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)

Rat mesangial cells contain both calcium-dependent protein kinase C (PKC) activity, which phosphorylates histone H1 and endogenous proteins, and calcium-independent, phospholipid-dependent PKC activity, which phosphorylates only endogenous proteins. The calcium-dependent PKC was identified as PKC alpha by immunoblot analysis and hydroxyapatite chromatography (HPLC). The calcium-insensitive, phospholipid-dependent isoform was identified as PKC delta using similar techniques. The inhibition of these two PKC isoforms by the protein kinase inhibitor H7 [1-(iso-quinolinyl sulphonyl)-2-methyl piperazine] was examined using both histone H1 and endogenous proteins as substrates. Phosphorylations catalyzed by the calcium-dependent PKC isoform alpha were almost 90% inhibited when histone H1 was used, and only 55% when endogenous proteins were the substrate. In contrast, the phosphorylation of endogenous proteins catalysed by the calcium-insensitive, phospholipid-dependent PKC delta was not significantly affected by the inhibitor.
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PMID:Immunological identification of protein kinase C-alpha and protein kinase C-delta in cultured rat mesangial cells: differential sensitivity of the two isoforms towards the protein kinase inhibitor H7. 141 92

Recent reports described a down-regulation of gamma-aminobutyric acid (GABA)-receptor function in several types of central neurones by cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). Surprisingly, we found that in cerebellar Purkinje cells (PCs) the membrane permeable-compound 8-bromo-cAMP (500 microM) induced a long-lasting potentiation of both, whole-cell current responses to bath-applied GABA and amplitudes of miniature inhibitory synaptic currents (mIPSCs). When dialyzing the PCs with the specific protein kinase inhibitor peptide (PKIP, 400 micrograms ml-1), the same manipulation failed to induce a potentiation. These results strongly suggest that, in contrast to its action in other types of neurones, activation of PKA up-regulates the GABAA receptor function in cerebellar PCs.
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PMID:Potentiation of GABA-mediated currents by cAMP-dependent protein kinase. 142 Nov 7

The protein kinase C family of enzymes is thought to be important in mediating signal transduction. Ro 31-8830 is a novel, potent inhibitor of protein kinase C, derived from the non-selective protein kinase inhibitor staurosporine. In this paper we demonstrate the selectivity of Ro 31-8830 for protein kinase C over other protein kinases and its ability to inhibit protein kinase-C-mediated events in platelets and lymphocytes. In addition, we describe a novel system for the in vivo evaluation of inhibitors of protein kinase C, and we demonstrate the oral anti-inflammatory activity of Ro 31-8830. This finding has implications for the treatment of inflammatory disorders in the clinic.
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PMID:Oral, anti-inflammatory activity of a potent, selective, protein kinase C inhibitor. 145 83

Staurosporine, a microbial-derived protein kinase inhibitor, reversibly blocked non-synchronized, replicating cultures of the human lung epithelial cell line EKVX in the G1 phase of cell cycle and inhibited DNA synthesis and cell replication. The mechanism of this cell-cycle arrest in EKVX cells by staurosporine was likely due to inhibition of protein kinase C (PKC) because: 1) dose-dependent inhibition of DNA synthesis occurred at levels of staurosporine that inhibit phosphorylation of PKC substrate, 2) inhibition of DNA synthesis was also seen after treatment with another PKC inhibitor H7, but not by the chemically similar HA1004, which has a relative inhibitory specificity for cAMP-dependent protein kinase, and 3) the DNA synthesis was not inhibited by specific tyrosine kinase inhibitors Genistein and Lavendustin A at concentrations that inhibit tyrosine kinase activity. Removal of staurosporine from cell culture media resulted in a rebound in PKC activity and synchronized DNA synthesis in EKVX cultures. The reversibility of the inhibition was noted even after 5 days of treatment with staurosporine, and DNA synthesis remained synchronized for at least two rounds of cell replication after removal of staurosporine. Flow cytometric analysis confirmed that more than 90% of the cell population was blocked in the G1 phase after cells were treated with staurosporine for 24 h. Agents such as staurosporine may be useful for synchronizing cell populations to study cell-cycle specific biochemical events important for the regulation of cell replication in the EKVX cell line.
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PMID:Reversible G1 arrest of a human lung epithelial cell line by staurosporine. 150 20

cAMP-dependent protein kinase mediates a variety of cellular responses in most eukaryotic cells. Many of these responses are cytoplasmic, whereas others appear to require nuclear localization of the catalytic subunit. In order to understand further the molecular basis for subcellular localization of the catalytic subunit, the effect of the heat stable protein kinase inhibitor (PKI) was investigated. The subcellular localization of the catalytic (C) subunit was determined both in the presence and absence of PKI, by microinjecting fluorescently labeled C subunit into single living cells. When injected alone, a significant fraction of the dissociated C subunit localized to the nucleus. When coin-injected with an excess of PKI, little of the C subunit localized to the nucleus, suggesting that accumulation of catalytic subunit in the nucleus requires either enzymatic activity or a nuclear localization signal. Inactivation of the catalytic subunit in vitro by treatment with N-ethylmaleimide did not prevent localization in the nucleus, indicating that enzymatic activity was not a prerequisite for nuclear localization. In an effort to search for a specific signal that might mediate nuclear localization, a complex of the catalytic subunit with a 20-residue inhibitory peptide derived from PKI (PKI(5-24)) was microinjected. In contrast to intact PKI, the peptide was not sufficient to block nuclear accumulation. In the presence of PKI(5-24), the C subunit localized to the nucleus in a fashion analogous to that of dissociated, active C subunit despite evidence of no catalytic activity in situ. Thus, nuclear localization of the C subunit appears to be independent of enzymatic activity but most likely dependent upon a signal. The signal is apparently masked by both the regulatory subunit and PKI but not by the inhibitory peptide.
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PMID:Effect of the thermostable protein kinase inhibitor on intracellular localization of the catalytic subunit of cAMP-dependent protein kinase. 151 25

1. Plasticity at the connections between sensory neurons and their follower cells in Aplysia has been used extensively as a model system to examine mechanisms of simple forms of learning. Earlier studies have concluded that serotonin (5-HT) is a key modulatory transmitter and that it exerts its short-term actions via cAMP-dependent activation of protein kinase A. Subsequently, it has become clear that other kinase systems such as protein kinase C (PKC) also may be involved in the actions of 5-HT. 2. Application of phorbol esters, which activate PKC, produced a slowly developing spike broadening but had little effect on excitability (a process known to be primarily cAMP dependent). Moreover, the effects of phorbol esters and 5-HT on spike duration were not additive, suggesting that they may share some common mechanisms. 3. The protein kinase inhibitor staurosporine suppressed both 5-HT-induced slowly developing spike broadening and, under certain conditions, facilitation of transmitter release. Staurosporine did not inhibit 5-HT-induced enhancement of excitability. The effectiveness of staurosporine on spike broadening was dependent on the time at which spike broadening was examined after application of 5-HT. Staurosporine appeared to have little effect on spike broadening 3 min after application of 5-HT, whereas it inhibited significantly 5-HT-induced spike broadening at later times. The staurosporine-insensitive component of 5-HT-induced spike broadening may be mediated by cAMP. 4. The results suggest that the activation of PKC plays a key role in components of both 5-HT-induced spike broadening and facilitation of synaptic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of protein kinase C in serotonin-induced spike broadening and synaptic facilitation in sensorimotor connections of Aplysia. 152 80

The protein kinase inhibitor 1-(5'-isoquinolinesulfonyl)-2-methylpiperazine (H7) has been widely used because of its ability to inhibit cyclic AMP- and cyclic GMP-dependent protein kinases (PKA and PKG) and protein kinase C (PKC) at roughly equal concentrations; it is much less potent on other kinases. Previous studies in other laboratories have found that H7 samples from different commercial sources have different properties in cellular studies and protein kinase C inhibition assays. We now report the results of chemical and biological tests which show that H7 samples also differ in chemical structure, again depending on their commercial source. Chemical synthesis and NMR spectroscopy indicate that H7 from most suppliers has the structure originally proposed for H7, while "H7" from another supplier is in fact its 3-methylpiperazine positional isomer.
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PMID:The structure and biological activities of the widely used protein kinase inhibitor, H7, differ depending on the commercial source. 153 Jun 23

A cytosolic insulin-sensitive serine kinase has been purified to apparent homogeneity in parallel from livers of control or acutely insulin-treated rats. The kinase is labile and requires rapid purification for stability. The kinase migrates as a band of apparent Mr = 90,000 on denaturing gels and elutes as a monomer on Superose 12 gel filtration. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis and renaturation, the 90-kDa band presumed to be the kinase shows kinase activity toward myelin basic protein in situ. Substrates of the kinase include Leu-Arg-Arg-Ala-Ser-Leu-Gly (Kemptide), ribosomal protein S6, S6 peptide, a proline-rich peptide substrate, microtubule-associated protein 2, and myelin basic protein. The kinase also phosphorylates histones H1 and H2B, but does not autophosphorylate to a significant stoichiometry. The activity of the kinase is inhibited by fluoride, glycerophosphate, p-nitrophenyl phosphate, p-nitrophenol, heparin, quercetin, poly-L-lysine, and potassium phosphate, but is unaffected by calcium, cAMP, spermine, protein kinase inhibitor peptide, phorbol myristate acetate, calcium plus phosphatidylserine, or vanadate. The kinase will utilize magnesium (10 mM) as well as manganese (1 mM) as a cofactor for maximal phosphotransferase activity. The kinase is not detected by immunoblotting with antibodies directed against protein kinase C or type II S6 kinase. Taken together, these properties distinguish this kinase from other insulin-sensitive kinases that have been described previously. The purified kinase from livers of insulin-treated rats shows a 5-20-fold higher specific activity compared to enzyme prepared from control rats, suggesting a covalent modification as the mechanism of activation. Incubation of purified, insulin-stimulated kinase with purified phosphatase 2A leads to deactivation of the kinase activity, and the phosphatase inhibitor nitrophenyl phosphate blocks this deactivation. The insulin-activated kinase fails to immunoblot with anti-tyrosine phosphate antibodies. Taken together, these results indicate that insulin activates this novel cytosolic protein kinase by a mechanism that causes its phosphorylation on serine or threonine residues.
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PMID:Purification and characterization of a cytosolic insulin-stimulated serine kinase from rat liver. 153 38

The ras gene product (p21) is thought to transduce signals from various growth and differentiation factors. p21 is a GTP-binding protein, and its activity is regulated by the bound GDP/GTP ratio. We analysed p21-bound nucleotides in cell lysates of rat pheochromocytoma cell line PC12 cells stimulated with various factors. Nerve growth factors (NGF) rapidly increased the relative amount of active p21-GTP complex to as much as 20% of the total amount of p21 within 2 min. The amount of p21-GTP then declined to 8% after 10 min, and this level was sustained for at least 2 h. Epidermal growth factor (EGF) also stimulated a rapid accumulation of p21-GTP to the same extent as seen with NGF, but the amount of p21-GTP declined to 5% after 10 min and gradually returned to the basal level within 60 min. In contrast, basic fibroblast growth factor, interleukin 6 and dibutyryl cAMP, which induce neuronal differentiation of PC12 cells, did not stimulate the accumulation of p21-GTP at any time point examined. Phorbol 12-myristate 13-acetate also had no effect. Interestingly, the protein kinase inhibitor K-252a specifically suppressed the NGF-induced accumulation of p21-GTP, but did not suppress the EGF-induced response. These results strongly suggest that an active p21-GTP complex transduces the differentiation signal from NGF. It may also be suggested that the process of activating p21 is mediated by a K-252a-sensitive protein kinase(s).
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PMID:Nerve growth factor induces rapid accumulation of the GTP-bound form of p21ras in rat pheochromocytoma PC12 cells. 154 49

BHK cells blocked at any of several points in the cell cycle override their drug-induced arrest and proceed in the cycle when exposed concurrently to the protein kinase inhibitor 2-aminopurine (2-AP). For cells arrested at various points in interphase, 2-AP-induced cell cycle progression is made evident by arrival of the drug-treated cell population in mitosis. Cells that have escaped from mimosine G1 arrest, from hydroxyurea or aphidicolin S-phase arrest, or from VM-26-induced G2 arrest subsequently have all the hallmarks of mitosis--such as a mitotic microtubule array, nuclear envelope breakdown, and chromatin condensation. In a synchronous population, the time course of arrival in mitosis and its duration in 2-AP-treated cells that have escaped drug-induced cell cycle blocks is indistinguishable from control cells. Cells arrested in mitosis by nocodazole or taxol quickly escape mitotic arrest and enter interphase when exposed to 2-AP. 2-AP by itself does not influence the timing of cell cycle progression. We conclude that 2-AP acts to override checkpoints in every phase of the cell cycle, perhaps by inhibiting a protein kinase responsible for control of multiple cell cycle checkpoints.
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PMID:2-Aminopurine overrides multiple cell cycle checkpoints in BHK cells. 154 93


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