Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although it is known that transforming growth factor (TGF)-beta induces vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle cells, the underlying mechanisms are still poorly understood. In the present study, we examined whether the mitogen-activated protein (MAP) kinase superfamily is involved in TGF-beta-stimulated VEGF synthesis in aortic smooth muscle A10 cells. TGF-beta stimulated the phosphorylation of p42/p44 MAP kinase and p38 MAP kinase, but not that of SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase). The VEGF synthesis induced by TGF-beta was not affected by PD98059 or U0126, specific inhibitors of the upstream kinase that activates p42/p44 MAP kinase. We confirmed that PD98059 or U0126 did actually suppress the phosphorylation of p42/p44 MAP kinase by TGF-beta in our preparations. PD169316 and SB203580, specific inhibitors of p38 MAP kinase, significantly reduced the TGF-beta-stimulated synthesis of VEGF (each in a dose-dependent manner). PD169316 or SB203580 attenuated the TGF-beta-induced phosphorylation of p38 MAP kinase. These results strongly suggest that p38 MAP kinase plays a part in the pathway by which TGF-beta stimulates the synthesis of VEGF in aortic smooth muscle cells.
 ...
PMID:Involvement of p38 MAP kinase in TGF-beta-stimulated VEGF synthesis in aortic smooth muscle cells. 1150 Sep 37

We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.
 ...
PMID:p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts. 1152 43

SPARC/osteonectin/BM-40 is a matricellular protein that is thought to be involved in angiogenesis and endothelial barrier function. Previously, we have detected high levels of SPARC expression in endothelial cells (ECs) adjacent to carcinomas of kidney and tongue. Although SPARC-derived peptide showed an angiogenic effect, intact SPARC itself inhibited the mitogenic activity of vascular endothelial growth factor (VEGF) for ECs by the inhibiting phosphorylation of flt-1 (VEGF receptor 1) and subsequent ERK activation. Thus, the role of SPARC in tumor angiogenesis, stimulation or inhibition, is still unclear. To clarify the role of SPARC in tumor growth and progression, we determined the effect of VEGF on the expression of SPARC in human microvascular EC line, HMEC-1, and human umbilical vein ECs. VEGF increased the levels of SPARC protein and steady-state levels of SPARC mRNA in serum-starved HMEC-1 cells. Inhibitors (SB202190 and SB203580) of p38, a mitogen-activated protein (MAP) kinase, attenuated VEGF-stimulated SPARC production in ECs. Since intact SPARC inhibits phosphorylation ERK MAP kinase in VEGF signaling, it was suggested that SPARC plays a dual role in the VEGF functions, tumor angiogenesis, and extravasation of tumors mediated by the increased permeability of endothelial barrier function.
 ...
PMID:Induction of SPARC by VEGF in human vascular endothelial cells. 1155 45

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

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

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

We have previously reported the discovery of VEGF183, a novel isoform of vascular endothelial growth factor (VEGF), whose nucleotide sequence revealed an 18-bp deletion in the exon 6A-encoded region of VEGF. The following study was done to characterize VEGF183 and to determine its biological activity in vitro and in vivo. Recombinant human VEGF183 was expressed in Escherichia coli (rhVEGF183) or in human 293 embryonic kidney cells (293-VEGF183) and tested for stimulation of permeability of dermal vessels in normal rats as well as for mitogenic activity and phosphorylation of mitogen-activated protein kinases (MAPK) in cultured human umbilical vein endothelial cells (HUVECs). While small amounts of VEGF183 were secreted into the conditioned media (CM) of 293 cells expressing VEGF183 (293-VEGF183 cells), most of the VEGF183 remained cell surface-bound and could be released into the CM following treatment with plasmin or heparin. CM from 293-VEGF183 cells treated with heparin or plasmin induced about a twofold increase in cell numbers and stimulated MAPK phosphorylation in HUVECs as compared with CM from untreated 293-VEGF183 cells or from heparin- or plasmin-treated 293 cells containing the vector alone. Intradermal injections of rhVEGF183 promoted increased permeability of dermal vessels to Evan's blue dye. Our study shows that VEGF183 is predominantly a cell-anchored protein that promotes increased vascular permeability in vivo but requires extracellular cleavage or release by heparin or plasmin to promote its mitogenic activity in vitro.
 ...
PMID:Ectodomain shedding of VEGF183, a novel isoform of vascular endothelial growth factor, promotes its mitogenic activity in vitro. 1180 42

Vitamin D3 plays an important role in the regulation of mineral homeostasis, cell differentiation, and proliferation. However, the exact role of vitamin D3 in vascular smooth muscle cells remains unclear. In the present study, we investigated whether vitamin D3 induces vascular endothelial growth factor (VEGF) release in aortic smooth muscle A10 cells. 1,25-Dihydroxyvitamin D3 (1,25(OH)2VD3), an active form of vitamin D3, stimulated the VEGF release while 24,25-dihydroxyvitamin D3 (24,25(OH)2VD3), an inactive form of vitamin D3, had little effect on the release. The stimulatory effect of 1,25(OH)2VD3 was dose dependent in the range between 10 pM and 10 nM. 1,25(OH)2VD3 induced the phosphorylation of p38 mitogen-activated protein (MAP) kinase but 24,25(OH)2VD3 did not. PD169316 and SB203580, specific inhibitors of p38 MAP kinase, significantly reduced the 1,25(OH)2VD3-stimulated release of VEGF. On the contrary, SB202474, a negative control for p38 MAP kinase inhibitor, had little effect on the VEGF release. PD169316 attenuated the 1,25(OH)2VD3-induced phosphorylation of p38 MAP kinase. These results strongly suggest that 1,25(OH)2VD3 stimulates the release of VEGF in aortic smooth muscle cells via p38 MAP kinase activation.
 ...
PMID:1,25-dihydroxyvitamin D3 stimulates vascular endothelial growth factor release in aortic smooth muscle cells: role of p38 mitogen-activated protein kinase. 1181 42

The reproductive hormone, relaxin, is structurally similar to insulin and insulin-like growth factor (IGF). Although a number of cellular responses to relaxin have been described, intracellular signaling mechanisms that link relaxin receptor engagement to alterations in gene expression remain uncharacterized. In the present study, relaxin treatment of a well-characterized target, human endometrial stromal cells, resulted in rapid activation of p42/44 mitogen-activated protein (MAP) kinase, as well as of MAPK (or ERK) kinase (MEK). Using a selective chemical inhibitor of MEK, it was further demonstrated that MEK phosphorylation is critical for relaxin-induced MAP kinase activation. Relaxin treatment also induced MAP kinase activation in THP-1 monocytic cells and in human smooth muscle cells, indicating that it may be a major signaling transducer utilized by the relaxin receptor. In contrast to insulin or IGF-1, relaxin did not trigger the PI 3-kinase/Akt pathway, perhaps accounting in part for relaxin's unique biological profile. Relaxin was also found to cause activation of the transcription factor CREB, a substrate of the MAP kinase pathway. Finally, activation of the MAP kinase pathway was shown to be essential for optimal stimulation of expression of the gene for vascular endothelial growth factor.
 ...
PMID:Relaxin activates the MAP kinase pathway in human endometrial stromal cells. 1196 93

A rate-limiting step of tumor cell metastasis is matrix degradation by active matrix metalloproteinases (MMPs). It is known that reactive oxygen species are involved in tumor metastasis. Sustained production of H(2)O(2) by phenazine methosulfate (PMS) induced activation of pro-MMP-2 through the induction of membrane type 1-MMP (MT1-MMP) expression in HT1080 cells. MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 and -2 levels were changed negligibly by PMS. A one time treatment with H(2)O(2) did not induce activation of MMPs. It was also demonstrated that superoxide anions and hydroxyl radicals were not related to PMS action. PMS-induced pro-MMP-2 activation was regulated by the receptor tyrosine kinases, especially the receptors of platelet-derived growth factor and vascular endothelial growth factor, and downstream on the phosphatidylinositol 3-kinase/NF-kappa B pathway but not Ras, cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinases. PMS did not induce pro-MMP-2 activation in T98G and NIH3T3 cells. This may be related to a low level of MT1-MMP, indicating a threshold level of MT1-MMP is important for pro-MMP-2 activation. Furthermore, PMS increased cell motility and invasion but decreased cell-cell interaction. Cell-matrix interaction was not affected by PMS.
 ...
PMID:Sustained production of H(2)O(2) activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-kappa B pathway. 1205 32


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