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)

Trapidil is a PDGF antagonist that can inhibit the proliferation of the PDGF-producing glioma cells, U251MG. As the mechanism of growth-regulation by trapidil remains unclear, we studied its effect on the growth of U251MG cells. We performed a cell cycle analysis and examined the intracellular transduction pathway and oncogene expression in serum-stimulated glioma cells with or without trapidil. After the serum starvation for 3 days, glioma cell proliferation was stimulated by the addition of serum. Cell cycle analysis showed that cell cycle perturbations induced by trapidil included a decreased transition rate from G0-G1 to S phase, suggesting that some metabolic event is required for progress through the G0-G1 phase and that this event is sensitive to trapidil. Internal signal transduction mechanisms are central in the molecular control of cell growth. One such regulator is the protein kinase C(PKC) system and the c-fos gene is likely to be a direct target of intracellular signal transduction pathways. Therefore, we hypothesize that the intracellular PKC activity and c-fos expression of the trapidil-treated cells are suppressed. We posit that trapidil affects the intracellular signal transduction pathway PKC activity and c-fos expression in cells stimulated with serum containing growth factors.
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PMID:The mechanism of growth-regulation of glioma cells by trapidil. 767 82

Arachidonic acid metabolites have been implicated in multiple steps of carcinogenesis. Their role in tumor cell metastasis, the ultimate challenge for the treatment of cancer patients, are however not well-documented. Arachidonic acid is primarily metabolized through three pathways, i.e., cyclooxygenase, lipoxygenase, and P450-dependent monooxygenase. In this review we focus our attention on one specific lipoxygenase, i.e., 12-lipoxygenase, and its potential role in modulating the metastatic process. In mammalian cells there exist three types of 12-lipoxygenases which differ in tissue distribution, preferential substrates, and profile of their metabolites. Most of these 12-lipoxygenases have been cloned and sequenced, and the molecular and biochemical determinants responsible for catalysis of specific substrates characterized. Solid tumor cells express 12-lipoxygenase mRNA, possess 12-lipoxygenase protein, and biosynthesize 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid], as revealed by numerous experimental approaches. The ability of tumor cells to generate 12(S)-HETE is positively correlated to their metastatic potential. A large collection of experimental data suggest that 12(S)-HETE is a crucial intracellular signaling molecule that activates protein kinase C and mediates the biological functions of many growth factors and cytokines such as bFGF, PDGF, EGF, and AMF. 12(S)-HETE plays a pivotal role in multiple steps of the metastatic 'cascade' encompassing tumor cell-vasculature interactions, tumor cell motility, proteolysis, invasion, and angiogenesis. The fact that 12-lipoxygenase is expressed in a wide diversity of tumor cell lines and 12(S)-HETE is a key modulatory molecule in metastasis provides the rationale for targeting these molecules in anti-cancer and anti-metastasis therapeutic protocols.
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PMID:12-lipoxygenases and 12(S)-HETE: role in cancer metastasis. 771 97

Although the Na+/Ca2+ exchanger is one of the major Ca2+ extrusion systems in excitable tissues, little is known about its regulation via protein phosphorylation. We now present evidence that the Na+/Ca2+ exchanger is phosphorylated in quiescent and growth factor-stimulated cultured aortic smooth muscle cells. The Na+/Ca2+ exchanger was isolated from 32P-labeled cells by immunoprecipitation with a specific polyclonal antibody. Phosphorylation of the exchanger was increased by up to 1.7-fold in response to platelet-derived growth factor-BB (PDGF-BB), alpha-thrombin, or phorbol 12-myristate 13-acetate (PMA). However, angiotensin II did not enhance the phosphorylation significantly. The extent of phosphorylation appeared to correlate with the growth factor-induced increase in cell 1,2-diacylglycerol. At least four phosphopeptides (P1 to P4) were detected by tryptic phosphopeptide map analysis of the phosphorylated exchanger, suggesting that phosphorylation occurred at multiple sites. PDGF-BB and PMA increased phosphorylation of the same phosphopeptides (in particular P1). Phosphorylated amino acids were exclusively serine residues in both quiescent and stimulated cells. We found that growth factors enhanced Na+/Ca2+ exchange activity and that there was a good correlation between the growth factor-induced stimulations of phosphorylation and exchange activity. PDGF-BB-induced activation of the exchanger was abolished by prior long treatment of cells with PMA. These results suggest that the Na+/Ca2+ exchanger is activated by protein kinase C-dependent phosphorylation in response to growth factors in vascular smooth muscle cells.
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PMID:Growth factor-induced phosphorylation and activation of aortic smooth muscle Na+/Ca2+ exchanger. 772 10

Interleukin-1 (IL-1) is a potent bone resorbing cytokine with diverse biological effects. We previously reported that IL-1 inhibits PDGF-AA-induced biological activities including PDGF-AA-induced tyrosyl phosphorylation. In the present studies, we first investigated and compared the tyrosyl phosphorylation pattern induced by EGF, IGF-1, PDGF-AA, and bFGF in human osteoblastic cells. We then examined the effect of IL-1 on the tyrosyl phosphoproteins induced by each ligand. Immunoblot analyses show that EGF, IGF-1, and PDGF-AA each elicit a different pattern of tyrosyl phosphorylated proteins in normal human osteoblastic cells. IL-1 beta inhibits PDGF-AA induced autophosphorylation by down-regulation of the PDGF-alpha receptor, as demonstrated by immunoprecipitation experiments. For other ligand-induced tyrosyl phosphoproteins, IL-1 beta reduced the intensity of EGF-induced pp55,000, and IGF-1 induced pp185,000 and pp175,000. These experiments indicate that IL-1 inhibits phosphorylation of specific proteins induced by growth factors. By using inhibitors of secondary message pathways, we determined that the inhibitory effect of IL-1 beta on PDGF-AA receptor binding and receptor tyrosyl autophosphorylation was not dependent on protein kinase A, protein kinase C, or the formation of prostaglandins. These data suggest the existence of an alternative pathway that may participate in IL-1 beta signaling.
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PMID:Interleukin-1 modulates phosphorylation of proteins in human osteoblastic cells. 774 36

To investigate the responsiveness to phorbol ester-mediated malignant cell transformation of Balb/c 3T3 variant clones that were morphologically phorbol ester-sensitive and -resistant, we used an in vitro two-stage transformation assay in which cells were treated with 0.1 microgram/ml of MCA as an initiator and subsequently with 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. The morphologically TPA-sensitive variant, TR5, and the parent cells showed a relatively low sensitivity to TPA-induced cell transformation, whereas the morphologically TPA-resistant variant, TR4 cells, exhibited 50- to 100-fold higher sensitivity to phorbol ester-induced cell transformation than the parent or the TR5 cells. We investigated the effects of TPA on protein kinase C activity, 80 kDa PKC substrate phosphorylation, the organization of actin stress fibers, DNA synthesis, and anchorage-independent growth in the three cell clones. They showed similar responses to these biological and biochemical events, indicating that these PKC-mediated events may not be the causes of the differential responsiveness of the variant cells to TPA-induced cell transformation. We further examined their responsiveness to growth factor-mediated and spontaneous induction of membrane ruffling. When these cells were stimulated by PDGF in their growing phase, membrane ruffling was rapidly induced in the three cells. However, the PDGF-mediated membrane ruffling was completely suppressed in parent and TR5 but not TR4 cells in the confluent, contact-inhibited (steady-state) growth phase. Similar responses were observed by other growth factors such as insulin, IGF-I, acidic or basic FGF. In addition, when the cells were cultured beyond confluence in the presence of TPA, spontaneous membrane ruffling was induced continuously up to termination of culture in TR4 but not in parent and TR5 cells. These results suggest that the deficiency in cell contact-mediated inhibition of membrane ruffling may be responsible for hypersensitivity of TR4 cells to TPA-induced cell transformation.
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PMID:Differential susceptibility of morphologically TPA-resistant and -sensitive Balb/c 3T3 variants to TPA-induced cell transformation: relationship to induction of membrane ruffling. 782 Aug 74

In cultured human fibroblasts the transport of anionic amino acids through the sodium-dependent system X-AG is stimulated rapidly and transiently by phorbol 12,13-dibutyrate. Transport stimulation is consistent with an effect due to the activation of protein kinase C. Bradykinin (1 microM) and PDGF-AA (100 ng/ml) also stimulate the activity of system X-AG. The bradykinin effect appears to be fully dependent upon PKC activation whereas the stimulation of aspartate transport by PDGF-AA is also due to PKC-independent mechanisms.
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PMID:The regulation of sodium-dependent transport of anionic amino acids in cultured human fibroblasts. 792 56

The murine myeloid progenitor cell line 32D was recently shown to undergo monocytic differentiation when protein kinase C-delta (PKC-delta) was overexpressed and activated by 12-O-tetradecanoylphorbol-13-acetate (TPA) (H. Mischak, J.H. Pierce, J. Goodnight, M.G. Kazanietz, P.M. Blumberg, and J.F. Mushinski, J. Biol. Chem. 268:20110-20115, 1993). Tyrosine phosphorylation of PKC-delta occurred when PKC-delta-transfected 32D cells were stimulated by TPA (W. Li, H. Mischak, J.-C. Yu, L.-M. Wang, J.F. Mushinski, M.A. Heidaran, and J.H. Pierce, J. Biol. Chem. 269:2349-2352, 1994). In order to elucidate the role played by PKC-delta in response to activation of a receptor tyrosine kinase, we transfected platelet-derived growth factor beta receptor (PDGF-beta R) alone (32D/PDGF-beta R) or together with PKC-delta (32D/PDGF-beta R/PKC-delta) into 32D cells. NIH 3T3 cells which endogenously express both PDGF-alpha R and PDGF-beta R were also transfected with PKC-delta (NIH 3T3/PKC-delta). Like TPA treatment, PDGF-BB stimulation caused striking phosphorylation of PKC-delta in vivo and translocation of some PKC-delta from the cytosol fraction to the membrane fraction in both cell systems. Some of the phosphorylation induced by PDGF-BB treatment was found to be on a tyrosine residue(s). Tyrosine-phosphorylated PKC-delta was observed only for the membrane fraction after stimulation with PDGF-BB or TPA. The enzymatic activity of PKC-delta in the membrane fraction also increased after stimulation with TPA or PDGF, providing a positive correlation between PKC-delta tyrosine phosphorylation and its activation. Overnight treatment of 32D/PDGF-beta R/PKC-delta cells with PDGF-BB induced monocytic differentiation as judged by an increase in expression of cell surface macrophage differentiation markers. PDGF-BB had much weaker effects on 32D/PDGF-beta R cell differentiation, suggesting that increased PKC-delta expression enhanced monocytic differentiation. These results indicate that PKC-delta is a downstream molecule in the PDGFR signaling pathway and may play a pivotal role in PDGF-beta R-mediated cell differentiation.
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PMID:Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta. 793 92

To determine the subcellular distribution of PKC after GFs treatment we have employed a combined immunochemical and in situ confocal microscopy analysis. In quiescent Swiss 3T3 cells only a faint PKC positivity was observable in the nucleus while a strong reaction was seen in the cytoplasm. IGF-I and to a lesser extent PDGF and EGF induced, after 45 min of treatment, a nuclear translocation of PKC detected by a pan-anti-PKC antibody and nuclear fluorescence was distributed in the nuclear interior except for the nucleolar regions. Bombesin and FGF did not affect the sub-cellular distribution of the enzyme. To further the understanding of which PKC isoform was involved in the translocation process, we have tested nine isozyme-specific anti-PKC antibodies. Immunoblotting analysis revealed the presence in Swiss 3T3 fibroblasts of alpha, beta I, epsilon and zeta isoforms. In isolated nuclei from GF-exposed cells only the alpha isozyme was detected: immunostaining was very intense after IGF-I treatment and clearly observable after PDGF and EGF stimulation. This result was strongly supported by the in situ confocal microscopy which parallels the Western blot analysis. These data demonstrate that several, but not all, GFs acting through tyrosine kinase receptor induce the intranuclear translocation of PKC alpha and, because of the dramatic effect of IGF-I, strengthen the case for a link between the activation of nuclear inositol lipid cycle and PKC translocation induced by this GF.
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PMID:Selective nuclear translocation of protein kinase C alpha in Swiss 3T3 cells treated with IGF-I, PDGF and EGF. 801 64

Platelet-derived growth factor receptor (PDGF-R) phosphorylation at tyrosines 740/751 and insulin receptor phosphorylation of insulin receptor substrate-1 effects the recruitment and activation of phosphatidylinositol-3-OH kinase (PI(3)K). Changes in PI(3)K activity correlate with cell growth but its downstream signal transducers are unknown. Activation of the 70/85K S6 kinases (pp70S6k) by serine phosphorylation results in 40S ribosomal protein S6 phosphorylation and is important for G1 cell-cycle transition in a variety of cells. Although receptor tyrosine kinases activate the microtubule-associated protein kinase cascade through SH2-/SH3-adaptor proteins, Sos and c-Ras, it is unclear how tyrosine kinases are coupled to the pp70S6k phosphorylation cascade. Here we report that PI(3)K mediates PDGF or insulin receptor signalling to pp70S6k. PI(3)K-mediated activation of pp70S6k is independent of conventional protein kinase C isoforms. Additionally, rapamycin blocks pp70S6k activation by all mitogens, without inhibiting PI(3)K, and acts downstream in this signalling system.
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PMID:PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. 801 12

Intracellular signaling pathways regulating vascular smooth muscle (VSM) cell growth and hypertrophy can be initiated by activation of receptor tyrosine kinases and/or protein kinase C (PKC). Mitogen-activated protein kinases (MAP kinases) are cytosolic serine/threonine kinases, proposed to act as a point of convergence for diverse growth factors utilizing these signaling pathways. The goals of this study were (1) to determine whether MAP kinase is expressed in cultured rat aortic VSM, (2) to assess the activation of MAP kinase by known proliferative and hypertrophic stimuli, and (3) to determine if stimulation of a PKC-dependent signaling pathway in these cells results in MAP kinase activation. MAP kinase activity was measured in cytosolic extracts of aortic VSM by quantifying myelin basic protein phosphorylation. Three peaks of activity were resolved chromatographically and identified as MAP kinase isoforms (MW 42, 44, and 46 kDa) by immunoblotting with antipeptide antibodies specific for MAP kinase. MAP kinase activity in quiescent growth-arrested cells (157 +/- 19 pmole 32P/min/mg) was markedly stimulated within 15 min by known mitogens (10% serum, 731 +/- 40 pmole 32P/min/mg; 40 ng/ml PDGF, 670 +/- 105 pmole 32P/min/mg; P < 0.01) and partially sustained for at least 90 min (serum, 606 +/- 34 pmole 32P/min/mg; PDGF, 323 +/- 59 pmole 32P/min/mg P < 0.05). Angiotensin II (AII, 0.1 microM) and a pharmacological PKC activator, phorbol 12,13-dibutyrate (PDB, 0.1 microM), are reported to be nonmitogenic hypertrophic stimuli in these cells. These stimuli transiently increased MAP kinase activity with a peak at 5 min (AII, 328 +/- 15 pmole 32P/min/mg; PDB, 592 +/- 41 pmole 32P/min/mg; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of MAP kinase activity by growth stimuli in vascular smooth muscle. 804 Nov 41


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