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 benzophenanthridine alkaloid chelerythrine is a potent, selective antagonist of the Ca++/phospholopid-dependent protein kinase (Protein kinase C: PKC) from the rat brain. Half-maximal inhibition of the kinase occurs at 0.66 microM. Chelerythrine interacted with the catalytic domain of PKC, was a competitive inhibitor with respect to the phosphate acceptor (histone IIIS) (Ki = 0.7 microM) and a non-competitive inhibitor with respect to ATP. This effect was further evidenced by the fact that chelerythrine inhibited native PKC and its catalytic fragment identically and did not affect [3H]- phorbol 12,13 dibutyrate binding to PKC. Chelerythrine selectively inhibited PKC compared to tyrosine protein kinase, cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase. The potent antitumoral activity of celerythrine measured in vitro might be due at least in part to inhibition of PKC and thus suggests that PKC may be a model for rational design of antitumor drugs.
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PMID:Chelerythrine is a potent and specific inhibitor of protein kinase C. 224 23

Chelerythrine (CHELE), a specific, potent protein kinase C (PKC) inhibitor, disrupts memory formation for a one-trial peck-avoidance task. Three predictions were made about how CHELE, injected into chick brain near the time of training, would affect memory formation, based on previous work with two classes of protein kinase inhibitors (M. R. Rosenzweig et al., 1992; P. A. Serrano et al., 1994) and the in vitro inhibition of PKC by CHELE: (a) CHELE, injected into the intermediate medial hyperstriatum ventrale, would significantly impair memory formation; (b) the amnestic dose would be approximately 10 nmol; (c) CHELE would not produce amnesia for about 45 min after training, but significantly impair memory by 60 min. Experimental tests confirmed each prediction. This study adds to evidence that PKC activity is part of a cascade of neurochemical events initiated by learning and that PKC activity shortly after training is necessary for long-term memory.
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PMID:Protein kinase C inhibitor chelerythrine disrupts memory formation in chicks. 761 17

The role of protein phosphatases in the regulation of K flux pathways of the trout red blood cell has been investigated using the phosphatase inhibitors calyculin A and okadaic acid. Both inhibitors completely blocked an oxygenation-activated Cl-dependent K flux with a 50% inhibitory concentration of 17 and 675 nmol/l, respectively, but not the hypotonically activated Cl-independent K uptake. N-ethylmaleimide (NEM) and staurosporine caused an increase in the Cl-dependent flux. In both cases preincubation with calyculin A blocked activation but, when added during activation, it prevented any further increase with NEM but abolished the staurosporine-induced uptake. K uptake that was activated by NEM and "clamped" by calyculin A was volume sensitive, indicating a dual influence on this pathway. Chelerythrine, a protein kinase inhibitor, activated a Cl-independent K uptake that was unaffected by calyculin A. It is concluded that activation and deactivation of both Cl-dependent and Cl-independent pathways require changes in the phosphorylation of an as yet unidentified target protein(s), although with different sets of protein kinase and/or phosphatases. These observations also suggest a complex model of kinase-phosphatase regulation and provide drugs for the pharmacological definition and manipulation of Cl-dependent and Cl-independent K flux pathways.
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PMID:Role of protein phosphorylation in control of K flux pathways of trout red blood cells. 781 Jun 6

In cultured bovine adrenal chromaffin cells, a nonselective protein kinase inhibitor, staurosporine, inhibits secretory function and induces neurite outgrowth. In the present study, effects of other nonselective protein kinase inhibitors (K-252a, H-7, and H-8) and reportedly selective protein kinase inhibitors (KN-62 and chelerythrine chloride) were examined on bovine adrenal chromaffin cell morphology, secretory function, and 45Ca2+ uptake. Treatment of chromaffin cells with 10 microM K-252a, 50 microM H-7, or 50 microM H-8 induced changes in cell morphology within 3 h; these compounds also induced a time-dependent inhibition of stimulated catecholamine release. Chelerythrine chloride, a selective inhibitor of Ca2+/phospholipid-dependent protein kinase, did not induce outgrowth or inhibit secretory function under our treatment conditions. KN-62, a selective inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMK II), significantly inhibited stimulated catecholamine release (IC50 value of 0.32 microM), but had no effect on cell morphology. The reduction of secretory function induced by 1 microM KN-62 was significant within 5 min and rapidly reversible. Unlike H-7, H-8, and staurosporine, KN-62 significantly inhibited stimulated 45Ca2+ uptake. KN-04, a structural analogue of KN-62 that does not inhibit CaMK II, inhibited stimulated 45Ca2+ uptake and catecholamine release like KN-62. These studies indicate that KN-62 inhibits secretory function via the direct blockade of activated Ca2+ influx. The nonselective inhibitors, K-252a, H-7, H-8, and staurosporine, inhibit secretory function by another mechanism, perhaps one involving alterations in the cytoskeleton.
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PMID:Effects of protein kinase inhibitors on morphology and function of cultured bovine adrenal chromaffin cells: KN-62 inhibits secretory function by blocking stimulated Ca2+ entry. 852 41

To investigate molecular mechanisms controlling plant morphogenesis, we examined the morphology of primary roots of Arabidopsis thaliana and the organization of cortical microtubules in response to inhibitors of serine/threonine protein phosphatases and kinases. We found that cantharidin, an inhibitor of types 1 and 2A protein phosphatases, as previously reported for okadaic acid and calyculin A (R.D. Smith, J.E. Wilson, J.C. Walker, T.I. Baskin [1994] Planta 194: 516-524), inhibited elongation and stimulated radial expansion. Of the protein kinase inhibitors tested, chelerythrine, 6-dimethylaminopurine, H-89, K252a, ML-9, and staurosporine all inhibited elongation, but only staurosporine appreciably stimulated radial expansion. To determine the basis for the root swelling, we examined cortical microtubules in semithin sections of material embedded in butyl-methyl-methacrylate. Chelerythrine and 100 nM okadaic acid, which inhibited elongation without causing swelling, did not change the appearance of cortical arrays, but calyculin A, cantharidin, and staurosporine, which caused swelling, disorganized cortical microtubules. The stability of the microtubules in the aberrant arrays was not detectably different from those in control arrays, as judged by similar sensitivity to depolymerization by cold or oryzalin. These results identify protein phosphorylation and dephosphorylation as requirements in one or more steps that organize the cortical array of microtubules.
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PMID:Inhibitors of protein kinases and phosphatases alter root morphology and disorganize cortical microtubules. 904 96

Granulocyte colony stimulating factor (G-CSF) regulates survival, proliferation, differentiation, and activation of myeloid cells. It binds to a high affinity receptor (G-CSF-R) expressed on myeloid cells, for which the signal transduction mechanisms other than protein tyrosine kinase (PTK) activation have not been completely identified. We explored the potential involvement of protein kinase-C (PKC) in G-CSF-R signal transduction. In this report, we provide direct evidence of PKC activation by G-CSF-R. G-CSF treatment of peripheral blood neutrophils, granulocytic cell lines (HL-60, NFS-60, KG-1), and monocytic cell lines (WEHI-3B,U-937) resulted in PKC activation. Chelerythrine chloride and HA-100, an isoquinolinesulfonamide derivative, the specific inhibitors of PKC, 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid (BAPTA), a chelator of intracellular calcium, and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester (TMB-8), an inhibitor of intracellular calcium release, blocked G-CSF-induced PKC activation in HL-60 cells, and reduced CD11b upregulation in neutrophils, but did not affect ligand-binding or down-modulation of G-CSF-R. Methyl 2,5-dihydroxycinnamate (MDHC), a potent inhibitor of protein tyrosine kinases (PTK), also inhibited PKC activation in response to G-CSF treatment, suggesting that PKC activation may occur downstream of PTK activation. Our results demonstrate the involvement of PKC in G-CSF-R signal transduction, and suggest a common signaling pathway in myeloid cells of granulocytic and monocytic lineages.
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PMID:Granulocyte colony-stimulating factor-induced activation of protein kinase-C in myeloid cells. 925 86

In human MCF-7 breast cancer cells, both protein kinase A (PKA) and different members of the protein kinase C (PKC) family are stimulated upon binding of epidermal growth factor (EGF) to cell surface receptors. Selective stimulation of calcium-dependent PKCs with 10(-6) to 10(-9) M Thymeleatoxin significantly increased the proliferation rate of MCF-7 cells over 5 days in culture. This stimulation was blocked by the PKC antagonist Chelerythrine. In contrast, selective activation of PKA by addition of 1 mM dibutyryl cyclic AMP (dBcAMP) did not affect the proliferation rate of MCF-7 cells. Similarly, activation of the adenylate cyclase by 1 microM Forskolin and inhibition of PKA by the cyclic AMP analogue Rp-cAMPS did not modulate the proliferation rate of these cells. Activation of PKC stimulated the expression of the immediate early gene c-fos but c-myc expression was not significantly enhanced. On the other hand, PKA activation increased both c-myc and c-fos expression in MCF-7 cells. These results suggest that PKA activation and c-myc expression are not obligatory for proliferation of MCF-7 cells.
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PMID:Selective modulation of protein kinase A and protein kinase C activities in epidermal growth factor (EGF)-stimulated MCF-7 breast cancer cells. 934 12

The hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] promotes differentiation of a number of cell types including HL-60 promyelocytic leukemia cells. It is now established that protein kinase Cbeta (PKCbeta) plays a critical role in HL-60 cell maturation to a monocyte/macrophage phenotype. In the present study, we investigated the importance of PKCbeta levels and activation in 1,25-(OH)2D3-mediated differentiation of HL-60 cells. Cell differentiation promoted by 1,25-(OH)2D3 at 48 hr was 39 +/- 3% (mean +/- SEM) nitroblue tetrazolium (NBT) positive and at 72 hr it was 35 +/- 2% NBT positive and 70% CD14 positive. Thus, promotion of cell differentiation by 20 nM 1,25-(OH)2D3 treatment was maximal at 48-72 hr. When PKCbeta levels and cell differentiation were assayed at 72 hr, treatment with 20 nM 1,25-(OH)2D3 for the initial 6 hr increased PKCbeta levels by 175% but had little effect on cell differentiation (7 +/- 2% NBT positive; 11% CD14 positive). The effect of ionomycin, a calcium ionophore, on PKCbeta levels and cell differentiation also was examined. Alone, 5 microM ionomycin promoted few cells (3% CD14 positive) to differentiate. In contrast, cells treated with 5 microM ionomycin for 66 hr after a 6-hr pretreatment with 20 nM 1,25-(OH)2D3 resulted in 34 +/- 5% NBT positive cells and 73% CD14 positive cells. Quantitatively, this induction of differentiation was identical to that observed in cultures continuously treated with 1,25-(OH)2D3 (35 +/- 2% NBT positive; 70% CD14 positive). Therefore, ionomycin seemed to replace the requirement for the continuous presence of 1,25-(OH)2D3. Chelerythrine chloride (3 microM), a specific PKC inhibitor, blocked differentiation promoted by 1,25-(OH)2D3 alone (82 +/- 2% inhibition) or in sequence with ionomycin (86 +/- 3% inhibition). Taken together, our data show that the capacity of 1,25-(OH)2D3 to both increase PKCbeta levels and activate PKC is utilized to promote HL-60 cell differentiation. These data further suggest that 1,25-(OH)2D3 has a genomic action to increase PKCbeta levels and also a nongenomic action requiring its continuous presence to promote HL-60 cell differentiation.
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PMID:Promotion of HL-60 cell differentiation by 1,25-dihydroxyvitamin D3 regulation of protein kinase C levels and activity. 935 91

Antigen processing in B cells is initiated by antigen binding to the surface B cell antigen receptor (BCR). The BCR is a signaling receptor which also functions to endocytose bound antigen for subsequent intracellular processing and presentation with class II molecules. Previously, using subcellular fractionation, we showed that although the surface BCR constitutively traffics from the cell surface to the class II peptide-loading compartment (IIPLC), cross-linking the BCR regulates trafficking, resulting in a more rapid movement of the BCR to the IIPLC (Song et al., 1995, J. Immunol. 155, 4255). The rate of degradation of both the BCR and the bound antigen was also accelerated following BCR cross-linking. Here we provide evidence that the effect of cross-linking the BCR on antigen processing is in part dependent on signal cascades initiated by the BCR. We show that the protein kinase inhibitors Genistein and Chelerythrine, which block BCR signaling, reduce BCR-enhanced antigen processing in a dose-dependent manner. The kinase inhibitors have a small effect on the rate of internalization of the BCR and antigen following BCR cross-linking and significantly decrease the accelerated trafficking to the IIPLC. The increased rate of degradation of the BCR and antigen induced by BCR cross-linking is also decreased by the kinase inhibitors. BCR signaling does not appear to have a global effect on intracellular membrane trafficking as cross-linking the BCR did not alter the rate of trafficking of newly synthesized class II molecules to the IIPLC. Thus, the signaling function of the BCR appears to play a significant role in regulating discrete steps in the intracellular antigen processing pathway.
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PMID:Signaling through the B cell antigen receptor regulates discrete steps in the antigen processing pathway. 962 30

Protein kinase C (PKC) regulates cystic fibrosis transmembrane conductance regulator (CFTR) channel activity but the PKC signaling mechanism is not yet known. The goal of these studies was to identify PKC isotype(s) required for control of CFTR function. CFTR activity was measured as 36Cl efflux in a Chinese hamster ovary cell line stably expressing wild-type CFTR (CHO-wtCFTR) and in a Calu-3 cell line. Chelerythrine, a PKC inhibitor, delayed increased CFTR activity induced with phorbol 12-myristate 13-acetate or with the cAMP-generating agents (-)-epinephrine or forskolin plus 8-(4-chlorophenylthio)adenosine 3',5'- cyclic monophosphate. Immunoblot analysis of Calu-3 cells revealed that PKC-alpha, -betaII, -delta, -epsilon, and -zeta were expressed in confluent cell cultures. Pretreatment of cell monolayers with Lipofectin plus antisense oligonucleotide to PKC-epsilon for 48 h prevented stimulation of CFTR with (-)-epinephrine, reduced PKC-epsilon activity in unstimulated cells by 52.1%, and decreased PKC-epsilon mass by 76.1% but did not affect hormone-activated protein kinase A activity. Sense oligonucleotide to PKC-epsilon and antisense oligonucleotide to PKC-delta and -zeta did not alter (-)-epinephrine-stimulated CFTR activity. These results demonstrate the selective regulation of CFTR function by constitutively active PKC-epsilon.
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PMID:Antisense oligonucleotide to PKC-epsilon alters cAMP-dependent stimulation of CFTR in Calu-3 cells. 981 85


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