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)

We performed a parallel evaluation of 5 automated reticulocyte counters to produce the immature reticulocyte fraction (IRF). We analyzed 225 samples from healthy control subjects, 115 from patients with various diseases, 38 with advanced aplasia, and 22 in early erythropoietic recovery after chemotherapy or bone marrow transplantation. The reference intervals were different for each instrument (ADVIA 120, 0.04-0.25; CELL DYN 4000, 0.15-0.35; GEN-S, 0.20-0.37; SE 9500 RET 0.05-0.21; VEGA RETIC: 0.06-0.23). The imprecision, obtained by 1-way analysis of variance on duplicates, was satisfactory for clinical use for all methods (coefficient of variation, 7.6%-20.5% in healthy subjects), although it was higher than the analytic goal based on biologic variability within subjects. The comparison of different methods shows that agreement is good only between SE 9500 RET CELL DYN 4000, and VEGA RETIC (r2 = 0.72-0.78). The study of diagnostic performance in distinguishing aplasia from early bone marrow recovery shows slightly different results (area under the curve from 0.70 for ADVIA 120 to 0.96 for SE 9500 RET). Even with slight differences, the fluorescence-based methods seem to be more robust than other methods for IRF measurement.
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PMID:Five fully automated methods for performing immature reticulocyte fraction: comparison in diagnosis of bone marrow aplasia. 1204 38

Blood vessels form either by the assembly and differentiation of mesodermal precursor cells (vasculogenesis) or by sprouting from preexisting vessels (angiogenesis). Endothelial-specific receptor tyrosine kinases and their ligands are known to be essential for these processes. Targeted disruption of vascular endothelial growth factor (VEGF) or its receptor kdr (flk1, VEGFR2) in mouse embryos results in a severe reduction of all blood vessels, while the complete loss of flt1 (VEGFR1) leads to an increased number of hemangioblasts and a disorganized vasculature. In a large-scale forward genetic screen, we identified two allelic zebrafish mutants in which the sprouting of blood vessels is specifically disrupted without affecting the assembly and differentiation of angioblasts. Molecular cloning revealed nonsense mutations in flk1. Analysis of mRNA expression in flk1 mutant embryos showed that flk1 expression was severely downregulated, while the expression of other genes (scl, gata1, and fli1) involved in vasculogenesis or hematopoiesis was unchanged. Overexpression of vegf(121+165) led to the formation of additional vessels only in sibling larvae, not in flk1 mutants. We demonstrate that flk1 is not required for proper vasculogenesis and hematopoiesis in zebrafish embryos. However, the disruption of flk1 impairs the formation or function of vessels generated by sprouting angiogenesis.
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PMID:Analysis of a zebrafish VEGF receptor mutant reveals specific disruption of angiogenesis. 1219 22

The capillary network in the masseter muscle develops dramatically with the differentiation of muscle fibres after birth, especially around weaning. Here, developmental changes in mRNA expression for four splicing variants of vascular endothelial growth factor (VEGF) and for two distinct VEGF receptors (Fms-like tyrosine kinase (Flt-1) and kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/Flk-1)) were studied in rat masseter. The relative abundance of VEGF (120) mRNA was the highest, representing 35% of total VEGF mRNA on day 7 after birth and gradually decreased with age to become approximately 5% on day 37. In contrast, VEGF (188) mRNA was very low in the newborn rat, but increased sharply before weaning and reached 40-50% of the total on day 50. Neither VEGF (144) nor VEGF(164) mRNA showed any significant change in abundance after birth. The expression of KDR/Flk-1 mRNA was transiently high in the early postnatal stage and gradually decreased with age, Flt-1 mRNA was stably expressed at a constant level after birth. These findings suggest that different combinations of VEGF isoforms and their receptors regulate angiogenesis in the development of the masseter muscle.
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PMID:Differential gene expression of vascular endothelial growth factor isoforms and their receptors in the development of the rat masseter muscle. 1220 74

Vascular endothelial cell growth factor (VEGF) was originally described as a potent vascular permeability factor (VPF) that importantly contributes to vascular pathobiology. The signaling pathways that underlie VEGF/VPF-induced permeability are not well defined. Furthermore, endogenous vascular peptides that regulate this important VPF function are currently unknown. We report here that VPF significantly enhances permeability in aortic endothelial cells via a linked signaling pathway, sequentially involving Src, ERK, JNK, and phosphatidylinositol 3-kinase/AKT. This leads to the serine/threonine phosphorylation and redistribution of actin and the tight junction (TJ) proteins, zona occludens-1 and occludin, and the loss of the endothelial cell barrier architecture. Atrial natriuretic peptide (ANP) inhibited VPF signaling, TJ protein phosphorylation and localization, and VPF-induced permeability. This involved both guanylate cyclase and natriuretic peptide clearance receptors. In vivo, transgenic mice that overexpress ANP showed significantly less VPF-induced kinase activation and vascular permeability compared with non-transgenic littermates. Thus, ANP acts as an anti-permeability factor by inhibiting the signaling functions of VPF that we define here and by preserving the endothelial cell TJ functional morphology.
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PMID:Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide. 1221 3

Pituitary tumorigenesis is a poorly understood process involving dysregulation of the cell cycle, proliferation, and angiogenesis. The novel securin pituitary tumor transforming gene (PTTG) disrupts cell division and stimulates fibroblast growth factor (FGF)-2-mediated angiogenesis. We investigated expression of the angiogenic vascular endothelial growth factor (VEGF) and its receptor KDR/Flk-1 in 103 human pituitary tumors, and we assessed functional relationships between these genes in vitro. Nonfunctioning tumors (n = 81) demonstrated markedly raised VEGF mRNA (3.2-fold, P < 0.05) and protein concentrations, compared with normal pituitaries (n = 10). KDR was also highly induced in nonfunctioning tumors (14-fold, P < 0.001, n = 78) as well as in the whole cohort of pituitary tumors, compared with normal pituitary samples (14-fold, P < 0.0001, n = 100). In vitro, PTTG induced VEGF, but not KDR, expression in fetal neuronal NT2 cells (2.7-fold, P < 0.001, n = 8), MCF-7 breast carcinoma cells (1.9-fold, P = 0.03, n = 10), and choriocarcinoma JEG-3 cells (P = 0.0002, n = 8). A mutated PTTG construct that cannot be phosphorylated showed identical VEGF up-regulation (2.9-fold, P < 0.001, n = 8) in NT2 cells, compared with wild-type PTTG, but a further mutated construct with abrogation of the key protein:protein interaction domain of PTTG resulted in a significant reduction in VEGF stimulation, compared with wild-type (0.37-fold reduction, P < 0.001, n = 8). FGF-2 findings mirrored those of VEGF, although antibody depletion of secreted FGF-2 in the cell medium failed to influence VEGF up-regulation by PTTG. Overall, our findings implicate altered VEGF and KDR signaling in pituitary tumorigenesis, and we propose that PTTG stimulation of FGF-2 and VEGF expression in the presence of up-regulated growth factor receptors may account for angiogenic growth and progression of human pituitary tumors.
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PMID:Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors. 1221 78

Vascular endothelial growth factor (VEGF) plays an important role during endochondral bone formation in hypertrophic cartilage remodelling. We examined VEGF and VEGF receptor expression in tibiae from fetuses, newborns and children immunohistochemically. Expression of mRNA for the different VEGF splice forms and for VEGF receptors KDR and FLT-1 was analysed by reverse transcription-polymerase chain reaction (RT-PCR). VEGF could be immunolocalized intracellularly in the hypertrophic chondrocytes of the growth plate and in the chondrocytes around cartilage canals of the epiphysis, respectively. The resting zone and the proliferative zone of the growth plate were VEGF-negative. In cartilage samples of all growth plates analysed, VEGF121 and VEGF165 were identified as the only VEGF splice forms expressed. RT-PCR for VEGF mRNA of normal hyaline cartilage was negative. At vessels growing into the hypertrophic cartilage FLT-1 (VEGFR-1) and KDR (VGEFR-2) could be visualized. Reverse transcription-polymerase chain reaction (RT-PCR) substantiated the results regarding FLT-1 and KDR expression. The results of our study suggest that the splice forms VEGF121 and VEGF165 and the receptors KDR and FLT-1 of the known angiogenetic peptide VEGF play a role in process of endochondral ossification.
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PMID:Expression of VEGF121 and VEGF165 in hypertrophic chondrocytes of the human growth plate and epiphyseal cartilage. 1222 Jan 23

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) functions by activating two receptor tyrosine kinases, Flt-1 (VEGFR-1) and KDR (VEGFR-2), both of which are selectively expressed on the primary vascular endothelium. KDR is responsible for VPF/VEGF-stimulated endothelial cell (EC) proliferation and migration, whereas Flt-1 down-modulates KDR-mediated EC proliferation. Flt-1 mediates down-regulation of EC proliferation through pertussis toxin-sensitive G proteins, betagamma subunits, small GTPase CDC42, and partly by Rac-1. However, the molecular mechanism by which KDR mediates EC migration is not clear yet. Here we show for the first time that activation of RhoA and Rac1 is fully and partially required for KDR-mediated human umbilical vein endothelial cell (HUVEC) migration, respectively, and that CDC42, however, is not involved. Furthermore, overexpression of the RhoA dominant negative mutant RhoA-19N does not affect VPF/VEGF-stimulated KDR phosphorylation, intracellular Ca(2+) mobilization, and mitogen-activated protein kinase phosphorylation. Utilizing the receptor chimeras (EGDR and EGLT) in which the extracellular domain of the epidermal growth factor receptor (EGFR) was fused to the transmembrane domain and the intracellular domains of KDR and Flt-1, respectively, we demonstrate that RhoA activation is mediated by EGDR, not by EGLT, and that EGDR mediates activation of Rac1, not CDC42. Furthermore, the EGDR-mediated RhoA and Rac1 activation is regulated by G proteins Gq/11, Gbetagamma, and phospholipase C independent of phosphatidylinositol 3-kinase and intracellular Ca(2+) mobilization. Interestingly, the RhoA activation can be partially inhibited by overexpression of Rac1-17N, but overexpression of RhoA-19N has no effect on Rac1 activation. Finally, Gq/11 and Gbetagamma subunits are also required for VPF/VEGF-stimulated HUVEC migration. Taken together, our results indicate that KDR stimulates endothelial cell migration through a heterotrimeric G protein Gq/11 and Gbetagamma-mediated RhoA pathway.
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PMID:KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11-mediated activation of a small GTPase RhoA. 1224 99

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), has been shown to increase potently the permeability of endothelium and is highly expressed in breast cancer cells. In this study, we investigated the role of VEGF/VPF in breast cancer metastasis to the brain. Very little is known about the role of endothelial integrity in the extravasation of breast cancer cells to the brain. We hypothesized that VEGF/VPF, having potent vascular permeability activity, may support tumor cell penetration across blood vessels by inducing vascular leakage. To examine this role of VEGF/VPF, we used a Transwell culture system of the human brain microvascular endothelial cell (HBMEC) monolayer as an in vitro model for the blood vessels. We observed that VEGF/VPF significantly increased the penetration of the highly metastatic MDA-MB-231 breast cancer cells across the HBMEC monolayer. We found that the increased transendothelial migration (TM) of MDA-MB-231 cells resulted from the increased adhesion of tumor cells onto the HBMEC monolayer. These effects (TM and adhesion of tumor cells) were inhibited by the pre-treatment of the HBMEC monolayer with the VEGF/VPF receptor (KDR/Flk-1) inhibitor, SU-1498, and the calcium chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl)ester. These treatments of the HBMEC monolayer also inhibited VEGF/VPF-induced permeability and the cytoskeletal rearrangement of the monolayer. These data suggest that VEGF/VPF can modulate the TM of tumor cells by regulating the integrity of the HBMEC monolayer. Taken together, these findings indicate that VEGF/VPF might contribute to breast cancer metastasis by enhancing the TM of tumor cells through the down-regulation of endothelial integrity.
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PMID:Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. 1244 67

The present study was conducted to examine changes of mRNAs encoding vascular endothelial growth factor (VEGF) and its receptors (KDR/Flk-1 and Flt-1), and CD34, which is known to be a specific marker for endothelial cells, during the development and maintenance of the caprine corpora lutea (CL). Effects of a potent GnRH antagonist (GA), which was previously shown to suppress release of luteinizing hormone (LH), on expressions of those mRNAs during the CL development were also investigated. Goats were divided into control (n = 12) and GA-treated groups (n = 6). The goats were treated with saline or GA (50 microg/kg, sc) on days 0 (day of ovulation), 4, and 8 (control only), and CL collected on a subset of goats (n = 3 for each day) on days 0 (no saline), 4, 8, or 14 (control only). Ribonuclease protection assay was performed to quantitate the mRNAs in the CL using specific cRNA probes generated by RT-PCR and in vitro transcription. Level of CD34 mRNA significantly increased from day 0 to 8 (CL development) in the control group (P < 0.05). Long and short forms were detected in the caprine CL by RT-PCR for VEGF mRNA and analyses of their sequences showed that they correspond to mRNAs encoding VEGF(165) and VEGF(121), respectively. Level of VEGF(165) mRNA significantly increased from day 4 to 8 and day 8 to 14 (CL maintenance) in the control group (P < 0.05) while VEGF(121) mRNA did not change during the whole period. Level of KDR/Flk-1 mRNA significantly increased from day 0 to 8 (P < 0.05) while Flt-1 mRNA significantly increased from day 8 to 14 (P < 0.005) in the control group. In the GA-treated group, levels of all of the mRNAs did not alter remarkably as compared with those in the control group. These results suggest that rise of KDR/Flk-1 and VEGF(165) mRNAs during the caprine CL development may be associated with enhanced angiogenesis and that increment of VEGF(165) and Flt-1 mRNAs during the CL maintenance may play nonangiogenic roles. The present study also indicates that the changes of VEGF(165) and KDR/Flk-1 mRNAs during the CL development are probably not regulated by LH.
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PMID:Changes of messenger RNAs encoding vascular endothelial growth factor and its receptors during the development and maintenance of caprine corpora lutea. 1250 48

Our previous work showed that, compared with parental U87MG human glioblastoma cells, vascular endothelial growth factor (VEGF) mRNA levels are decreased in U87/T691, a derivative line in which epidermal growth factor receptor (EGFR) signaling is inhibited by introduction of a truncated p185(Neu) protein (A. Maity et al., Cancer Res., 60: 5879-5886, 2000). The effect of EGFR activation on VEGF was mediated at the level of transcription via a phosphatidylinositol 3'-kinase (PI3K)-dependent pathway. In the current study we investigated the effect of PTEN, a negative regulator of PI3K signaling commonly mutated in glioblastoma cells, on VEGF expression. Several glioblastoma cell lines containing mutant PTEN, including U87MG, U87/T691, and U251MG, were infected with adenovirus expressing wild-type PTEN. This led to a decrease in the levels of both VEGF mRNA and phosphorylated Akt, a marker for PI3K activation. Treatment of U87MG cells with LY294002, a PI3K inhibitor, or cotransfection with a vector expressing wild-type PTEN decreased VEGF promoter activity using reporters containing either 1.5 kb of the promoter or a fragment extending from -88 to +54 bp. Activity of the -88/+54 VEGF promoter was down-regulated by dominant negative Akt and up-regulated by constitutively active myristoylated Akt. Introduction of wild-type PTEN and pharmacological inhibition of EGFR decreased VEGF mRNA expression and VEGF promoter activity in U87MG cells to a greater extent that did either manipulation by itself. Therefore, in human glioblastoma cells, PTEN mutation can cooperate with EGFR activation to increase VEGF mRNA levels by transcriptionally up-regulating the proximal VEGF promoter via the PI3K/Akt pathway.
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PMID:PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. 1251 3


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