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)

We have previously reported that primary sinusoidal endothelial cells from the rat liver are highly dependent on VEGF for cell proliferation in in vitro culture. However, even in the presence of VEGF, essentially all the SE cells could not survive longer than 7 days, leading to growth factor-resistant cell death. The death had characteristics typical of apopotosis, such as DNA fragmentation, staining with TUNEL reagent and nuclear condensation. We found that the cell death was blocked by the treatment of TPA in a dose-dependent manner and was preceded by a remarkable increase in PKCdelta at a protein level. Furthermore, PKCdelta-specific inhibitor, Rottrelin, significantly suppressed this VEGF-resistant apoptosis of cultured SE cells, whereas conventional PKC-specific inhibitor, Go6976 could not. TPA was found to downregulate the overexpression of PKCdelta. Thus, we suggest that the VEGF-resistant apoptosis is a new type of endothelial cell death and that PKCdelta is an essential mediator for this process.
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PMID:The overexpression of PKCdelta is involved in vascular endothelial growth factor-resistant apoptosis in cultured primary sinusoidal endothelial cells. 1116 32

Endothelial nitric-oxide synthase (eNOS) is an important regulatory enzyme in the cardiovascular system catalyzing the production of NO from arginine. Multiple protein kinases including Akt/PKB, cAMP-dependent protein kinase (PKA), and the AMP-activated protein kinase (AMPK) activate eNOS by phosphorylating Ser-1177 in response to various stimuli. During VEGF signaling in endothelial cells, there is a transient increase in Ser-1177 phosphorylation coupled with a decrease in Thr-495 phosphorylation that reverses over 10 min. PKC signaling in endothelial cells inhibits eNOS activity by phosphorylating Thr-495 and dephosphorylating Ser-1177 whereas PKA signaling acts in reverse by increasing phosphorylation of Ser-1177 and dephosphorylation of Thr-495 to activate eNOS. Both phosphatases PP1 and PP2A are associated with eNOS. PP1 is responsible for dephosphorylation of Thr-495 based on its specificity for this site in both eNOS and the corresponding synthetic phosphopeptide whereas PP2A is responsible for dephosphorylation of Ser-1177. Treatment of endothelial cells with calyculin selectively blocks PKA-mediated dephosphorylation of Thr-495 whereas okadaic acid selectively blocks PKC-mediated dephosphorylation of Ser-1177. These results show that regulation of eNOS activity involves coordinated signaling through Ser-1177 and Thr-495 by multiple protein kinases and phosphatases.
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PMID:Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. 1129 21

Vascular endothelial growth factor receptor-3 (VEGFR-3/Flt4) binds two known members of the VEGF ligand family, VEGF-C and VEGF-D, and has a critical function in the remodelling of the primary capillary vasculature of midgestation embryos. Later during development, VEGFR-3 regulates the growth and maintenance of the lymphatic vessels. In the present study, we have isolated and cultured stable lineages of blood vascular and lymphatic endothelial cells from human primary microvascular endothelium by using antibodies against the extracellular domain of VEGFR-3. We show that VEGFR-3 stimulation alone protects the lymphatic endothelial cells from serum deprivation-induced apoptosis and induces their growth and migration. At least some of these signals are transduced via a protein kinase C-dependent activation of the p42/p44 MAPK signalling cascade and via a wortmannin-sensitive induction of Akt phosphorylation. These results define the critical role of VEGF-C/VEGFR-3 signalling in the growth and survival of lymphatic endothelial cells. The culture of isolated lymphatic endothelial cells should now allow further studies of the molecular properties of these cells.
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PMID:Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. 1153 40

Diabetic nephropathy seems to occur as a result of an interaction of metabolic and haemodynamic factors. Glucose dependent pathways are activated within the diabetic kidney. These include increased oxidative stress, renal polyol formation and accumulation of advanced glycated end-products. Haemodynamic factors are also implicated in the pathogenesis of diabetic nephropathy and include increased systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin system and endothelin. These haemodynamic pathways, independently and with metabolic pathways, activate intracellular second messengers such as protein kinase C and MAP kinase, nuclear transcription factors such as NF-kappaB and various growth factors such as the prosclerotic cytokine, TGF-beta and the angiogenic, permeability enhancing growth factor, VEGF. These pathways ultimately lead to increased renal albumin permeability and extracellular matrix accumulation which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. Therapeutic strategies involved in the management and prevention of diabetic nephropathy include currently available treatments such as intensified glycaemic control and antihypertensive agents, particularly those which interrupt the renin-angiotensin system. More novel strategies to influence vasoactive hormone action or to inhibit various metabolic pathways such as inhibitors of advanced glycation, specific protein kinase C isoforms and aldose reductase are at present under experimental and clinical investigation. It is predicted that multiple therapies will be required to reduce the progression of diabetic nephropathy.
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PMID:Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. 1171 27

Acute intensive insulin therapy is an independent risk factor for diabetic retinopathy. Here we demonstrate that acute intensive insulin therapy markedly increases VEGF mRNA and protein levels in the retinae of diabetic rats. Retinal nuclear extracts from insulin-treated rats contain higher hypoxia-inducible factor-1alpha (HIF-1alpha) levels and demonstrate increased HIF-1alpha-dependent binding to hypoxia-responsive elements in the VEGF promoter. Blood-retinal barrier breakdown is markedly increased with acute intensive insulin therapy but can be reversed by treating animals with a fusion protein containing a soluble form of the VEGF receptor Flt; a control fusion protein has no such protective effect. The insulin-induced retinal HIF-1alpha and VEGF increases and the related blood-retinal barrier breakdown are suppressed by inhibitors of p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol (PI) 3-kinase, but not inhibitors of p42/p44 MAPK or protein kinase C. Taken together, these findings indicate that acute intensive insulin therapy produces a transient worsening of diabetic blood-retinal barrier breakdown via an HIF-1alpha-mediated increase in retinal VEGF expression. Insulin-induced VEGF expression requires p38 MAPK and PI 3-kinase, whereas hyperglycemia-induced VEGF expression is HIF-1alpha-independent and requires PKC and p42/p44 MAPK. To our knowledge, these data are the first to identify a specific mechanism for the transient worsening of diabetic retinopathy, specifically blood-retinal barrier breakdown, that follows the institution of intensive insulin therapy.
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PMID:Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. 1190 Nov 89

The autocrine motility factor (AMF) is known as a cytokine regulating tumor cells motility via AMF receptor (AMFR) and promotes their metastasis. Recently, AMFRs have been found on the surface of host cells and it was showed that AMF possibly affects them. The signaling of AMF-AMFR in the host endothelial cells induces expression of a vascular endothelial growth factor receptor (VEGFR) Flt-1 and AMFR feedback that is regulated at the transcriptional level. AMF-exposure stimulated the Flt-1 expression on human umbilical vein endothelial cells (HUVECs) surface and this AMF-treated cells exhibited high-responsibility against VEGF. The protein kinase C (PKC) and phosphatidylinositol 3 kinase (PI3K) play an important role in this signal transduction. The findings of our study suggest the possibility of "tumor AMF-->host AMFR-->PKC, PI3K-->-->VEGFR or AMFR-->angiogenesis, metastasis" as a new signal cross talk between the tumor and the host.
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PMID:Autocrine motility factor secreted by tumor cells upregulates vascular endothelial growth factor receptor (Flt-1) expression in endothelial cells. 1220 71

Activation of the protein kinase Akt/PKB mediates VEGF-dependent endothelial cell survival and eNOS activation. Here we examined the role of PKC in mediating VEGF-induced Akt activation. The PKC inhibitors GF109203X and calphostin C inhibited VEGF-induced Akt activation. Rottlerin and Go6976, inhibitors with specificities for PKC delta and alpha, respectively, also strongly inhibited VEGF-induced Akt activation. VEGF-induced Akt activation was prevented by down-regulation of PKC induced by prolonged pretreatment with the phorbol ester, PMA. VEGF induced phosphorylation of PKC delta at Thr 505 in the activation loop, and this phosphorylation was inhibited by LY294002, suggesting that modulation of PKC delta activation by VEGF occurs distal to phosphatidylinositol 3'-kinase. PKC and PI3K inhibitors both strongly reduced the stimulation of branching tubulogenesis by VEGF in vitro. The finding that PKC mediates VEGF-induced Akt activation identifies a novel signal transduction pathway through which Akt can be regulated by growth factors acting through receptor protein tyrosine kinases, and indicates that PKC-mediated Akt activity may play an essential role in VEGF-stimulated angiogenesis.
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PMID:Vascular endothelial growth factor induces protein kinase C (PKC)-dependent Akt/PKB activation and phosphatidylinositol 3'-kinase-mediates PKC delta phosphorylation: role of PKC in angiogenesis. 1237 7

We tested the hypothesis that VEGF regulates endothelial hyperpermeability to macromolecules by activating the ERK-1/2 MAPK pathway. We also tested whether PKC and nitric oxide (NO) mediate VEGF-induced increases in permeability via the ERK-1/2 pathway. FITC-Dextran 70 flux across human umbilical vein endothelial cell monolayers served as an index of permeability, whereas Western blots assessed the phosphorylation of ERK-1/2. VEGF-induced hyperpermeability was inhibited by antisense DNA oligonucleotides directed against ERK-1/2 and by blockade of MEK and Raf-1 activities (20 microM PD-98059 and 5 microM GW-5074). These blocking agents also reduced ERK-1/2 phosphorylation. The PKC inhibitor bisindolylmaleimide I (10 microM) blocked both VEGF-induced ERK-1/2 activation and hyperpermeability. The NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (200 microM) and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidiazoline-1-oxyl-3-oxide (100 microM) abolished VEGF-induced hyperpermeability but did not block ERK-1/2 phosphorylation. These observations demonstrate VEGF-induced hyperpermeability involves activation of PKC and NOS as well as Raf-1, MEK, and ERK-1/2. Furthermore, our data suggest that ERK-1/2 and NOS are elements of different signaling pathways in VEGF-induced hyperpermeability.
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PMID:VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide. 1238 27

Hepatocyte growth factor (HGF/SF)-induced expression of vascular endothelial growth factor (VEGF/VPF) has been implicated in paracrine amplification of angiogenesis, contributing to angiogenic responses during inflammation, wound healing, collateral formation and tumor growth. We have shown previously that HGF/SF-mediated VEGF/VPF expression by keratinocytes is primarily dependent on transcriptional activation, and we mapped the HGF/SF-responsive element to a GC-rich region between bp -88 and -65. Sp1-like factors bind to this element constitutively; however the VEGF/VPF promoter is transactivated by HGF/SF in the absence of induced binding activity. In experimental approaches to clarify molecular mechanisms of Sp1-dependent VEGF/VPF gene transcription, neither HGF/SF-dependent changes in nuclear expression nor in relative DNA binding activity of Sp family members to the indicated element were observed. Thus, HGF/SF was hypothesized to induce VEGF/VPF gene transcription via increased transactivation activity of Sp1 owing to biochemical modification. In immunoprecipitation studies, HGF/SF was found to increase the amount of serine-phosphorylated Sp1, revealing a likely mechanism of HGF/SF-induced VEGF/VPF expression, as phosphorylation may enhance the transcriptional activity of Sp1. The contribution of different signaling molecules to HGF/SF-induced VEGF/VPF transcription was demonstrated by the use of chemical inhibition, of expression of kinase-deficient signaling proteins, and by the use of antisense oligonucleotides. Herein, we provide evidence that PI 3-kinase, MEK1/2 and PKC-zeta play a significant role in HGF/SF-induced VEGF/VPF promoter activation. Together, our results elucidate a critical pathway of paracrine amplification of angiogenesis, suggesting that HGF/SF-induced Sp1 phosphorylation may activate VEGF/VPF promoter activity that requires the contribution of distinct signaling molecules.
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PMID:Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription. 1248 9

Gap junction channels provide the basis for the electrical syncytial properties of the heart as a communicating electrical network. Cardiac gap junction channels are predominantly composed of connexin 40 or connexin 43. The conductance of these channels (g(j)) can be regulated pharmacologically: substances which activate protein kinase C, protein kinase A or protein kinase G may alter Cx43 gap junction conductance. However, for PKC, this seems to be subtype specific. Thus, antiarrhythmic peptides can enhance g(j) via activation of PKCepsilon, while FGF-2 reduces g(j) via PKCepsilon. Lipophilic drugs can uncouple the channels. Besides an acute regulation of g(j), the expression of the cardiac connexins can also be regulated. A decrease in Cx43 with a concomitant increase in Cx40 has been found in end-stage failing hearts, while in renovascular hypertension, an increase in Cx43 has been described. Mediators like endothelin-1, angiotensin-II, TGF-beta, VEGF, and cAMP have been shown to increase Cx43. Interestingly, endothelin-1 and angiotensin-II increased Cx43 but did not affect Cx40 expression. In contrast, in humans suffering from atrial fibrillation (AF), the content in Cx40 can be enhanced while Cx43 was unaltered, although in several other studies, other changes of the cardiac connexins were found, which might be related to the type of AF. Regarding the role of calcium, the content in both Cx40 and Cx43 was decreased in cultured neonatal rat cardiomyocytes after 24 h administration of 100 nM verapamil. Thus, gap junctional channels can be affected pharmacologically either acutely by modulating gap junction conductance or chronically by altering gap junction protein expression. Interestingly, it appears that the expression of Cx43 and Cx40 can be differentially regulated.
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PMID:Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. 1256 16


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