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

Vascular endothelial growth factor (VEGF) is a specific mitogen for vascular endothelial cells and has been implicated in tumor angiogenesis. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter in two-stage carcinogenesis experiments in mouse skin. To elucidate the role of VEGF in the angiogenesis of these experimental tumors, the effect of okadaic acid on VEGF gene expression was examined. In NIH 3T3, Rat1, HeLa, and A431 cells, VEGF mRNA was upregulated by 5- to 10-fold after incubation with okadaic acid. Furthermore, the amount of VEGF protein in the culture medium was significantly increased after stimulation with okadaic acid. Interestingly, okadaic acid-induced upregulation of VEGF mRNA was not suppressed by protein kinase C (PKC) inhibitor or by tumor necrosis factor alpha blocking antibody, although TPA-induced VEGF upregulation was strongly suppressed by PKC inhibitor. Our results indicate that okadaic acid is a new and potent inducer of VEGF, suggesting the involvement of VEGF as an angiogenic factor during multistep carcinogenesis in vivo.
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PMID:Okadaic acid stimulates the expression of vascular endothelial growth factor gene. 1055 13

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has a strong association with growth and metastasis of various cancers. We analyzed the expression of VEGF mRNA levels in human breast-tumor derived GI-101A cells and in human promyelocytic leukemia derived HL-60 cells using RT-PCR technique. During our RT-PCR analysis we detected the expression of three splice variants of VEGF mRNA at 400, 520 and, 650 bp lengths, which were amplified by a single set of VEGF specific forward and reverse primers. The three RT-PCR products detected by us in these cells correspond to the mRNA splice variants coding for the three isoforms of VEGF respectively, VEGF(121), VEGF(165), and VEGF(189). Treatment of GI-101A and HL-60 cells with phorbol 12, 13-dibutyrate (PDB) or diethylstilbestrol (DES) resulted in a significant increase of VEGF mRNA levels in a dose dependent manner. Both treatments increased the levels of all three splice variants of VEGF mRNA and a maximum increase was detected with 10 microM concentrations of PDB or DES treatments after 2 h. Interestingly, both PDB and DES mediated stimulation of VEGF mRNA expression was completely blocked by the PKC inhibitor chelerythrine. Quantitation of VEGF levels by ELISA technique confirmed that changes seen in mRNA levels following different treatments altered the release of VEGF. Our results suggest that PDB and DES mediated effects on VEGF expression in GI-101A and HL-60 cells occur at the gene transcription level.
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PMID:Expression of vascular endothelial growth factor mRNA in GI-101A and HL-60 cell lines. 1077 88

The mechanism(s) underlying lead neurotoxicity are not fully elucidated. cDNA expression microarray analysis identified lead-sensitive genes in immortalized human fetal astrocytes (SV-FHA). Of the represented genes expressed, vascular endothelial growth factor (VEGF) was one of the most sensitive. Lead induced VEGF mRNA 3-fold and VEGF protein approximately 2-fold with maximum mRNA induction following incubation with 10 micrometer lead acetate for 24 h. Phorbol 12-myristate 13-acetate (PMA), a potent protein kinase C (PKC) activator, increased VEGF mRNA 2-fold and PKC inhibition by GF-109203 completely blocked VEGF induction by lead. Expression of dominant-negative PKC-epsilon, but not PKC-alpha, completely inhibited VEGF mRNA induction by lead. Lead activated the transcription factor AP-1 and increased AP-1-dependent luciferase expression >2-fold. Transfection of cells with a c-jun dominant-negative effectively inhibited both AP-1 activation and VEGF mRNA induction by lead. Hypoxia-inducible factor 1 (HIF-1) activity in SV-FHAs was moderately increased by lead (86%) and PMA (96%). Pretreatment with GF-109203 completely inhibited these effects of lead and PMA. However, lead did not alter HIF-1-dependent luciferase expression and a HIF-1alpha dominant-negative had no effects on the induction of VEGF mRNA by lead. These findings indicate that lead induces VEGF expression in SV-FHAs via a PKC/AP-1-dependent and HIF-1-independent signaling pathway.
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PMID:Induction of vascular endothelial growth factor in human astrocytes by lead. Involvement of a protein kinase C/activator protein-1 complex-dependent and hypoxia-inducible factor 1-independent signaling pathway. 1088 16

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a multifunctional cytokine, is regulated by different factors including degree of cell differentiation, hypoxia, and certain oncogenes namely, ras and src. The up-regulation of VPF/VEGF expression by Ras has been found to be through both transcription and mRNA stability. The present study investigates a novel pathway whereby Ras promotes the transcription of VPF/VEGF by activating protein kinase Czeta (PKCzeta). The Ras-mediated overexpression of VPF/VEGF was also found to be inhibited by using the antisense or the dominant-negative mutant of PKCzeta. In co-transfection assays, by overexpressing oncogenic Ha-Ras (12 V) and PKCzeta, there was an additive effect up to 4-fold in activation of Sp1-mediated VPF/VEGF transcription. It has been shown through electrophoretic mobility shift assay that Ras promoted the PKCzeta-induced binding of Sp1 to the VPF/VEGF promoter. In the presence of PDK-1, a major activating kinase for PKC, the Ras-mediated activation of VPF/VEGF promoter through PKCzeta was further increased, suggesting that PKCzeta can serve as an effector for both Ras and PDK-1. In other experiments, with the use of a dominant-negative mutant of phosphatidylinositol 3-kinase, the activation of VPF/VEGF promoter through Ras, PDK-1, and PKCzeta was completely repressed, indicating phosphatidylinositol 3-kinase as an important component of this pathway. Taken together, these data elucidate the signaling mechanism of Ras-mediated VPF/VEGF transcriptional activation through PKCzeta and also provide insight into PKCzeta and Sp1-dependent transcriptional regulation of VPF/VEGF.
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PMID:Role of protein kinase Czeta in Ras-mediated transcriptional activation of vascular permeability factor/vascular endothelial growth factor expression. 1106 Mar 1

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that plays a central role in angiogenesis. In this study, we investigated the mechanism of VEGF expression in HepG2 human hepatoblastoma cells under hypoglycemia. The shortage of glucose significantly enhanced VEGF mRNA expression in a time-dependent manner as well as increased DNA-binding activity of AP-1 that plays an important role in VEGF transcription. In addition, treatment of a potent PKC inhibitor, H-7 in glucose-deprived HepG2 cells suppressed hypoglycemia-elevated VEGF expression as well as the increased AP-1 DNA-binding activity. Moreover, we observed that Ca2+ levels remarkably increased under low glucose condition. Consistently, an intracellular Ca2+ chelator, BAPTA/AM significantly decreased hypoglycemia-induced VEGF expression and AP-1 DNA-binding activity. Therefore, these results indicate that increase of intracellular Ca2+ level induces the activation of PKC, which induce the activation of AP-1 leading to the increase of VEGF in glucose-deprived environment. Furthermore, it provides one link in regulation of VEGF with hypoglycemia as well as information to understand how hypoglycemia induces VEGF expression and subsequently leads to tumor angiogenesis.
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PMID:Hypoglycemia-induced VEGF expression is mediated by intracellular Ca2+ and protein kinase C signaling pathway in HepG2 human hepatoblastoma cells. 1111 15

Ischemic preconditioning (IP) exerts cardioprotection through protein kinase C (PKC) activation, whereas myocardial ischemia enhances vascular endothelial growth factor (VEGF) mRNA expression. However, the IP effect or the involvement of PKC on the VEGF expression is unknown in myocardial infarction. We investigated whether IP enhances VEGF gene expression and angiogenesis through PKC activation in the in vivo myocardial infarction model. Sprague-Dawley rats were assigned into the following 3 groups: the sham group; the IP group, which underwent 3 cycles of 3 minutes of ischemia and 5 minutes of reperfusion (IP procedure); and the non-IP group. The latter 2 groups were subsequently subjected to left anterior descending coronary artery occlusion. To examine the involvement of PKC, the PKC inhibitor chelerythrine (5 mg/kg) or bisindolylmaleimide (1 mg/kg) was injected intravenously before the IP procedures. PKCepsilon was translocated to the nucleus after 10 minutes of ischemia after the IP procedure but was not translocated in the non-IP and the sham groups. VEGF mRNA expression 3 hours after infarction was significantly higher in the IP group than in the non-IP and the sham groups. Capillary density in the infarction was significantly higher, whereas the infarct size was smaller in the IP group than in the non-IP group at 3 days of infarction. Chelerythrine but not bisindolylmaleimide blocked all of the IP effects on the nuclear translocation of PKCepsilon, enhancement of VEGF mRNA expression and angiogenesis, and infarct size limitation. These results show that IP may enhance VEGF gene expression and angiogenesis through nuclear translocation of PKCepsilon in the infarcted myocardium.
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PMID:Ischemic preconditioning upregulates vascular endothelial growth factor mRNA expression and neovascularization via nuclear translocation of protein kinase C epsilon in the rat ischemic myocardium. 1130 92

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with the growth and metastasis of various cancers and plays a prominent role in vesical angiogenesis regulation. In this study, we investigated the effect of the phorbol 12-myristate 13-acetate (PMA) on the expression of VEGF in human bladder transitional carcinoma cells (RT4). RT4 cells expressed three VEGF isoforms (VEGF(189), VEGF(165), VEGF(121)). PMA increased VEGF mRNA expression time-dependently with a peak at 4 h. PMA increased the half-life of VEGF mRNA. The amount of VEGF protein in conditioned media was increased by PMA in a dose-dependent manner with a maximal effect at 10(-7) M. Staurosporine and calphostin C (PKC inhibitors) decreased PMA-induced VEGF mRNA expression as opposed to protein kinase A or cyclic nucleotide-dependent protein kinase inhibitors. Thus, in RT4 cells, VEGF expression is up-regulated by PMA via the PKC signalling pathway and according to a posttranscriptional mechanism.
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PMID:Protein kinase C signalling pathway is involved in the regulation of vascular endothelial growth factor expression in human bladder transitional carcinoma cells. 1148 11

Stretch-induced expression of vascular endothelial growth factor (VEGF) is thought to be important in mediating the exacerbation of diabetic retinopathy by systemic hypertension. However, the mechanisms underlying stretch-induced VEGF expression are not fully understood. We present novel findings demonstrating that stretch-induced VEGF expression in retinal capillary pericytes is mediated by phosphatidylinositol (PI) 3-kinase and protein kinase C (PKC)-zeta but is not mediated by ERK1/2, classical/novel isoforms of PKC, Akt, or Ras despite their activation by stretch. Cardiac profile cyclic stretch at 60 cpm increased VEGF mRNA expression in a time- and magnitude-dependent manner without altering mRNA stability. Stretch increased ERK1/2 phosphorylation, PI 3-kinase activity, Akt phosphorylation, and PKC-zeta activity. Signaling pathways were explored using inhibitors of PKC, MEK1/2, and PI 3-kinase; adenovirus-mediated overexpression of ERK, PKC-alpha, PKC-delta, PKC-zeta, and Akt; and dominant negative (DN) mutants of ERK, PKC-zeta, Ras, PI 3-kinase and Akt. Although stretch activated ERK1/2 through a Ras- and PKC classical/novel isoform-dependent pathway, these pathways were not responsible for stretch-induced VEGF expression. Overexpression of DN ERK and Ras had no effect on VEGF expression in these cells. In contrast, DN PI 3-kinase as well as pharmacologic inhibitors of PI 3-kinase blocked stretch-induced VEGF expression. Although stretch-induced PI 3-kinase activation increased both Akt phosphorylation and activity of PKC-zeta, VEGF expression was dependent on PKC-zeta but not Akt. In addition, PKC-zeta did not mediate stretch-induced ERK1/2 activation. These results suggest that stretch-induced expression of VEGF involves a novel mechanism dependent upon PI 3-kinase-mediated activation of PKC-zeta that is independent of stretch-induced activation of ERK1/2, classical/novel PKC isoforms, Ras, or Akt. This mechanism may play a role in the well documented association of concomitant hypertension with clinical exacerbation of neovascularization and vascular permeability.
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PMID:Stretch-induced retinal vascular endothelial growth factor expression is mediated by phosphatidylinositol 3-kinase and protein kinase C (PKC)-zeta but not by stretch-induced ERK1/2, Akt, Ras, or classical/novel PKC pathways. 1169 3

1. Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin-induced granulation tissue in rats were analysed in vitro and in vivo. 2. Incubation of the minced granulation tissue in the presence of histamine (1 and 10 microM) increased the content of VEGF protein in the conditioned medium in a time- and concentration-dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration-dependent manner. 3. The increase in the content of VEGF protein in the conditioned medium by histamine (10 microM) was suppressed by the H(2) receptor antagonist cimetidine (IC(50) 0.37 microM), but not by the H(1) receptor antagonist pyrilamine maleate, the H(3) receptor antagonist thioperamide or the cyclo-oxygenase inhibitor indomethacin. 4. The histamine-induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp-cAMP (IC(50) 6.8 microM), and the protein kinase A inhibitor H-89 (IC(50) 12.5 microM), but not by the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein. 5. Simultaneous injection of cimetidine (400 microg) and indomethacin (100 microg) into the air pouch of rats additively reduced the carrageenin-induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye. 6. These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H(2) receptor-cyclic AMP-protein kinase A pathway and augments angiogenesis in the granulation tissue.
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PMID:Enhancement by histamine of vascular endothelial growth factor production in granulation tissue via H(2) receptors. 1172 47

Podocytes are the major site of vascular endothelial growth factor (VEGF) production in the kidney, and up-regulation of VEGF plays a critical role in the progression of diabetic nephropathy. Using a differentiated mouse podocyte cell line, we investigated the roles of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) on the expression of VEGF under high glucose conditions. High glucose induced up-regulation of VEGF mRNA and protein expression in podocytes via activation of PKC (PKC-alpha and -betaII isoforms) and ERK. High glucose stimulated [(3)H]leucine incorporation in the podocytes. High glucose and the PKC stimulator, phorbol 12-myristate 13-acetate (PMA) induced activator protein-1 (AP-1)-dependent transcriptional activity and expression of VEGF. In addition, these phenomena were blocked by specific inhibitors of PKC (GF10902X) and ERK kinase (PD98059). These observations suggested that high glucose-induced VEGF expression in podocytes was largely mediated through PKC and ERK pathways that may be involved in diabetic nephropathy.
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PMID:High glucose induced VEGF expression via PKC and ERK in glomerular podocytes. 1177 50


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