Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic sublethal hypoxia has been associated with changes in neurovascular behavior, mediated, in part, by induction of vascular endothelial growth factor-A (VEGF-A(165)). In this report we demonstrate that RBE4 cells (derived from rodent cerebral microvasculature), when cultured in three-dimensional collagen gels: (1) Are induced to undergo increased tube formation in response to VEGF-A(165) in a dose-dependent manner; (2) undergo apoptosis under mild hypoxic conditions; (3) are rescued from the effects of hypoxia by the addition of exogenous VEGF-A(165) in a dose-dependent and inhibitable manner or by co-culture with primary newborn rat astrocytes, which are induced to express increased amounts of VEGF-A in hypoxic conditions. Further, we demonstrate that: (4) The observed astrocyte-produced, VEGF-mediated protection from apoptosis (survival) is inhibitable with soluble recombinant VEGF receptor-1 (sFlt), and is associated with a robust induction of MAPK tyrosine phosphorylation. These findings illustrate the importance of VEGF in the process of neurovascular survival in response to injury in developing brain and provide insight into the signaling pathways involved.
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PMID:Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro. 1155 1

The expression of VEGF and the relapse-free survival rate of breast cancer patients are inversely related. While VEGF induces the proliferation and migration of vascular endothelial cells, its function in breast cancer cells is not well studied. We reported previously that fibronectin increased VEGF-dependent migration in breast cancer cells. Since VEGF has an extracellular matrix (ECM)-binding domain and possesses binding affinity for heparin, we sought to determine the effects of VEGF in breast cancer cells and the role of heparin and/or fibronectin in VEGF-induced signaling. Cells grown on plastic were compared to those grown on fibronectin or to those grown on plastic in the presence of heparin, and analysed for intracellular signaling, proliferation and migration in response to VEGF(165). Both heparin and fibronectin enhanced the binding of VEGF to T47D cells. After treatment with VEGF, [(3)H]thymidine incorporation, c-fos induction, and the number of migrating cells were significantly higher ( approximately twofold) in cells grown on fibronectin or in cells grown on plastic in the presence of heparin when compared to those grown on plastic only. Likewise, tyrosine phosphorylation of VEGF receptors, MAPK activity and PI3-kinase activity were all several-fold higher in cells seeded on fibronectin or in the presence of heparin as compared to cells exposed to VEGF alone. VEGF-dependent c-fos induction was found to be regulated through a MAPK-dependent, but PI3-kinase-independent pathway. In contrast, the migration of T47D cells in response to VEGF, in the presence of ECM, was regulated through PI3-kinase. Therefore, VEGF requires ECM components to induce a mitogenic response and cell migration in T47D breast cancer cells.
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PMID:VEGF(165) requires extracellular matrix components to induce mitogenic effects and migratory response in breast cancer cells. 1157 49

VEGF is a key regulator of vascular permeability. However, its signaling pathways are incompletely understood. We tested the hypothesis that VEGF regulates endothelial cell (EC) permeability by activating PKB/akt, NOS, and MAP kinase dependent pathways using human umbilical vein EC (HUVEC). Permeability was measured from FITC-dextran 70-kDa flux across the EC monolayer at baseline and after VEGF at 0.034, 0.068, 1, 10, and 100 nM. VEGF increased HUVEC permeability to FITC-dextran in a dose-dependent manner. VEGF (1 nM) increased permeability from 3.9 x 10(-6) +/- 0.7 x 10(-6) to 14.0 x 10(-6) +/- 1.7 x 10(-6) cm/s (mean +/- SEM; P < 0.001). Permeability changes were also assessed after treatment with 1, 10, and 100 nM wortmannin (PI 3-kinase inhibitor); 0.01, 0.1, and 1.0 nM LY294002 (PI 3-kinase inhibitor); 200 microM l-NMMA (NOS inhibitor); 2.7 microM AG126 (p42/44(MAPK) inhibitor); and 0.006, 0.06, and 0.6 microM SB203580 (p38(MAPK) inhibitor). All inhibitors blocked VEGF-induced permeability changes. Our data demonstrate that (1) VEGF increases permeability of EC monolayers in a dose-dependent fashion, and (2) VEGF-induced permeability is mediated through PI-3 kinase-PKB, NOS, and MAP-kinase signaling cascades. These observations suggest that microvascular hyperpermeability associated with inflammation and vascular disease is mediated by activation of these EC signaling pathways.
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PMID:VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways. 1167 28

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

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) promotes its function primarily by activating two receptor tyrosine kinases, Flt-1 (VEGFR-1) and KDR (VEGFR-2). Recently, it has been shown that KDR is responsible for VPF/VEGF-stimulated endothelial cell (EC) proliferation and migration, whereas Flt-1 activation down-modulates KDR-mediated EC proliferation. Although KDR-mediated EC proliferation and migration have been extensively studied, much less is known about Flt-1-mediated antiproliferation. Here, we demonstrate that Flt-1-mediated antiproliferative activity can be blocked completely by the dominant negative mutant of CDC42 (CDC42-17N) and partially by a Rac1 dominant negative mutant (Rac1-17N) but is not affected by a RhoA dominant negative mutant (RhoA-19N). Both CDC42-17N and Rac1-17N increase the intracellular Ca(2+) mobilization in response to VPF/VEGF but have no effect on KDR and MAPK phosphorylation. Using the chimeric-receptor EGLT in which the extracellular domain of epidermal growth factor receptor was fused to the transmembrane and intracellular domains of Flt-1, we also demonstrate that CDC42 and Rac1 are activated by EGLT. Previously, we showed that phosphatidylinositol 3-kinase is required for Flt-1-mediated antiproliferative activity, but phospholipase C is not required. As expected, CDC42 and Rac1 activation mediated by EGLT can be completely inhibited by PI3K inhibitors, wortmannin and LY294002, and the p85 dominant negative mutant but not by either the phospholipase C inhibitor, or an intracellular Ca(2+) chilator BAPTA/AM. Surprisingly, pertussis toxin and overexpression of the free Gbetagamma-specific sequestering minigene hbetaARK1(495) also inhibit EGLT-mediated CDC42 and Rac1 activation completely. Moreover, pertussis toxin treatment also increases the intracellular Ca(2+) mobilization and inhibits the antiproliferation activity, thus suggesting that pertussis toxin-sensitive G proteins and the Gbetagamma subunits are involved in the signaling pathway of Flt-1 that down-regulates EC proliferation. Taken together, these results further expand our understanding of Flt-1-mediated antiproliferative activity in VPF/VEGF-stimulated endothelium.
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PMID:Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins, beta gamma subunits, small GTPase CDC42, and partly by Rac-1. 1172 72

Under low-oxygen conditions, cells develop an adaptive program that leads to the induction of several genes, which are transcriptionally regulated by hypoxia-inducible factor 1 (HIF-1). On the other hand, there are other factors which modulate the HIF-1-mediated induction of some genes by binding to cis-acting motifs present in their promoters. Here, we show that c-Jun functionally cooperates with HIF-1 transcriptional activity in different cell types. Interestingly, a dominant-negative mutant of c-Jun which lacks its transactivation domain partially inhibits HIF-1-mediated transcription. This cooperative effect is not due to an increase in the nuclear amount of the HIF-1alpha subunit, nor does it require direct binding of c-Jun to DNA. c-Jun and HIF-1alpha are able to associate in vivo but not in vitro, suggesting that this interaction involves the participation of additional proteins and/or a posttranslational modification of these factors. In this context, hypoxia induces phosphorylation of c-Jun at Ser(63) in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser(63) and Ser(73) impair its functional cooperation with HIF-1. The functional interplay between c-Jun and HIF-1 provides a novel insight into the regulation of some genes, such as the one for VEGF, which is a key regulator of tumor angiogenesis.
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PMID:c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. 1173 18

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) has been recently identified as a mitogen specific for the endothelium of steroidogenic glands. Here we report a characterization of the signal transduction of EG-VEGF in a responsive cell type, bovine adrenal cortex-derived endothelial (ACE) cells. EG-VEGF led to a time- and dose-dependent phosphorylation of p44/42 MAPK. This effect was blocked by pretreatment with pertussis toxin, suggesting that G alpha(i) plays an important role in mediating EG-VEGF-induced activation of MAPK signaling. The inhibitor of p44/42 MAPK phosphorylation PD 98059 resulted in suppression of both proliferation and migration in response to EG-VEGF. EG-VEGF also increased the phosphorylation of Akt in a phosphatidylinositol 3-kinase-dependent manner. Consistent with such an effect, EG-VEGF was a potent survival factor for ACE cells. We also identified endothelial nitric-oxide synthase as one of the downstream targets of Akt activation. Phosphorylation of endothelial nitric-oxide synthase in ACE cells was stimulated by EG-VEGF with a time course correlated to the Akt phosphorylation. Our data demonstrate that EG-VEGF, possibly through binding to a G-protein coupled receptor, results in the activation of MAPK p44/42 and phosphatidylinositol 3-kinase signaling pathways, leading to proliferation, migration, and survival of responsive endothelial cells.
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PMID:Characterization of endocrine gland-derived vascular endothelial growth factor signaling in adrenal cortex capillary endothelial cells. 1175 15

HIF-1 is the main transcription factor responsible for increased gene expression in hypoxia: VEGF, erythropoietin, GLUT-1, and glycolytic enzymes are such target genes and all participate in the adaptative response of cells to hypoxia. AP-1 activation by hypoxia has also been demonstrated in several cell lines and it cooperates with HIF-1 for increasing VEGF gene transcription in hypoxia. Both HIF-1 and AP-1 activation by hypoxia seems to involve members of the MAP kinase family. Here, we summarize the data indicating that ERK and JNK are needed for activation of HIF-1 and AP-1, respectively.
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PMID:HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases. 1179 93

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

Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.
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PMID:Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. 1197 39


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