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)

Platelet-derived growth factor and phorbol ester cause an increase in vascular endothelial growth factor (VEGF) mRNA expression in control NIH 3T3 fibroblasts and NIH 3T3 fibroblasts overexpressing human protein kinase C (PKC) alpha. In the case of phorbol ester-induced VEGF expression, the VEGF mRNA levels were significantly higher in cells overexpressing human PKC alpha as compared to control cells. In cells stimulated with platelet-derived growth factor or phorbol ester, induction of expression was lost after down-regulation of PKC. This indicates that PKC is involved in the signal transduction leading to VEGF expression.
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PMID:Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. 151 46

Vascular endothelial growth factor (VEGF) is an angiogenic polypeptide that has been isolated from a variety of tumorigenic and nontransformed cell lines. Because of the importance of blood vessel growth to cell and tissue development, we have examined VEGF gene expression in a variety of mouse tissues and rodent models of cellular differentiation. Using a cloned murine VEGF cDNA we show that VEGF mRNA is expressed at relatively low levels in many adult mouse tissues examined. However, this message is dramatically induced in two models of cell differentiation: 3T3-adipose conversion and C2C12 myogenic differentiation. VEGF protein secretion is also induced in adipocyte differentiation. VEGF mRNA is markedly regulated in a pheochromocytoma (PC12) cell model of transformation and differentiation. The transformed undifferentiated cells express moderate levels of VEGF mRNA and this expression is virtually extinguished when cells differentiate into non-malignant neuron-like cells. Experiments employing phorbol esters and cAMP analogues indicate that VEGF mRNA expression is stimulated in preadipocytes by both protein kinase C and protein kinase A-mediated pathways. These results suggest that VEGF mRNA levels are closely linked to the process of cellular differentiation; they also clearly demonstrate that expression of this angiogenic factor is specifically regulated in a transformed cell line, possibly via aberrant activation of cellular second messenger pathways.
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PMID:Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. 164 16

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen, which also enhances vascular permeability. Because this angiogenic factor has been suggested to play a role in brain tumor biology, we have begun to investigate the regulation of VEGF expression in cultures of rat type I astrocytes. In this report, we have focused on the influence of hypoxia on VEGF expression. Under standard in vitro conditions (21% O2) VEGF expression in astrocytes in barely detectable by northern analysis. However, after exposure to 0.2% O2 for as little as 3 h VEGF mRNA levels are markedly increased reaching a maximum by approximately 8 h of exposure. Treatment of astrocytes with CoCl2 or desferrioxamine results in a similar induction of VEGF, suggesting that the oxygen sensor regulating VEGF expression in astrocytes is a heme-containing molecule. Although acute treatment with TPA (6 h) induces VEGF expression, chronic exposure to TPA (24 h) to deplete PKC activity does not reduce the hypoxia-induced VEGF expression. These data indicate that VEGF induction in astrocytes can proceed through PKC-dependent and -independent pathways. Furthermore, chronic exposure to TPA or treatment with herbimycin A results in the enhancement of the hypoxia-mediated increase in VEGF mRNA levels. These results suggest that PKC and herbimycin-sensitive tyrosine kinase may serve as negative regulators of the hypoxia-activated signal transduction pathway that leads to the induction of VEGF expression. However, treatment of astrocytes with the nonspecific kinase inhibitors H7 and H8 reduced the level of VEGF induction by hypoxia, indicating that some type of kinase activity is required in this signaling pathway.
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PMID:Hypoxia-induced vascular endothelial growth factor expression in normal rat astrocyte cultures. 755 44

Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of vascular endothelial growth factor in cardiac myocytes. 772 92

Many tumor cells produce vascular endothelial growth factor (VEGF), which is thought to be a pivotal mediator of tumor neoangiogenesis. Expression of the VEGF gene can be induced by tumor promoting phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), which activate protein kinase C (PKC). Here we show that in transient transfection assays a mutated form of the murine p53 tumor suppressor gene (ala135-->val) induces expression of VEGF mRNA and potentiates TPA stimulated VEGF mRNA expression. In NIH 3T3 cells which stably overexpress the temperature sensitive p53 (ala135-->val), displaying mutant phenotype at 37 degrees C and wildtype phenotype at 32.5 degrees C, induction of VEGF mRNA and protein by activated PKC is strongly synergistic with mutant, but not wildtype p53. Mutant p53 specifically increases TPA induction of VEGF without affecting the expression of other TPA inducible genes. TPA dependent VEGF expression is also enhanced by human p53 mutated at amino acid 175. Thus, our data link PKC and p53, the gene most frequently altered in human tumors, with the regulation of tumor angiogenesis.
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PMID:Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. 810 42

Vascular endothelial growth factor (VEGF) is a specific growth factor for endothelial cells, and its abundant expression has been reported in kidney glomeruli. In this study, we focused on glomerular endothelial cells (GEN) as a possible source of VEGF secretion and sought to uncover a potential autocrine role of VEGF for GEN. Ribonuclease protection assay demonstrated VEGF mRNA expression in cultured GEN, and 46-kDa VEGF protein was detected in the conditioned medium by immunoblot analysis using polyclonal antibody raised against the NH2-terminal portion of VEGF. Removal of fetal bovine serum (FBS) from the culture medium for 2 h decreased VEGF mRNA abundance, which was restored by the readdition of FBS (10%) within 2 h. The effect of FBS was completely abolished by protein kinase inhibitor H-7 (10 microM), suggesting that FBS-stimulated VEGF mRNA induction involves activation of protein kinases. The treatment of GEN with 10(-7) M 12-O-tetradecanoylphorbol-13-acetate (TPA) increased the VEGF mRNA abundance fivefold, supporting the idea that VEGF expression is regulated by protein kinase C. [3H]thymidine incorporation into GEN treated with TPA (10(-7) M) was inhibited by neutralizing antibody for VEGF. Thus VEGF was identified as an autocrine growth factor for GEN in vitro. Its physiological role might be the regulation of GEN proliferation, and the induction of VEGF expression by FBS and TPA suggests its involvement in the response of glomerular capillary endothelial cells to injury in certain pathophysiological states.
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PMID:Glomerular endothelial cells in culture express and secrete vascular endothelial growth factor. 830 87

Subretinal neovascularization is a severe sight-threatening complication into age-related macular degeneration. Previous immunohistochemical studies on surgically removed neovascular membranes have revealed that these membranes, in addition to the neovascular stroma, are comprised of several different cell types such as retinal pigment epithelial (RPE) cells, choroidal fibroblasts and vascular endothelial cells. Since vascular endothelial growth factor (VEGF) potently and specifically induces angiogenesis it was investigated whether VEGF is expressed and/or inducible in choroidal fibroblasts and RPE cells. Choroidal fibroblasts and RPE cells were isolated from human adult post-mortem eyes and expression of VEGF mRNA and protein was measured. By using Northern blotting, both choroidal fibroblasts and RPE cells were found to express VEGF mRNA at low levels. In order to examine whether this VEGF expression was further inducible, the intracellular effector enzyme protein kinase C was activated by phorbol esters. This activation resulted in a prominent increase in VEGF mRNA in choroidal fibroblasts, but not in RPE cells, with a maximal increase detected after 6 h. Elevation of intracellular cyclic AMP levels by forskolin had no clear effect on VEGF mRNA in either cell type. Stimulation with interleukin-1, transforming growth factor beta, tumour necrosis factor alpha and platelet derived growth factor was tested to see if VEGF expression is cytokine inducible. Both interleukin-1 and transforming growth factor beta induced VEGF expression in choroidal fibroblasts although with different time courses. Whereas the transforming growth factor beta effect was transient the interleukin-1 effect was sustained for at least 48 h. None of the cytokines tested affected VEGF expression in RPE cells. By using Western blotting, it was further found that stimulation with interleukin-1 induced VEGF protein expression in choroidal fibroblasts but not in RPE cells. In conclusion, choroidal fibroblasts respond by elevated VEGF mRNA levels after phorbol ester, interleukin-1 and transforming growth factor beta stimulation and elevated VEGF protein levels after phorbol ester and interleukin-1 stimulation suggesting that choroidal fibroblasts may be target cells for increased VEGF synthesis secondary to paracrine cytokine production.
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PMID:Expression and regulation of vascular endothelial growth factor in choroidal fibroblasts. 858 29

Hyperglycemia is an independent risk factor for the development of diabetic microvascular disease. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is a potent cytokine family that induces angiogenesis and markedly increases endothelial permeability. VPF is produced by many cell types, including vascular smooth muscle (VSM) cells, and has been implicated in the pathogenesis of neovascularization and endothelial dysfunction in diabetes. This study used cultured human VSM cells to study the regulation of VPF production and determine whether elevated glucose concentrations, per se, are a sufficient stimulus for increased VPF production by human cells. In human VSM cells, high extracellular glucose concentrations (20 mmol/l) increased VPF mRNA expression within 3 h (3-fold vs. glucose 5 mmol/l) and significantly increased VPF peptide production within 24 h (1.5-fold) in a time- and glucose concentration-dependent manner. The high glucose-induced increase in VPF mRNA expression was rapidly reversed after normalizing the extracellular glucose concentration and was specific for a high D-glucose concentration, as these effects were not reproduced by osmotic control media containing elevated concentrations of mannitol or L-glucose. High glucose concentrations activate protein kinase C (PKC) in human VSM cells, and PKC inhibitors (H-7 or chelerythrine chloride) or PKC downregulation each prevented the glucose-induced increases in VPF mRNA expression by human VSM cells. In conclusion, high glucose concentrations directly increase VPF mRNA expression and peptide production by human VSM cells via a PKC-dependent mechanism. These results demonstrate a cellular mechanism, whereby hyperglycemia could directly contribute to the development of endothelial dysfunction and neovascularization in diabetes.
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PMID:Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. 928 52

Hemodynamic abnormalities have been implicated in the pathogenesis of the increased glomerular permeability to protein of diabetic and other glomerulopathies. Vascular permeability factor (VPF) is one of the most powerful promoters of vascular permeability. We studied the effect of stretch on VPF production by human mesangial cells and the intracellular signaling pathways involved. The application of mechanical stretch (elongation 10%) for 6 h induced a 2.4-fold increase over control in the VPF mRNA level (P < 0.05). There was a corresponding 3-fold increase in VPF protein level by 12 h (P < 0. 001), returning to the baseline by 24 h. Stretch-induced VPF secretion was partially prevented both by the protein kinase C (PKC) inhibitor H7 (50 microM: 72% inhibition, P < 0.05) and by pretreatment with phorbol ester (phorbol-12-myristate-13 acetate 10(-)7 M: 77% inhibition, P < 0.05). A variety of protein tyrosine kinase (PTK) inhibitors, genistein (20 microg/ml), herbimycin A (3.4 microM), and a specific pp60(src) peptide inhibitor (21 microM) also significantly reduced, but did not entirely prevent, stretch-induced VPF protein secretion (respectively 63%, 80%, and 75% inhibition; P < 0.05 for all). The combination of both PKC and PTK inhibition completely abolished the VPF response to mechanical stretch (100% inhibition, P < 0.05). Stretch induces VPF gene expression and protein secretion in human mesangial cells via PKC- and PTK-dependent mechanisms.
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PMID:Mechanical stretch induces vascular permeability factor in human mesangial cells: mechanisms of signal transduction. 934 71

Mutation or loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is regularly found in sporadic renal cell carcinomas (RCC), well vascularized malignant tumors that characteristically overexpress vascular permeability factor/vascular endothelial growth factor (VPF/VEGF). The wild-type VHL (wt-VHL) gene product acts to suppress VPF/VEGF expression, which is overexpressed when wt-VHL is inactive. The present study investigated the pathways by which VHL regulates VPF/VEGF expression. We found that inhibition of protein kinase C (PKC) represses VPF/VEGF expression in RCC cells that regularly overexpress VPF/VEGF. The wt-VHL expressed by stably transfected RCC cells forms cytoplasmic complexes with two specific PKC isoforms, zeta and delta, and prevents their translocation to the cell membrane where they otherwise would engage in signaling steps that lead to VPF/VEGF overexpression. Other experiments implicated mitogen-activated protein kinase (MAPK) phosphorylation as a downstream step in PKC regulation of VPF/VEGF expression. Taken together, these data demonstrate that wt-VHL, by neutralizing PKC isoforms zeta and delta and thereby inhibiting MAPK activation, plays an important role in preventing aberrant VPF/VEGF overexpression and the angiogenesis that results from such overexpression.
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PMID:The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. 934 79


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