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)

To evaluate the effect of Ligustrazine on the expression of VEGF in bone marrow stromal cells (BMSCs) of radiation injured mice and to explore the effect of VEGF on the recovery of hematopoiesis and the mechanism of signal transduction, the protein expression of VEGF, focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) in BMSCs were assayed by Western blot, the cell cycle and apoptosis rate of BMSCs were tested by flow cytometry. The effect of Ligustrazine on the hematopoiesis was evaluated at the same time. The results showed that the protein expression of VEGF in BMSCs was decreased significantly after irradiation and increased slowly with the time. The value in Ligustrazine-treated group almost reached normal level, but it remained lower than that in control group on day 14. The changes of phosphorylated FAK and MAPK protein expression had the same tendency. After (60)Co gamma-irradiation, the BMSCs were arrested in G0-G1 phase and apoptosis rate increased; these values recovered slowly with the time and remained higher than that in normal control group on day 14. The recovery of these values in Ligustrazine-treated group was sooner than that in irradiated control group, and they almost reached to the normal levels on day 14. It is concluded that irradiation could inhibit the expression of VEGF in BMSCs and induce apoptosis. The Ligustrazine promotes the recovery of bone marrow microenvironment probably by increasing the expression of phosphorylated FAK and MAPK in BMSCs.
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PMID:[Effect of Ligustrazine on the expression of vascular endothelial growth factor in bone marrow stromal cells of radiation injured mice]. 1498 77

Vasoactive intestinal peptide (VIP) upregulates the expression of vascular endothelial cell growth factor (VEGF(189), VEGF(165) and VEGF(121)) mRNAs in human prostate cancer LNCaP cells, as shown by reverse transcriptase-polymerase chain reaction (RT-PCR). Real-time RT-PCR indicated that the effect was maximal by 1-2 h and must be accounted for increased transcription since VIP decreased VEGF(165) mRNA stability. VIP stimulated VEGF(165) protein synthesis as measured by ELISA. VIP regulation of VEGF expression was mediated by VPAC(1) receptor and was cAMP/protein kinase A (PKA) dependent. Phosphoinositide 3-kinase (PI3-K) and mitogen-activated protein kinase MEK1/2 systems may also be involved as shown with specific kinase inhibitors. These actions together with the observation of VIP-induced neuroendocrine differentiation in LNCaP cells suggest a proangiogenic potential of VIP in prostate cancer.
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PMID:Vasoactive intestinal peptide increases vascular endothelial growth factor expression and neuroendocrine differentiation in human prostate cancer LNCaP cells. 1509 99

Transforming growth factor-beta1 (TGF-beta1) plays a pivotal role in the angiogenesis during the development of placenta, but the intracellular signaling mechanism by which TGF-beta1 stimulates this process remains poorly understood. In this article, we demonstrated that exposure of normal human cytotrophoblast cells to TGF-beta1 stimulated the secretion of the VEGF gene encoding vascular endothelial growth factor, which is a key factor in angiogenesis. Meanwhile, treatment of normal human cytotrophoblast cells with TGF-beta1-induced expression of HIF-1a, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. Our data indicated that TGF-beta1 induced extracellular signal- regulated kinase (ERK) 1/2 phosphorylation in normal human cytotrophoblast cells. Moreover, treating cells with PD98059, an inhibitor of ERK1/2 signaling, inhibited TGF-beta1 stimulation of VEGF secretion and HIF-1a protein expression. These data indicated that in normal human cytotrophoblast cells, TGF-beta1 induced HIF-1a-mediated VEGF secretion, and TGF-beta1-stimulated-ERK1/2 activation may be involved in this process.
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PMID:Involvement of ERK1/2 pathway in TGF-beta1-induced VEGF secretion in normal human cytotrophoblast cells. 1509 41

We demonstrate that human umbilical vein endothelial cells (HUVEC) grown in co-culture (CC) with U87 glioblastoma cells transfected with green fluorescent protein (GFP-U87) exhibit resistance to radiation-mediated apoptosis. cDNA macroarray analysis reveals increases in the accumulation of RNAs for HUVEC genes encoding cell adhesion molecules, growth factor-related proteins, and cell cycle regulatory/DNA repair proteins. An increase in protein expression of integrin alphav, integrin beta1, MAPK(p42), Rad51, DNA-PK(CS), and ataxia telangiectasia gene (ATM) was detected in HUVEC grown in CC with GFP-U87 cells compared with HUVEC grown in mono-culture. Treatment with anti-VEGF antibody decreases the expression of integrin alphav, integrin beta1, DNA-PK(CS) and ATM with a corresponding increase in ionizing radiation (IR)-induced apoptosis. These data support the concept that endothelial cells growing in the tumor microenvironment may develop resistance to cytotoxic therapies due to the up-regulation by tumor cells of endothelial cells genes associated with survival.
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PMID:Glioblastoma cells block radiation-induced programmed cell death of endothelial cells. 1513 73

A number of studies have revealed that various growth factors are produced in the malignant progression of endocrine tumors. Growth factors, classified based on their signal transduction pathways, exert the functions by binding to cell surface specific receptors, and promote the growth of tumors by autocrine and paracrine mechanisms. Growth factors such as VEGF and bFGF are also detected in endocrine tumors, and play an important role in the growth and metastasis of tumors via induction of angiogenesis. In the signal transduction pathways growth factors activate various kinases such as mitogen-activated protein kinase and/or phosphatidylinositol 3-kinase/Akt. Signaling cross-talk of growth factors, cytokines and steroid hormones has been observed in various endocrine tumors.
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PMID:[Endocrine tumors and growth factors]. 1514 11

Activated protein C (APC), a natural anticoagulant, has recently been demonstrated to activate the mitogen-activated protein kinase (MAPK) pathway in endothelial cells in vitro. Because the MAPK pathway is implicated in endothelial cell proliferation, it is possible that APC induces endothelial cell proliferation, thereby causing angiogenesis. We examined this possibility in the present study. APC activated the MAPK pathway, increased DNA synthesis, and induced proliferation in cultured human umbilical vein endothelial cells dependent on its serine protease activity. Antibody against the endothelial protein C receptor (EPCR) inhibited these events. Early activation of the MAPK pathway was inhibited by an antibody against protease-activated receptor-1, whereas neither late and complete activation of the MAPK pathway nor endothelial cell proliferation were inhibited by this antibody. APC activated endothelial nitric oxide synthase (eNOS) via phosphatidylinositol 3-kinase-dependent phosphorylation, followed by activation of protein kinase G, suggesting that APC bound to EPCR might activate the endothelial MAPK pathway by a mechanism similar to that of VEGF. APC induced morphogenetic changes resembling tube-like structures of endothelial cells, whereas DIP-APC did not. When applied topically to the mouse cornea, APC clearly induced angiogenesis in wild-type mice, but not in eNOS knockout mice. These in vitro events induced by APC might at least partly explain the angiogenic activity in vivo. This angiogenic activity of APC might contribute to maintain proper microcirculation in addition to its antithrombotic activity.
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PMID:Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. 1516 95

The immunosuppressive agent cyclosporin A (CsA), a calcineurin inhibitor which blocks T cell activation has provided the pharmacologic foundation for organ transplantation. CsA exerts additional effects on non-immune cell populations and may adversely effect microvascular endothelial cells, contributing to chronic rejection, a long-term clinical complication and significant cause of mortality in solid-organ transplants, including patients with small bowel allografts. Growth of new blood vessels, or angiogenesis, is a critical homeostatic mechanism in organs and tissues, and regulates vascular populations in response to physiologic requirements. We hypothesized that CsA would inhibit the angiogenic capacity of human gut microvessels. Primary cultures of human intestinal microvascular endothelial cells (HIMEC) were used to evaluate CsA's effect on four in vitro measures of angiogenesis, including endothelial stress fiber assembly, migration, proliferation and tube formation, in response to the endothelial growth factor VEGF. We characterized the effect of CsA on intracellular signaling mechanisms following VEGF stimulation. CsA affected all VEGF induced angiogenic events assessed in HIMEC. CsA differentially inhibited signaling pathways which mediated distinct steps of the angiogenic process. CsA blocked VEGF induced nuclear translocation of the transcription factor NFAT, activation of p44/42 MAPK, and partially inhibited JNK and p38 MAPK. CsA differentially affected signaling cascades in a dose dependent fashion and completely blocked expression of COX-2, which was integrally linked to HIMEC angiogenesis. These data suggest that CsA inhibits the ability of microvascular endothelial cells to undergo angiogenesis, impairing vascular homeostatic mechanisms and contributing to the vasculopathy associated with chronic rejection.
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PMID:Cyclosporin A differentially inhibits multiple steps in VEGF induced angiogenesis in human microvascular endothelial cells through altered intracellular signaling. 1517 1

VEGF expression by proximal tubular epithelial cells may play a critical role in maintaining peritubular capillary endothelium in renal disease. Two major processes involved in renal injury include hypoxia (from vasoconstriction or vascular injury) and transforming growth factor (TGF)-beta-dependent fibrosis, both of which are known to stimulate VEGF. Because the TGF-beta/Smad pathway is activated in hypoxia, we tested the hypothesis that the induction of VEGF in hypoxia could be partially dependent on TGF-beta. Rat proximal tubular (NRK52E) cells treated with TGF-beta under normoxic conditions secreted VEGF at 24 h, and this was significantly reduced by blocking Smad activation by overexpressing the inhibitory Smad7 or by blocking p38 and ERK1/2 MAP kinase activation or protein kinase C activation with specific inhibitors. With acute hypoxia, rat proximal tubular cells also express VEGF mRNA and protein as well as TGF-beta. However, the induction of VEGF occurs before synthesis of TGF-beta and is not blocked by either a TGF-beta antagonist, by Smad7 overexpression, or by blockage of ERK1/2, whereas induction is blocked by PKC inhibition or partially blocked by a p38 inhibitor. Finally, the addition of TGF-beta with hypoxia results in significantly more VEGF expression than either stimulation alone. Thus TGF-beta and hypoxia act via additive/synergistic but distinct pathways to stimulate VEGF in proximal tubular cells, a finding that may be important in understanding how VEGF is stimulated in renal disease.
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PMID:Differential regulation of VEGF by TGF-beta and hypoxia in rat proximal tubular cells. 1518 3

Melanoma differentiation-associated gene-7 (mda-7), recently classified as interleukin-24 (approved gene symbol IL24), is thought to be a tumor suppressor gene based on the loss of its expression in many different types of cancer. Gene therapy by adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to inhibit the growth of several different tumor cell lines, in vitro and in vivo. We previously demonstrated that Ad-mda7 radiosensitized non-small-cell lung cancer (NSCLC) cell lines by enhancing an apoptosis pathway through the activation of JNK and c-Jun. In the present study, we investigated the efficacy of intratumoral administration of Ad-mda7 combined with ionizing radiation for treating A549 xenograft tumors in nude mice. Substantial and long-lasting inhibition of tumor growth was evident following the combined treatment. Histological examination revealed marked reduction of angiogenic factors (bFGF, VEGF) and microvessel density and enhanced apoptosis in the tumors treated with the combination therapy compared to those treated with Ad-mda7 alone or radiation alone. To confirm the radiosensitizing effect of secreted MDA-7 protein, we performed clonogenic survival assays using human umbilical vein endothelial cells (HUVECs), A549 cells, and normal human lung fibroblasts, CCD16 cells, pretreated with the conditioned medium from 293 cells that had been stably transfected with mda-7 or a control vector. The results showed that MDA-7 protein sensitized HUVECs to ionizing radiation but not A549 cells or CCD16 cells. Our results suggest that Ad-mda7 in combination with radiation enhances apoptosis in the tumors and that secreted MDA-7 protein inhibits angiogenesis by sensitizing endothelial cells to ionizing radiation without affecting other normal cells. We conclude that the combination of mda-7 gene therapy and radiotherapy may be a feasible and effective strategy for treatment of NSCLC.
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PMID:Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. 1519 48

The mechanism by which the CXC chemokine platelet factor 4 (PF-4) inhibits endothelial cell proliferation is unclear. The heparin-binding domains of PF-4 have been reported to prevent vascular endothelial growth factor 165 (VEGF(165)) and fibroblast growth factor 2 (FGF2) from interacting with their receptors. However, other studies have suggested that PF-4 acts via heparin-binding independent interactions. Here, we compared the effects of PF-4 on the signalling events involved in the proliferation induced by VEGF(165), which binds heparin, and by VEGF(121), which does not. Activation of the VEGF receptor, KDR, and phospholipase Cgamma (PLCgamma) was unaffected in conditions in which PF-4 inhibited VEGF(121)-induced DNA synthesis. In contrast, VEGF(165)-induced phosphorylation of KDR and PLCgamma was partially inhibited by PF-4. These observations are consistent with PF-4 affecting the binding of VEGF(165), but not that of VEGF(121), to KDR. PF-4 also strongly inhibited the VEGF(165)- and VEGF(121)-induced mitogen-activated protein (MAP) kinase signalling pathways comprising Raf1, MEK1/2 and ERK1/2: for VEGF(165) it interacts directly or upstream from Raf1; for VEGF(121), it acts downstream from PLCgamma. Finally, the mechanism by which PF-4 may inhibit the endothelial cell proliferation induced by both VEGF(121) and VEGF(165), involving disruption of the MAP kinase signalling pathway downstream from KDR did not seem to involve CXCR3B activation.
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PMID:Platelet factor 4 disrupts the intracellular signalling cascade induced by vascular endothelial growth factor by both KDR dependent and independent mechanisms. 1529 8


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