Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In human umbilical vein endothelial cells, the protein kinase C (PKC) stimulation during the early G1 phase leads to potentiations in growth factor-stimulated DNA synthesis, the activation of cdc2 and cdk2 cyclin-dependent kinases, and the mRNA expression of cdc2, cyclins A, D1 and E, but not cdk2 or cdk4. Conversely, the PKC stimulation in the late G1 phase completely inhibits DNA synthesis, the activation of cyclin-dependent kinases, and the mRNA expression of the same set of molecules except cyclin D1. Further, we found that the PKC stimulation bimodally regulates the message levels of E2F1 and B-myb, which are transcription factors implicated in the control of the mammalian cell cycle progression. These results indicate that the PKC signal transduction pathway, depending on the timing of activation in the G1 phase, either positively or negatively regulates the message level of growth-regulating genes that are crucial for the G1 to S phase progression.
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PMID:E2F1, B-myb and selective members of cyclin/cdk subunits are targets for protein kinase C-mediated bimodal growth regulation in vascular endothelial cells. 812 11

Staurosporine (SSP) is an inhibitor of a variety of protein kinases with an especially high affinity towards protein kinase C. Whereas SSP has been shown to halt the cell cycle progression of various normal, nontransformed cell types in G1, most virus transformed or tumor cells are unaffected in G1 but arrest in G2 phase. SSP has also been observed to increase the appearance of cells with higher DNA content, suggestive of endoreduplication, in cultures of tumor cells. Using multivariate flow cytometry (DNA content vs. expression of cyclin B, nuclear p120 protein, or protein reactive with Ki-67 antibody) which makes it possible to discriminate cells with identical DNA content but at different phases of the cycle, we have studied the cell cycle progression of human lymphocytic leukemic MOLT-4 cells in the presence of 0.1 microM SSP. MOLT-4 cells did not arrest in G1 or G2 phase in the presence of the inhibitor. Rather, they failed to undergo cytokinesis, entering G1 phase at higher DNA ploidy (tetraploidy; G1T), and then progressed through ST (rereplication) into G2T and MT. The rates of entrance to G2 and G2T were essentially identical, indicating that the rates of cell progression through S and ST as well as through G2 and G2T, respectively, were similar. Cells entrance to mitosis and mitotic chromatin condensation were also similar at the diploid and tetraploid DNA content level and were unaffected by 0.1 microM SSP. No evidence of growth imbalance (altered protein or RNA to DNA ratio) was observed in the case of tetraploid cells. The data show that, in the case of MOLT-4 cells, all events associated with the chromosome or DNA cycle were unaffected by SSP; the only target of the inhibitor appears to be kinase(s) controlling cytokinesis.
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PMID:Effect of staurosporine on MOLT-4 cell progression through G2 and on cytokinesis. 812 77

In human umbilical vein endothelial cells, activators of protein kinase C (PKC) exert cell cycle-dependent, bidirectional growth regulatory effects. Thus, phorbol 12,13-dibutyrate or 1,2-dioctanoylglycerol potentiates growth factor-induced DNA synthesis up to 3-fold when they act during the early G1 phase, whereas they completely inhibit the initiation of DNA synthesis when they act in the late G1 phase. In addition, the PKC activators induce a rapid inhibition of the ongoing DNA synthesis when they are applied after entry into the S phase. The effects of the PKC activators in both stimulatory and inhibitory directions are abolished in PKC-downregulated cells. The cell cycle-dependent, PKC-mediated bidirectional growth regulation is closely associated with either potentiation or inhibition of RB protein phosphorylation and the histone H1 kinase activity of cyclin-dependent kinases (cdks) cdc2 and cdk2, which normally accumulate along the G1 to the S phase transition. Northern and Western blot analyses of cdc2 and cdk2 have revealed that PKC regulates the cdks at multiple steps in distinct ways. Thus, for cdc2, the levels of mRNA and protein as well as the extent of post-translational modification are all subject to the PKC-mediated regulation. In contrast, the level of mRNA or protein of cdk2 is not affected by PKC stimulation at any phase of the cell cycle. These results demonstrate the existence of a complex array of PKC-cdk signaling pathways, which mediate temporally organized bimodal growth regulation in endothelial cells.
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PMID:Protein kinase C-mediated bidirectional regulation of DNA synthesis, RB protein phosphorylation, and cyclin-dependent kinases in human vascular endothelial cells. 822 19

A multitude of external signals induce extensive phosphorylation of Oncoprotein 18 (Op18), which suggests a putative role for this protein in signal transduction. We have recently identified two distinct proline-directed kinase families that phosphorylates Op18 with overlapping but distinct site preference. These two kinase families, mitogen-activated protein (MAP) kinases and cyclin-dependent cdc2 kinases, are involved in receptor- and cell cycle-regulated phosphorylation events, respectively. In the present study, site-specific phosphorylation of Op18 in response to stimulation of the antigen receptor-associated CD3 complex was analyzed in the Jurkat T cell-line. The results show that CD3-induced phosphorylation of Ser-25 of Op18, which is the primary MAP kinase phosphorylation site, can be induced by an apparently protein kinase C (PKC)-independent signal transduction pathway. We also demonstrate that Ser-16 of Op18 is specifically phosphorylated in response to the Ca2+ signal generated by CD3 stimulation or by the Ca2+ ionophore ionomycin. Ser-16 phosphorylation occurs independently of both PKC and MAP kinase activation. Using site-specific Op18 mutants and tryptic phosphopeptide mapping, we show that phosphorylation of Ser-16 of Op18 together with Ser-25, or Ser-25 and Ser-38, generates two Op18 phosphoisomers showing a dramatic electrophoretic retardation. In conclusion, site-mapping studies of Op18 reveal that CD3 stimulation results in an apparently PKC-independent activation of both the MAP kinase and a Ca(2+)-regulated kinase pathway, which results in phosphorylation of distinct sites of Op18. The data also pinpoints the specific phosphorylation events that result in electrophoretic retardation of Op18.
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PMID:Multiple signal transduction pathways induce phosphorylation of serines 16, 25, and 38 of oncoprotein 18 in T lymphocytes. 824 3

We show that the cyclin D1 gene is regulated by a variety of growth factors in human diploid fibroblasts (WI-38). Expression of cyclin D1 mRNA is low in quiescent WI-38 cells and reaches a maximum around 10 hours after serum stimulation, i.e. approximately 8 hours prior to the onset of DNA synthesis. A cyclin D1-specific antiserum raised against a bacterially expressed fusion protein detected a 39 kDa polypeptide in WI-38 cells. In agreement with the RNA expression data, cyclin D1 protein synthesis is also serum-inducible, reaching a maximum around 9 hours post-stimulation. The results obtained by pulse-chase experiments, cell fractionation and immunostaining techniques strongly suggest that cyclin D1 is a labile protein (t1/2 approximately 38 min), which is located in the nucleus. Cyclin D1 is directly induced by growth factors, i.e. in the presence of cycloheximide, and its expression does not significantly fluctuate during the cell cycle in synchronized cells. Cyclin D1 therefore fundamentally differs from "classical" cyclins, such as the mitotic cyclin B, whose expression is clearly cell cycle-dependent. Cyclin D1 may rather establish a direct link between growth control mechanisms and the cell cycle. Interestingly, cyclin D1 expression is stimulated by the protein kinase C activator TPA, but suppressed by dibutyryl-cAMP and the adenylate cyclase inducer forskolin, pointing to multiple regulatory pathways controlling cyclin D1 expression.
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PMID:Human cyclin D1 encodes a labile nuclear protein whose synthesis is directly induced by growth factors and suppressed by cyclic AMP. 838 78

We screened cdc2 kinase inhibitors from cultured mediums of micro organisms using purified mouse cyclin B-cdc2 kinase and a specific substrate peptide for cdc2 kinase. A selective inhibitor of cdc2 kinase was isolated from the cultured medium of Aspergillus species F-25799, and identified as butyrolactone I. Butyrolactone I inhibited cdc2 and cdk2 kinases but it had little effect on mitogen-activated protein kinase, protein kinase C, cyclic-AMP dependent kinase, casein kinase II, casein kinase I or epidermal growth factor-receptor tyrosine kinase. Its inhibitory effect was found to be due to competition with ATP. Butyrolactone I selectively inhibited the H1 histone phosphorylation in nuclear extracts. It also inhibited the phosphorylation of the product of retinoblastoma susceptibility gene in nuclear extracts and intact cells. Thus butyrolactone I should be very useful for elucidating the function of cdc2 and cdk2 kinases in cell cycle regulation.
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PMID:Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase. 839 80

The non-transmembrane protein tyrosine phosphatase, PTP1B, comprises 435 amino acids, of which the C-terminal 114 residues have been implicated in controlling both localization and function of this enzyme. Inspection of the sequence of the C-terminal segment reveals a number of potential sites of phosphorylation. We show that PTP1B is phosphorylated on seryl residues in vivo. Increased phosphorylation of PTP1B is seen to accompany the transition from G2 to M phase of the cell cycle. Two major tryptic phosphopeptides appear in two-dimensional maps of PTP1B from mitotic cells. One of these comigrates with the peptide generated following phosphorylation of PTP1B in vitro at Ser386 by the mitotic protein Ser/Thr kinase p34cdc2:cyclin B. The site of phosphorylation that is responsible for the pronounced retardation in the electrophoretic mobility of PTP1B from mitotic cells has been identified by site directed mutagenesis as Ser352. The identify of the kinase responsible for this modification is presently unknown. We also show that stimulation of HeLa cells with the phorbol ester TPA enhances phosphorylation of PTP1B. Two dimensional phosphopeptide mapping reveals that the bulk of the phosphate is in a single tryptic peptide. The site, identified as Ser378, is also the site of phosphorylation by protein kinase C (PKC) in vitro. Thus the TPA-stimulated phosphorylation of PTP1B in vivo appears to result directly from phosphorylation by PKC. The effect of phosphorylation on the activity of PTP1B has been examined in immunoprecipitates from TPA-treated and nocodazole-arrested cells. TPA treatment does not appear to affect activity directly, whereas the activity of PTP1B from nocodazole-arrested cells is only 70% of that from asynchronous populations.
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PMID:Multi-site phosphorylation of the protein tyrosine phosphatase, PTP1B: identification of cell cycle regulated and phorbol ester stimulated sites of phosphorylation. 849 Nov 87

The transcription factors SBF and DSC1/MBF bind SCB and MCB promoter elements, respectively, and are essential for the cell cycle progression of Saccharomyces cerevisiae through the control of G1 cyclin gene expression. We isolated a gene (BRY1; Bacterial Response regulator in Yeast) able to activate either MCB or SCB promoter elements on a reporter plasmid which, when overexpressed, can bypass the normally essential requirement for SBF and DSC1/MBF by the stimulation of CLN1 and CLN2 expression. In the case of CLN2 at least, this expression depends upon the MCB and SCB promoter elements. In wild-type yeast, the disruption of BRY1 has no apparent phenotype, but under conditions where the activities of SBF and DSC1/MBF are reduced, BRY1 becomes essential. Our data imply the existence of a third pathway affecting cyclin expression. BRY1 is the same gene as SKN7 which has significant sequence homology to the receiver domains found in response regulator proteins from the bacterial two-component signal transduction pathways. SKN7 is thought to affect cell wall structure, and when highly overexpressed we find that BRY1/SKN7 is lethal perhaps because of perturbations in cell wall biosynthesis. The lethality is partially rescued by genes from the protein kinase C pathway, but genetic data imply that BRY1/SKN7 and protein kinase C are not in the same pathway. Our results suggest that Bry1/Skn7 can influence the expression of MCB- and SCB-driven gene expression in budding yeast, perhaps including genes involved in cell wall metabolism, via a two-component signal transduction pathway which activates Bry1/Skn7 in response to an unidentified signal.
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PMID:A yeast transcription factor bypassing the requirement for SBF and DSC1/MBF in budding yeast has homology to bacterial signal transduction proteins. 852 25

7-Hydroxystaurosporine (UCN-01) is a potent inhibitor of protein kinase C (PKC) isozymes alpha, beta, and gamma [Seynaeve et al., Mol. Pharmacol, 45: 1207-1214, 1994] that also has antitumor effects in vivo. To determine whether inhibition of PKC can be related to inhibition of cell growth with induction of apoptosis, we compared the effects of UCN-01 to those of the highly selective bisindolylmaleimide PKC antagonist GF 109203X in leukemic T-cell lines. Both compounds potently inhibited PKC activity when added to T-cell membrane preparations and reversed phorbol ester-induced c-fos gene expression in intact cells. However, whereas UCN-01 potently inhibited growth of Jurkat, Molt-3, Molt-4, and Hut-78 cells (IC50 = 20-65 nM, irreversible after 24 h of exposure), GF 109203X had IC50s for cell growth of 3.6-5.0 muM. Less than 3 h after addition, UCN-01 but not GF 109203X-treated cells displayed loss of cells with G2-M DNA content, appearance of a hypodiploid DNA fraction, and evidence of internucleosomal DNA fragmentation. Six h after treatment, cells appeared to accumulate with S-phase DNA content. These effects correlated with selective UCN-01 but not GF 109203X-induced decrease in total and tyrosine phosphorylation of cyclin-dependent kinases (cdks) 1 and 2, and with increases in the histone H1 kinase activities of cdk1 and cdk2. UCN-01 was relatively less potent in inhibition of properly activated cdk1 and cdk2 when added in vitro to H1 kinase assays (IC50 = 1000 and 600 nM, respectively). We conclude that inhibition of PKC alone is not sufficient to account for the actions of UCN-01 and are led to the hypothesis that inappropriate cdk activation either correlates with or actually mediates cell growth inhibition with apoptosis in T lymphoblasts exposed to UCN-01.
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PMID:Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. 854 21

The Waf1/Cip1 protein induces cell cycle arrest through inhibition of the activity of cyclin-dependent kinases and proliferating cell nuclear antigen. Expression of the WAF1/CIP1 gene is induced in a p53-dependent manner in response to DNA damage but can also be induced in the absence of p53 by agents such as growth factors, phorbol esters, and okadaic acid. WAF1/CIP1 expression in U937 human leukemic cells is induced by both phorbol ester, a protein kinase C activator, and by okaidaic acid, an inhibitor of phosphatases 1 and 2A. Both of these agents induce the differentiation of these leukemic cells toward macrophages. We demonstrate that phorbol esters and okadaic acid stimulate transcription from the WAF1/CIP1 promoter in U937 cells. This transcription is mediated by a region of the promoter between -154 and +16, which contains two binding sites for the transcription factor Sp1. Deletion or mutation of these Sp1 sites reduces WAF1/CIP1 promoter response to phorbol ester and okadaic acid, while a reporter gene under the control of a promoter containing only multiple Sp1 binding sites and a TATA box is induced by phorbol ester and okadaic acid. The WAF1/CIP1 promoter is also highly induced by exogenous Sp1 in the Sp1-deficient Drosophila Schnieder SL 2 cell line. These results suggest that phorbol ester and okadaic acid activate transcription of the WAF1/CIP1 promoter through a complex of proteins that includes Sp1 and basal transcription factors.
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PMID:The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells. 855 3


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