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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have demonstrated that vascular endothelial growth factor (VEGF) and its receptor VEGFR2 (flk-1) are expressed by neurons during development and following hypoxic-ischemic events. Moreover, fetal CNS tissue explants exposed to exogenous VEGF exhibit increased neuronal Map-2 expression, suggesting that VEGF could have an effect on neuronal maturation. To determine whether this effect is of a direct nature, we examined the expression of Map-2 in the presence of VEGF in primary CNS neuronal cultures. After 3 days in culture, a statistically significant dose-dependent increase in the length of Map-2(+) processes was observed, with the peak occurring at 10 ng/ml of VEGF. Immunohistochemical analysis of the cultures demonstrated the presence of VEGFR2 after VEGF treatment, as well as the expression of the VEGF receptor VEGFR1 (flt-1). Treatment of the cultures with antisense oligonucleotides against VEGFR2, but not against VEGFR1, abolished the effect of VEGF on the length of Map-2(+) processes. RT-PCR analyses of Map-2 and VEGFR1 indicated that mRNAs of these two genes are upregulated in the presence of VEGF. The addition of wortmannin, an inhibitor of PI3K/Akt signal-transduction pathway, to the media did not affect the VEGF-dependent increase in Map-2(+) length. In contrast PD98059, which inhibits the MAPK pathway, partially abolished this effect of VEGF. These experiments suggest that VEGF has a direct effect on neuronal growth and maturation under normoxic conditions during CNS development, which is mediated by the VEGFR2 receptor via the MAPK pathway.
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PMID:Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures. 1475 19

Vascular endothelial growth factor (VEGF)--a stimulus of angiogenesis--is produced by epidermal keratinocytes, and elevated levels have been found in plaques of psoriasis. Polymorphisms in the VEGF gene regulate production of VEGF. We postulated that patients with psoriasis may have altered systemic expression of VEGF consequent upon programming at the genomic level. We investigated the genetic basis of VEGF expression in patients with type 1 (onset before age 40 y) chronic plaque psoriasis compared to healthy controls and also measured plasma levels of VEGF and its receptors flt-1 and KDR. Patients with severe disease, and those with onset of psoriasis between the ages of 20 and 40 y showed significantly increased frequency of the +405 CC genotype (p=0.04 and p=0.02) and the C allele (p=0.03 and p=0.02), respectively, compared to healthy controls. Plasma levels of VEGF and flt-1 were significantly detectable in patients with psoriasis compared with controls (p<0.001); by contrast, mean plasma levels of KDR in psoriatic patients were comparable with controls. These results suggest that alterations in the biology of VEGF may be involved in the pathogenesis of psoriasis. VEGF, flt-1, and KDR could provide attractive targets for future psoriasis therapy.
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PMID:Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset. 1496 20

Transcriptional targeting is an important aspect of developing gene therapy vectors in order to restrict transgene expression to selected target cells. One approach, when using retroviral vectors, is to replace viral transcriptional control elements within the long terminal repeat (LTR) with sequences imparting the desired specificity. We have developed such hybrid LTR retroviruses, incorporating sequences from each of the human promoters for flt-1, ICAM-2 and KDR, as part of our antivascular cancer gene therapy strategy targeting tumour endothelial cells. The chosen fragments were used to replace the enhancer or combined enhancer and proximal promoter regions of the viral LTR. All showed activity in primary human breast microvascular endothelial cells, with viruses incorporating ICAM-2 sequences exhibiting the greatest specificity versus nonendothelial cells in vitro and a marked alteration of specificity towards endothelial cells in a subcutaneous xenograft model in vivo. Moreover, our study documents the effect of enhancer and/or proximal promoter deletion on LTR activity and reports that differential dependence in different cell lines can give the false impression of specificity if experiments are not adequately controlled. This finding also has implications for other retroviral vector designs seeking to provide transcriptional specificity and for their safety with respect to prevention of gene activation at sites of proviral integration.
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PMID:Retroviral hybrid LTR vector strategy: functional analysis of LTR elements and generation of endothelial cell specificity. 1499 28

The interaction of vessel endothelial cell growth factor (VEGF) and its receptors (flt-1, FLK-1/KDR) regulates tumor angiogenesis. Therefore, blocking the binding of VEGF and the corresponding receptor has become critical for antitumor angiogenesis biological therapy. Our study extracted sFLK-1 fragment from embryo mouse liver using RT-PCR, recombined it to retrovirus vector, and transfected it to tumor cell lines (S180 and B16) by the liposome mediated method, then we observed the biological behavior of transgenic cells in vivo. The results are: (1) Fragment (1034 bp) was extracted from E9, E11 embryo mouse liver tissue, which was identified by sequence analysis. (2) This fragment was cloned to retrovirus vector (PLXSN vector), which was further transfected to tumor cells lines (S180 and B16). SDS-PAGE indicated the suspension of transgenic cells present sVEGFR-2(sFLK-1) fragment; Western blot identified it. (3) In vivo study showed that the weight and size of tumor in the group of transgenic cells were smaller than in control groups. Microvessel density (MVD) and FLK-1 expression were obviously different between transgenic and control groups, but there were no differences in VEGF expression between transgenic and control groups. In short, the isolated soluble VEGFR2 fragment transfected to tumor cells can be secreted to extracellular suspension and can inhibit tumor angiogenesis in vivo.
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PMID:In vivo inhibition of tumor angiogenesis by a soluble VEGFR-2 fragment. 1501 Feb 91

Two distinct mechanisms, vasculogenesis and angiogenesis implement the formation of the vascular network in the embryo. Vasculogenesis gives rise to the heart and the first primitive vascular plexus inside the embryo and in its surrounding membranes, as the yolk sac circulation. Angiogenesis is responsible for the remodeling and expansion of this network. While vasculogenesis refers to in situ differentiation and growth of blood vessels from mesodermal derived hemangioblasts, angiogenesis comprises two different mechanisms: endothelial sprouting and intussusceptive microvascular growth (IMG). The sprouting process is based on endothelial cell migration, proliferation and tube formation. IMG divides existing vessel lumens by formation and insertion of tissue folds and columns of interstitial tissue into the vessel lumen. The latter are termed interstitial or intervascular tissue structures (ITSs) and tissue pillars or posts. Intussusception also includes the establishment of new vessels by in situ loop formation in the wall of large veins. The molecular regulation of these distinct mechanisms is discussed in respect to the most important positive regulators, VEGF and its receptors flk-1 (KDR) and flt-1, the Angiopoietin/tie system and the ephrin-B/EpH-B system. The cellular mechanisms and the molecular regulation of angiogenesis in the pathological state are summarized and the differences of physiological and pathological angiogenesis elaborated.
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PMID:Vasculogenesis and angiogenesis. 1501 50

Utilizing a cDNA expression library established from human prostate PC-3ML tumor cells, we have cloned a truncated flt-4 gene, termed flt-4t(Delta773-1081). We have then utilized RNase protection and ELISA to measure the relative levels of VEGF B, C, D and flt-1, KDR, flt-4 and flt-4t(Delta773-1081) expression in freshly isolated benign prostatic hyperplasia or BPH tissue (n=21), primary prostate cancers (n=82) and matching sentinel lymph node metastases from stage T2a-T2b/T3 tumors (n=52). Comparisons of the primary tumors with BPH showed that there was a significant upregulation of VEGF-B (P=0.003), VEGF D (P=0.005), flt-1 (P=0.003), KDR (P=0.002), flt-4 (P=0.007), and flt-4t(Delta773-1081) (P=0.001), but not VEGF-C (P=0.543). There was no correlation between VEGF-B and its receptor flt-1 (P=0.545), or VEGF-C and flt-4 (P=0.16) and KDR (P=0.23) receptor expression in tumor specimens. Conversely, there was no significant relationship between VEGF-D and the flt-4t(Delta773-1081) receptor (P=0.516) expression. Statistical analysis further showed that there was no significant correlation between VEGF-B, VEGF-C, VEGF-D, flt-1, KDR, flt-4 and flt-4t(Delta773-1081) with patient age (P>0.10), stage (P>0.10), PSA value (P>0.15) or tumor size (P>0.15). Likewise, there was no significant correlation between VEGF-B, VEGF-C, flt-1, KDR, and flt-4 with Gleason score (P>0.15). In comparison, flt-4t(Delta773-1081) levels clearly increased significantly in Gleason score 7 and Gleason score 8-10 tumors as well as in stage T2a-T2b/T3 tumors. The studies were extended to compare gene expression profiles in T2a-T2b and T3 tumors with (n=26) and without (n=26) matching sentinel lymph node metastases. The data showed that VEGF D and flt-4t(Delta773-1081) expression levels were significantly elevated in primary tumors with sentinel lymph node involvement compared to those lacking lymph node involvement (P>0.0022 and 0.006, respectively). These data suggest that targeting VEGF D and flt-4t(Delta773-1081) receptors may be particularly effective in the prevention of lymph node metastases.
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PMID:Expression of a flt-4 (VEGFR3) splicing variant in primary human prostate tumors. VEGF D and flt-4t(Delta773-1081) overexpression is diagnostic for sentinel lymph node metastasis. 1510 1

The contribution of VEGF (vascular endothelial growth factor) to angiogenesis and tumor aggressiveness has been shown in several tumor types, but no comparative data regarding the impact of the VEGF-subtypes on endothelial and tumor cell protection are available. Therefore, we analysed the cytoprotective effects of the two major soluble VEGF-subtypes, VEGF-121 and -165, on HUVEC cell cultures (human umbilical vein endothelial cells) and squamous cell carcinoma (SCC) cell lines after ionizing radiation. We performed clonogenic analyses and proliferation assays for evaluation of cell survival and proliferative activity. Experiments were performed employing different intensities up to 8 Gy with or without added recombinant VEGF-121 or -165 and compared to non-irradiated cultures. To evaluate a possible contribution of the VEGF-receptors, we performed immunohistochemical stainings of VEGF-R1 (flt), -R2 (KDR,flk), and Neuropilin-1. In the SCC cell lines and HUVEC cultures, cell survival and proliferative activity were reduced in a dosage-dependent manner. The addition of VEGF-121 yielded a significant increase of resistance from 1.2 to 2.7 Gy (+125%) for killing 50% of subjected cells, while VEGF-165 was less effective in this regard (+83%). Conversely, in HUVEC cultures, 50%-survival was increased more strongly by VEGF-165 compared to VEGF-121 (+100% vs. +43%). Accordingly, proliferation was more intensely stimulated in HUVECs by VEGF-165 than by VEGF-121. VEGF-receptors were expressed in all cell cultures analysed at comparable levels. We conclude that the two VEGF-subtypes differentially increase the survival of tumor and endothelial cells after irradiation in vitro. We hypothesise, that the release of VEGF by the tumor protects tumor cells and endothelium resulting in increased radiation resistance.
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PMID:VEGF-subtype specific protection of SCC and HUVECs from radiation induced cell death. 1558 41

The mucosal cells were isolated from the ampullary regions of 20 human oviducts and cultured with or without hCG in five different concentrations (1-100 ng/mL). As analyzed by the semiquantitative reverse-transcriptase polymerase chain reaction, hCG treatment significantly increased mRNA expression of vascular endothelial growth factor and its receptor flt-1 in the cultured mucosal cells in a dose-dependent manner but had no effect on the expression of another receptor, KDR.
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PMID:Upregulation of mRNA expression of vascular endothelial growth factor and its receptors by exogenous human chorionic gonadotropin in cultured oviduct mucosal cells. 1558 89

The non-angiogenic role of vascular endothelial growth factor (VEGF), and its receptors flt-1 and flk-1, together with downstream signaling pathways were examined in fetal and postnatal rat cerebral cortical organotypic explants. VEGF application in both paradigms caused a significant increase in astroglial proliferation and a dose-dependent increase in GFAP and nestin immunoreactivity. The VEGF receptor flt-1 was observed on most, though not all astrocytes, while flk-1 receptor immunoexpression was absent. Treatment with antisense oligonucleotides (AS-ODNs) to flt-1 resulted in a dramatic decrease in GFAP and nestin immunoreactivity, which further confirmed the role of flt-1 in mediating VEGF's gliotrophic effects, while AS-ODNs to flk-1 had no effect. VEGF-induced gliotrophic effects were found to be mediated by the MAPK/ERK and PI-3 kinase signaling pathways, since the both the MEK1 inhibitor, PD98059 and the PI-3 kinase inhibitor, Wortmannin abolished VEGF-induced astrocytic GFAP(+) expression. Although high dose VEGF application resulted in strong upregulation of both GFAP and nestin immunoreactivity in astrocytes, overlap of the two proteins was not observed in all cells, suggesting that some of the nestin(+) cells might be neural progenitors. Exposure to VEGF resulted in upregulation of both VEGF and bFGF mRNA at the one-day time point, and bFGF protein by 3 days; VEGF activated astrocytes expressed bFGF to a much greater degree than those in untreated explants. The increased expression of bFGF induced by VEGF, may serve in the proliferation of multipotential neural stem/progenitor cells in vitro. VEGF, an established angiogenic factor, appears to play a significant role in the growth and differentiation of astrocytes in the CNS.
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PMID:Astrocyte growth effects of vascular endothelial growth factor (VEGF) application to perinatal neocortical explants: receptor mediation and signal transduction pathways. 1575 57

We have established the well-defined cycling, pseudo-pregnant and pregnant rhesus monkey models, and used these to analyze expression of the common molecules specifically related to angiogenesis, apoptosis or proteolysis, such as vascular endothelial growth factor (VEGF) and its receptors KDR, flt-1, flt-4 and flk-1, basic fibroblast growth factor (bFGF) and its receptors Flg, transforming growth factor-alpha and beta1 (TGF-a/beta1), and TGF-beta1 receptor type I (TbetaR-I) and type II (TbetaR-II), as well as steroidogenic acute regulatory protein (StAR), tissue type plasminogen activator/urokinase plasminogen activator/plasminogen activator inhibitor type 1 (tPA/uPA/PAI-1) and matrix matalloproteinase type 1, -3/tissue inhibitor matalloproteinase type 1, -2, -3 (MMP-1, -3/TIMP-1, -2, -3), Fas/FasL, BcL-2/Bax, in the corpus luteum (CL), in the functional layer of the endometrium and in the materno-fetal boundary of the implantation site. We have demonstrated that: expression of these molecules in the monkey CL, endometrium and materno-fetal boundary of the implantation site is correlated well with CL functional and vascular development and with the processes involved in the establishment of the implantation window as well as with the early stages of placentation. A coordinated increase in tPA and its inhibitor PAI-1 expression in the monkey and rat CL may be instrumental in initiating luteal regression in both species, and correlated well with the timing of the closure of the implantation window, whereas high uPA activity in the CL is important for the early formation of the CL and for maintaining its function which is closely correlated to the period of establishment of the implantation window. Apoptosis, proteolysis and angiogenesis occur in the CL and in the endometrium during the time of establishment of the implantation window, as well as in the materno-fetal boundary of the implantation site at the early stages of placentation. It seems that these processes occur in these tissues in a coordinated and time- and cell-dependent manner, and are reliant on each other. Based on these observations, we have designed experiments to test the actions of some related available compounds on mouse implantation, used alone or in combination. The preliminary data showed that the compounds which could effectively affect apoptosis, angiogenesis or proteolysis in the implantation site were capable of effectively inhibiting implantation by acting on the endometrium and/or on the CL. Furthermore, the combined use of these compounds produced an obvious additive effect on inhibiting implantation. This finding suggested this may be a good approach for developing an anti-implantation agent.
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PMID:Involvement of molecules related to angiogenesis, proteolysis and apoptosis in implantation in rhesus monkey and mouse. 1579 44


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