Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro. 1155 1

Advanced glycation end products (AGEs) are generated during long term diabetes and are correlated with the development of diabetic complications, such as retinopathy. Diabetic retinopathy is characterized by an increased retinal neovascularization due to the action of the angiogenic factor, vascular endothelial growth factor (VEGF). In this report, we show that injection of insulin and glycated albumin (Alb-AGE) to mice increases VEGF mRNA expression in eyes. Insulin and Alb-AGE stimulate VEGF mRNA and protein expression in retinal epithelial cells (ARPE-19). Alb-AGE-induced VEGF expression is not modulated by the use of antioxidants, N-acetyl-l-cysteine or pyrrolidinedithiocarbamate, or by an inhibitor of phosphatidylinositol 3-kinase (PI3K), wortmannin. However, using an inhibitor of ERK activation, U0126, we show that Alb-AGE stimulates VEGF expression through an ERK-dependent pathway. Accordingly, we found that Alb-AGE activated mitogen-activate protein kinase, ERK1/2, JNK1/2, but not p38, and that Alb-AGE did not activate PI3K and PKB. Moreover, Alb-AGE activated the transcription factor, hypoxia inducible factor-1 (HIF-1) DNA binding activity. This activation is mediated by an increase in accumulation of the HIF-1alpha protein through an ERK-dependent pathway. Thus, stimulation of VEGF expression by Alb-AGE, through the activation of HIF-1, could play an important role in the development of diabetic retinopathy.
 ...
PMID:Regulation of vascular endothelial growth factor expression by advanced glycation end products. 1157 Dec 95

Although both vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors have been shown to be important in the regulation of vascular endothelial cell growth, the roles of phospholipase C (PLC)gamma and Ca(2+) in their downstream signaling cascades are still not clear. We have examined the effects of VEGF and FGF on PLCgamma phosphorylation and on changes in intracellular Ca(2+) levels in primary endothelial cells. VEGF stimulation leads to PLCgamma activation and increases in intracellular Ca(2+), which are correlated with mitogen-activated protein (MAP) kinase (MAPK) activation and cell growth. Inhibition of Ca(2+) increases by the Ca(2+) chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM resulted in marked inhibition of MAPK activation, which was shown to be linked to regulation of cell growth in these cells. In contrast, FGF stimulation did not lead to PLCgamma activation or to changes in intracellular Ca(2+) levels, although MAPK phosphorylation and stimulation of cell proliferation were observed. Neither BAPTA-AM nor the PLC inhibitor U-73122 had an effect on these FGF-stimulated responses. These data demonstrate a direct role for PLCgamma and Ca(2+) in VEGF-regulated endothelial cell growth, whereas this signaling pathway is not linked to FGF-mediated effects in primary endothelial cells. Thus endothelial cell-specific factors regulate the ability of VEGF receptors and FGF receptors to couple to this signaling pathway.
 ...
PMID:Role of PLCgamma and Ca(2+) in VEGF- and FGF-induced choroidal endothelial cell proliferation. 1160 Apr 7

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.
 ...
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

The mechanisms responsible for the divergent physiological responses of endothelial cells to vascular endothelial growth factor (VEGF) are incompletely understood. We hypothesized that VEGF elicits increased endothelial permeability and cell migration via differential activation of intracellular signal transduction pathways. To test this hypothesis, we established a model of VEGF-induced endothelial barrier dysfunction and chemotaxis with bovine pulmonary endothelial cells. We compared the effects of VEGF on transendothelial electrical resistance (TER), actin cytoskeletal remodeling, and chemotaxis of lung endothelial cells and then evaluated the role of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK)1/2 in VEGF-mediated endothelial responses. The dose response of pulmonary arterial and lung microvascular endothelial cells to VEGF differed when barrier regulation and chemotaxis were evaluated. Inhibition of tyrosine kinase, phosphoinositol 3-kinase, or p38 MAPK significantly attenuated VEGF-mediated TER, F-actin remodeling, and chemotaxis. VEGF-mediated decreased TER was also significantly attenuated by inhibition of ERK1/2 MAPK but not by inhibition of fetal liver kinase-1 (flk-1) or Src kinase. In contrast, VEGF-mediated endothelial migration was not attenuated by ERK1/2 inhibition but was abolished by inhibition of either flk-1 or Src kinase. These data suggest potential mechanisms by which VEGF may differentially mediate physiological responses in vivo.
 ...
PMID:Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells. 1170 47

The aim of this study was to identify signal transduction pathways activated by erythropoietin (EpO) and erythropoietin co-stimulatory factors (kit ligand), insulin-like growth factor, thrombopoietin, interleukin 3 and granulocyte-macrophage colony-stimulating factor) in normal human bone marrow CD34(+) cells and d 11 erythroid burst forming unit derived glycophorin+ cells. The activation of these signal transduction pathways was further correlated with various biological effects such as (i) cell proliferation, (ii) inhibition of apoptosis, (iii) activation of adhesion and (iv) secretion of the matrix metalloproteinases (MMPs) MMP-9 and MMP-2, and vascular endothelial growth factor (VEGF). We found that in human CD34(+) cells and erythroblasts erythropoietic factors may activate similar but different signalling pathways, and that activation of each of the JAK-STAT, MAPK p42/44 or PI-3K-AKT axes alone is not sufficient either to stimulate cell proliferation or inhibit apoptosis, suggesting that these processes are regulated by orchestrated activation of multiple signalling cascades. Accordingly, we found that although cell proliferation was more related to simultaneous activation of JAK-STAT and MAPK p42/44, the effect on cell survival correlated with activation of PI-3K-AKT, MAPK p42/44 and JAK-STAT proteins. We also demonstrated that differentiating normal human erythroid cells lose their adhesive properties and secrete angiopoietic factors such as MMP-9, MMP-2 and VEGF, and we postulate that this secretion by early erythroid cells may play a role in their maturation and egress from the haematopoietic niches of the bone marrow.
 ...
PMID:Biological significance of MAPK, AKT and JAK-STAT protein activation by various erythropoietic factors in normal human early erythroid cells. 1172 33

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.
 ...
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

Novel therapies in multiple myeloma (MM) target not only the tumor cell but also the bone marrow (BM) microenvironment. Thalidomide (Thal), as well as derivative immunomodulatory drugs (IMiDs), directly induce apoptosis or G1 growth arrest in MM cell lines and patient's MM cells which are resistant to melphalan (Mel), doxorubicin (Dox), and dexamethasone (Dex). Although Thal and IMiDs do not alter adhesion of MM cells to bone marrow stromal cells (BMSCs), they inhibit the upregulation of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion triggered by the binding of MM cells to BMSCs. Proteasome inhibitors represent another potential anticancer therapy targeting the MM cell and the BM microenvironment. The proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis in both human MM cell lines and freshly isolated patient's MM cells which are resistant to Mel, Dox, and Dex. PS-341 inhibits p44/42 mitogen-activated protein kinase (MAPK) growth signaling triggered by IL-6 and induces apoptosis, despite induction of p21 and p27, in p53 wild-type and p53 mutant MM cells. PS-341 adds to the anti-MM activity of dexamethasone and overcomes IL-6-mediated protection against dexamethasone-induced apoptosis. PS-341 blocks the paracrine growth of human MM cells by decreasing their adherence to BMSCs and related NF-kappaB-dependent induction of IL-6 secretion in BMSCs. Moreover, proliferation and MAPK growth signaling of those residual adherent MM cells is also inhibited. Tumor necrosis factor-alpha (TNF-alpha), which is produced by some MM cells, induces only low-level MM proliferation and MAPK activation in MM cells, but markedly upregulates IL-6 secretion from BMSCs and upregulates expression of adhesion molecules (VLA-4 and LFA-1) on MM cells and their receptors (VCAM-1 and ICAM-1) on BMSCs, with resultant increased binding of MM cells to BMSCs. Inhibition of TNF-alpha-induced NF-kappaB activation with PS-341 inhibits both the upregulation of these molecules on MM cells and BMSCs and the resultant increased adhesion. Therefore, inhibiting TNF-alpha and its sequelae may be useful treatment strategies in MM. Our data show that VEGF causes proliferation and enhances migration of MM as well as plasma cell leukemia (PCL) cells. VEGF induced twofold activation of cell migration in MM cells and more than 100-fold activation of cell migration in PCL cells, suggesting an important role of VEGF in the progression of MM to PCL. These data indicate that VEGF plays a pivotal role not only in neoangiogenesis in MM BM but also in proliferation and migration of tumor cells.
 ...
PMID:Novel therapies targeting the myeloma cell and its bone marrow microenvironment. 1174 Aug 18

Angiogenesis is an essential step for many physiological and pathological processes. Tumor necrosis factor (TNF) superfamily cytokines are increasingly recognized as key modulators of angiogenesis. In this study, we tested whether TNF-related activation-induced cytokine (TRANCE), a new member of the TNF superfamily, possesses angiogenic activity in vitro and in vivo. TRANCE stimulated DNA synthesis, chemotactic motility, and capillary-like tube formation in primary cultured human umbilical vein endothelial cells (HUVECs). Both Matrigel plug assay in mice and chick chorioallantoic membrane assay revealed that TRANCE potently induced neovascularization in vivo. TRANCE had no effect on vascular endothelial growth factor (VEGF) expression in HUVECs and TRANCE-induced angiogenic activity was not suppressed by VEGF-neutralizing antibody, implying that TRANCE-induced angiogenesis may be the result of its direct action on endothelial cells. TRANCE evoked a time- and dose-dependent activation of the mitogen-activated protein kinases ERK1/2 and focal adhesion kinase p125(FAK) in HUVECs, which are closely linked to angiogenesis. These signaling events were blocked by the Src inhibitor PP1 or the phospholipase C (PLC) inhibitor. Furthermore, these inhibitors and the Ca(2+) chelator BAPTA-AM suppressed TRANCE-induced HUVEC migration. These results indicate that the angiogenic activity of TRANCE is mediated through the Src-PLC-Ca(2+) signaling cascade upon receptor engagement in endothelial cells, suggesting the role of TRANCE in neovessel formation under physiological and pathological conditions.
 ...
PMID:TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. 1174 51

Overexpression of vascular endothelial growth factor (VEGF) is associated with disease progression in human glioblastomas. We recently showed that VEGF promoter activity is inversely correlated with tumor extracellular pH (pH(o)) in vivo in the human glioma (U87 MG) xenografts. Here we show that substitution of the neutral culture medium (pH 7.3) with acidic pH medium (pH 6.6) up-regulates VEGF mRNA and protein production in human glioblastoma cells as reflected by Northern blot analysis and enzyme-linked immunosorbent assay. Functional analysis of the VEGF promoter reveals that the sequence between -961 bp and -683 bp upstream of the transcription start site is responsible for the transcriptional activation of the VEGF gene by acidic pH. This region contains the binding site for AP-1. Consequently, AP-1 luciferase reporter gene was activated by acidic pH. Gel-shift analysis confirmed that AP-1 DNA binding activity is induced under acidic pH. While investigating the upstream signaling pathways, we found that ERK1/2 MAPK is activated and translocates to the nucleus to activate Elk-1, and inhibition of the activation of ERK by specific inhibitors of MEK1 blocks the up-regulation of VEGF by low pH. Dominant negative forms of Ras and Raf abolished the activation of VEGF promoter by acidic pH. These results show that acidic pH activates Ras and the ERK1/2 MAPK pathway to enhance VEGF transcription via AP-1, leading to increased VEGF production.
 ...
PMID:Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway: mechanism of low pH-induced VEGF. 1174 77


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>