hCG release while two non-tumor-promoting compounds, phorbol and 4 alpha-phorbol, failed to stimulate hCG release. hCG release by maximal effective dose of GnRH (10 mumol/l) or OAG (1 mumol/l) was further stimulated when cells were incubated with same concentrations of GnRH and OAG. OAG-stimulated hCG release was completely inhibited by a protein kinase C inhibitor, H-7, with ID50 of 23 nmol/l while H-7 did not affect GnRH-mediated hCG release. These results indicate that GnRH-stimulated hCG release is not mediated by protein kinase C pathway, however, the secretion of hCG is also regulated by the mechanism that involves protein kinase C activation.
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PMID:Effects of diacylglycerol and gonadotropin-releasing hormone on human chorionic gonadotropin release by cultured trophoblast cells. 163 9

5-Hydroxytryptamine (5-HT) has been shown to activate the hypothalamo-pituitary-adrenal axis, possibly by a direct action on hypothalamic CRF synthesis and release. In order to study the mechanisms involved in this effect, foetal hypothalamic cells were cultured and corticotropin-releasing factor-41 (CRF) release was measured by radioimmunoassay. 5-HT induced CRF release in a dose-dependent manner. Further studies were performed with a specific protein kinase C inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine) and a specific cyclic adenosine monophosphate-dependent protein kinase inhibitor, IP-20. Basal release of CRF-41 from the cultured hypothalamic cells was unaffected by IP-20 and was only diminished at a high (50 microM) concentration of H-7. 5-HT stimulated-CRF release, however, was blocked by both H-7 and IP-20. Dexamethasone and aldosterone both caused a dose-dependent inhibition of 5-HT induced CRF release. These results demonstrate that CRF can be released from hypothalamic neurons in response to 5-HT through a protein kinase C and protein kinase A dependent mechanism and that 5-HT stimulated CRF release can be inhibited by dexamethasone and aldosterone.
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PMID:5-Hydroxytryptamine stimulates corticosteroid-sensitive CRF release from cultured foetal hypothalamic cells. Role of protein kinases. 163

The effect of the CD28 activation pathway on the immunosuppressive action of CsA was assessed. Human peripheral blood lymphocytes were stimulated with anti-CD3, bryostatin (Bryo) a novel activator of protein kinase C (PKC) and anti-CD28 singly or in combination, to which graded doses of CsA were added to determine relative sensitivity. Proliferation, IL-2 production, and IL-2 receptor expression were assessed and the IC50 determined. Lymphocytes stimulated with Bryo exhibited a marginal proliferative response but expressed the IL-2 receptor despite the presence of CsA. Addition of anti-CD3 or anti-CD28 to Bryo-stimulated lymphocytes promoted a vigorous proliferative response. CsA effectively inhibited the proliferative response and IL-2 production induced with anti-CD3 and Bryo but did not inhibit the response of cells stimulated with anti-CD28 and Bryo. However, II-2 receptor expression in both sets of cultures were comparable due to the induction of IL-2 receptor by Bryo and was not inhibited by CsA. Costimulation of lymphocytes with anti-CD3 plus anti-CD28 resulted in a 2-3-fold enhancement of proliferation compared with lymphocytes stimulated with anti-CD3 alone. Addition of CsA to lymphocytes stimulated with anti-CD3 resulted in the dose-dependent suppression of the proliferative response and IL-2 production (IC50 = 10-25 nM) but less so for IL-2 receptor expression (IC50 = 100-150 nM). In comparison, the proliferative response and IL-2 production elicited by anti-CD3 + anti-CD28 was more resistant to the effects of CsA (IC50 = 100-200 nM). However, IL-2 receptor expression exhibited comparable sensitivity to CsA (IC50 = 100-200 nM) in the presence of anti-CD28. Combination drug:drug studies revealed that CsA and the protein kinase C inhibitor H-7 were additive for both anti-CD3 and anti-CD3 plus anti-CD28 response. On the other hand, the cGMP-dependent protein kinase inhibitor H-8 was synergistic with CsA in inhibiting the response of lymphocytes to anti-CD3 plus anti-CD28 but only additive for responses to anti-CD3. Taken together, these data suggest that CsA inhibits T cell activation at two distinct levels, leading to inhibition of IL-2 production and inhibition of IL-2 receptor expression. Activation of the CD28 pathway partially overcomes the inhibitory activity of CsA on IL-2 production and may be mediated by indirect activation of a cGMP-dependent protein kinase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of the CD28 activation pathway on the immunosuppressive action of cyclosporine. 164 6

This study investigated the intracellular signal transduction regulating the appearance of HLA class I antigens on Huh 6 cells induced by interferon-gamma. The expression was blocked by a protein kinase C inhibitor, H-7, but not by a calmodulin antagonist, W-7, nor by a protein kinase A inhibitor, H-8, at low dose. The antigen expression was induced by a direct activator of protein kinase C, phorbol myristate acetate, but not by calcium ionophore A23187 nor an analog of cAMP, dbcAMP. Therefore, we concluded that protein kinase C is involved in the expression of HLA class I antigens on Huh 6 cells induced by interferon-gamma but Ca(2+)-calmodulin and cAMP are not.
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PMID:Signal transduction pathways in the induction of HLA class I antigen expression on Huh 6 cells by interferon-gamma. 164 5

Neonatal mouse cardiac poly(A)+ mRNA microinjection into Xenopus oocytes directed the expression of a delayed rectifier K+ current. A cDNA encoding this channel, called mIsK, was cloned from a neonatal mouse heart cDNA library whose properties were studied after expression of the complementary RNA in Xenopus oocytes. Among the different known K+ channel blockers, only the class III antiarrhythmic clofilium inhibited mIsK in the 10-100 microM range. The channel was completely insensitive to other antiarrhythmics such as quinine, quinidine, sotalol or amiodarone. mIsK was enhanced by increasing intracellular Ca2+ and by microinjected Ca(2+)-calmodulin dependent protein kinase II. These stimulations were reversed by the calmodulin antagonist W7. Conversely, the phorbol ester PMA, the diacylglycerol analog OAG and microinjected purified protein kinase C inhibited mIsK. This inhibitory effect could be prevented by the protein kinase C inhibitor staurosporine. These results were consistent with the presence of consensus sequences for kinase II and kinase C in the mIsK structure. Cultured newborn mouse ventricular cardiac cells exhibited a delayed rectifier K+ current which had biophysical properties similar to those of cloned mIsK and which was inhibited by clofilium and protein kinase C activators. In situ hybridization experiments revealed that mIsK mRNA was homogeneously distributed in the cardiac tissue. Neonatal mouse heart expressed the most mIsK mRNA compared with various other rat and mouse tissues. Since this K+ channel generates a current which appears to be involved in the control of both the action potential duration and the beating rate, these results suggest an important role for the mIsK channel in cardiac cell physiology and cardiac pathology.
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PMID:Cloning, expression, pharmacology and regulation of a delayed rectifier K+ channel in mouse heart. 165 3

In this study we describe the activation of a protein kinase which phosphorylates a peptide, T669, comprising amino acids 663-681 of the epidermal growth factor receptor and containing the phosphate acceptor site Pro-Leu-Thr669-Pro. In the human epidermoid carcinoma cell line KB, T669 kinase activity in cytosolic extracts peaked (up to 15-fold compared with basal levels) 15-30 min after addition of interleukin-1 (IL-1) and closely paralleled receptor occupancy with a half-maximally effective concentration of approximately 100 pM IL-1 alpha. IL-1 treatment elevated T669 kinase activity to a variable extent in selected fibroblast lines, the hepatoma cell line HepG2, and the murine thymoma EL4 6.1. An IL-1 receptor-negative EL4 variant and the B cell lines 70Z/3, CB23, and RPMI 1788 did not respond in this way. All of the cell lines except 70Z/3 showed increased levels of T669 kinase when treated with the protein kinase C activator phorbol myristate acetate and/or with epidermal growth factor. This finding is in agreement with a previous study (Countaway, J. L., Northwood, I. C., and Davis, R. J. (1989) J. Biol. Chem. 264, 10828-10835). Activators of protein kinase A did not mimic the ability of IL-1 to stimulate T669 kinase activity, nor did the protein kinase C inhibitor staurosporine abrogate the effect of IL-1. T669 kinase activity from IL-1-stimulated KB cells was partially purified by ion exchange, hydrophobic interaction, and size exclusion chromatography. The partially purified enzyme phosphorylated myelin basic protein, a characteristic substrate of microtubule-associated protein-2 kinase (MAP-2 kinase) and the peptide Arg-Arg-Arg-(Tyr-Ser-Pro-Thr-Ser-Pro-Ser)4 from RNA polymerase II. Western blotting of chromatographic fractions revealed that T669 kinase activity corresponded with two proteins of 43 and 45 kilodaltons which cross-reacted with antibodies raised against peptide sequences of rat extracellular signal-regulated kinase-1/microtubule-associated protein-2 kinase. T669 kinase activity was critically dependent on the presence of phosphatase inhibitors. Since both the 43- and 45-kDa proteins, immunoprecipitated from [32P]phosphate-labeled cells, demonstrated a dramatic increase in their levels of serine, threonine, and tyrosine phosphorylation after brief treatment with IL-1, we conclude that IL-1 modulates the activity of these extracellular signal-regulated kinase/microtubule-associated protein-2 kinases by altering the level of their phosphorylation.
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PMID:Interleukin-1 represents a new modality for the activation of extracellular signal-regulated kinases/microtubule-associated protein-2 kinases. 165 5

Glial fibrillary acidic protein (GFAP) mRNA levels in the human astrocytoma line U-373MG were examined to explore further the effects of agents that regulate protein kinase C. U-373MG cells exhibit a biphasic change in steady-state GFAP mRNA in the presence of the phorbol ester phorbol-12-myristate-13-acetate (PMA). Short-term treatment with PMA results in increased GFAP mRNA, and long-term treatment results in decreased GFAP mRNA. Nuclear run-off experiments demonstrate that the PMA-induced decrease in GFAP mRNA levels is not at the level of GFAP gene transcription. PMA exerts its effect in the presence of protein synthesis inhibitors, demonstrating that de novo protein synthesis is not required for the PMA-induced changes in GFAP mRNA. Staurosporine, a protein kinase C inhibitor, reduces GFAP mRNA expression in a dose-dependent manner; in the presence of PMA the effect is additive. By contrast HA1004, an inhibitor of cAMP-dependent protein kinase, is not inhibitory to GFAP steady-state mRNA. Total protein kinase C activity was determined to be 2,398.8 +/- 94.3 pmol/min/mg protein, with most of the activity in the cytosol. Short-term PMA treatment results in the translocation of the cytosolic protein kinase C activity to the membrane. Long-term PMA treatment results in a decrease in total protein kinase C activity indicating that downregulation occurs. These studies demonstrate that in the U-373MG cells, protein kinase C inhibitors and long treatment with PMA result in a decrease in steady-state GFAP mRNA.
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PMID:Phorbol-12-myristate-13-acetate (PMA) and inhibitors of protein kinase C alter glial fibrillary acidic protein (GFAP) mRNA levels. 172 Jul 62


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