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)

Delayed hypersensitivity (DH) is a T cell-mediated form of immune response characterized by a predominantly perivascular, mononuclear cell infiltrate. The venules in DH reactions are hyperpermeable to plasma proteins, leading to extravasation of plasma fibrinogen and its extravascular clotting to form a fibrin gel that promotes induration and angiogenesis. The mechanisms responsible for microvascular hyperpermeability in DH are unknown. Recently, a cytokine named vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF) has been implicated in the chronic vascular hyperpermeability and angiogenesis of solid and ascites tumors, healing wounds, rheumatoid arthritis, and psoriasis. These findings suggested that VPF/VEGF might also have a role in the pathogenesis of DH. Two model systems were studied: allergic contact dermatitis to poison ivy in human volunteers and classical tuberculin hypersensitivity in rats. In both, in situ hybridization revealed that the mRNAs encoding VPF/VEGF were strikingly overexpressed in keratinocytes of the epidermis; scattered mononuclear cells infiltrating the dermis also overexpressed VPF/VEGF mRNA, to a greater extent in rat tuberculin than in human contact reactions. In contact reactions, mRNAs for two VPF/VEGF vascular endothelial cell receptors, flt-1 and KDR, were also strikingly overexpressed. Abundant fibrin deposition in both models confirmed that dermal microvessels were indeed hyperpermeable to plasma fibrinogen. These results implicate VPF/VEGF as a potentially important mediator in the pathogenesis of cell-mediated immunity and provide further evidence that products of epithelial cells may regulate the inflammatory response.
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PMID:Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensitivity skin reactions. 787 50

Vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), is a potent microvascular permeability enhancing cytokine and a selective mitogen for endothelial cells. It has been implicated in tumor angiogenesis and ascites fluid accumulation. Since development of the destructive synovial pannus in rheumatoid arthritis (RA) is associated with changes in vascular permeability (synovial fluid accumulation), synovial cell hyperplasia, and angiogenesis, we examined synovial fluids (SFs) and joint tissue for the expression and local accumulation of VPF/VEGF. VPF/VEGF was detected in all of 21 synovial fluids examined and when measured by an immunofluorimetric assay, ranged from 6.9 to 180.5 pM. These levels are biologically significant, since < 1 pM VPF/VEGF can elicit responses from its target cells, endothelial cells. Levels of VPF/VEGF were highest in rheumatoid arthritis fluids (n = 10), with a mean value (+/- SEM) of 59.1 +/- 18.0 pM, vs. 21.4 +/- 2.3 pM for 11 SFs from patients with other forms of arthritis (p = 0.042). In situ hybridization studies that were performed on joint tissues from patients with active RA revealed that synovial lining macrophages strongly expressed VPF/VEGF mRNA, and that microvascular endothelial cells of nearby blood vessels strongly expressed mRNA for the VPF/VEGF receptors, flt-1 and KDR. Immunohistochemistry performed on inflamed rheumatoid synovial tissue revealed that the VPF/VEGF peptide was localized to macrophages within inflamed synovium, as well as to microvascular endothelium, its putative target in the tissue. Together, these findings indicate that VPF/VEGF may have an important role in the pathogenesis of RA.
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PMID:Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. 800 92

Hepatocyte Growth Factor (HGF)/Scatter Factor secreted from sinusoidal endothelial cells and Kupffer cells in liver activates the c-Met tyrosine kinase receptor expressed on hepatocytes. Here we report yet another possible communication system through a different ligand and tyrosine kinase receptor in an opposite direction. We isolated and determined the primary structure of the entire coding region of rat flt-1 (fms-like tyrosine kinase), a receptor for Vascular Endothelial Growth Factor (VEGF). Using rat flt-1 cDNA as a probe we found that the flt-1 mRNA was expressed at very high levels in sinusoidal endothelial cells in normal rat liver, but was hardly detectable in hepatocytes. The transcripts of another VEGF receptor KDR/Flk-1 structurally related to Flt-1 was also expressed specifically in sinusoidal endothelial cells. On the other hand, VEGF mRNA was expressed weakly in hepatocytes, but not in the nonparenchymal cell fraction. Furthermore, in an in vitro culture system, VEGF demonstrated a remarkably specific growth-stimulatory activity as well as maintenance activity on the sinusoidal endothelial cells. These results suggest that hepatocytes regulate the proliferation and survival of the sinusoidal endothelial cells in liver in a paracrine manner. Therefore two reciprocal communication systems, VEGF-Flt receptor family and HGF-Met receptor, may exist in hepatic tissue.
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PMID:A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). 805 32

Transforming growth factor beta (TGF-beta) is a multifunctional polypeptide that regulates the proliferation and differentiation of various cells and has an angiogenic effect in vivo, although it inhibits the growth of cultured endothelial cells. We report here that TGF-beta treatment of quiescent cultures of mouse embryo-derived AKR-2B cells, which are growth-stimulated by TGF-beta, and human lung adenocarcinoma A549 cells, which are growth-inhibited by TGF-beta, results in the induction of vascular endothelial growth factor (VEGF) mRNA and protein. Maximal VEGF mRNA levels occurred 4-8 h after stimulation with a decline to background levels in 24 h. In contrast, the related placenta growth factor mRNA was not induced by TGF-beta in these cells. No VEGF receptor mRNA was seen in AKR-2B cells. Also, TGF-beta treatment of endothelial cells, which express the FLT1 and KDR/FLK-1 receptors for VEGF, did not cause VEGF induction. Because VEGF is known to be a strong angiogenic factor for endothelial cells, the results suggest that the angiogenic effect of TGF-beta on endothelial cells in blood vessels may be mediated at least partly by a paracrine induction of VEGF in other surrounding cell types.
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PMID:Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. 811 73

Vascular permeability factor (VPF), also known as vascular endothelial growth factor, is a secreted protein implicated in tumor-associated microvascular hyperpermeability and angiogenesis. Tumor cells in 11 of 12 renal cell carcinomas expressed high levels of VPF messenger RNA (mRNA) by in situ hybridization, the only exception being a case of the relatively avascular papillary variant. Expression was further accentuated adjacent to areas of necrosis. Both tumor cells and endothelial cells in small vessels adjacent to tumor stained strongly for VPF protein by immunohistochemistry. Endothelial cells did not express detectable VPF mRNA, but did express high levels of mRNA for the VPF receptors flt-1 and KDR indicating that the endothelial cell staining likely reflects binding of VPF secreted by adjacent tumor cells. Three transitional cell carcinomas also labeled strongly for VPF mRNA. These data suggest an important role for VPF in the vascular biology of these two common human malignancies.
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PMID:Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. 823 42

The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.
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PMID:The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. 824 83

Smooth muscle cells, macrophages, glial cells, keratinocytes, and transformed cells have been established as synthesis sites for vascular endothelial growth factor (VEGF). The modulating effects of VEGF are essentially limited to endothelial cells (ECs), the only cell type consistently shown to express VEGF receptors. VEGF has thus been considered to act exclusively via a paracrine pathway. We sought to determine whether the role of human ECs might, under selected conditions, extend beyond that of a target to involve contingency synthesis of VEGF. In both unstimulated human umbilical vein ECs (HUVECs) and human derma-derived microvascular ECs (HMECs), Northern analysis detected no VEGF transcripts. Phorbol-12-myristate 13-acetate (10(-7) M) treatment, however, induced VEGF mRNA expression in both HUVECs and HMECs, peaking at 3 and 6 h, respectively, and returning to undetectable levels by 12 h. In vitro exposure of HUVECs to a hypoxic environment (pO2 = 35 mm of mercury) for 12, 24, and 48 h and exposure of HMECs for 6, 12, 24, and 48 h induced VEGF mRNA in a time-dependent fashion. Re-exposure to normoxia (pO2 = 150 mm of mercury) for 24 h after 24 h of hypoxia returned VEGF mRNA transcripts to undetectable levels in HUVECs. Cobalt chloride and nickel chloride treatment each induced VEGF mRNA in ECs. Cycloheximide treatment further augmented expression of VEGF mRNA induced by cobalt chloride, nickel chloride, and hypoxia in HUVECs. VEGF protein production in hypoxia HUVECs was demonstrated immunohistochemically. Conditioned media from hypoxic HUVECs caused a 2-fold increase in the incorporation of tritiated thymidine. Finally, immune precipitates of anti-KDR probed with anti-Tyr(P) antibodies demonstrated evidence of receptor autophosphorylation in hypoxic but not normoxic HUVECs. These findings thus establish the potential for an autocrine pathway that may augment and/or amplify the paracrine effects of VEGF in stimulating angiogenesis.
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PMID:Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. 853 83

Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF), an endothelial cell (EC)-specific mitogen, stimulates angiogenesis in vivo, particularly in ischemic regions. VEGF/VPF expression by cells of hypoxic tissues coincides with expression of its two receptors, KDR and flt-1, by ECs in the same tissues. We investigated whether hypoxia or hypoxia-dependent conditions operate in coordinating this phenomenon. Human umbilical vein and microvascular ECs were exposed to direct hypoxia or to medium conditioned (CM) by myoblasts maintained in hypoxia for 4 d. Control ECs were maintained in normoxia or normoxia-CM. Binding of 125I-VEGF to ECs was then evaluated. Hypoxic treatment of ECs had no effect on 125I-VEGF binding. However, treatment of ECs with hypoxia-CM produced a threefold increase in 125I-VEGF binding, with peak at 24 h (P < 0.001, ANOVA). Scatchard analysis disclosed that increased binding was due to a 13-fold increase in KDR receptors/cell, with no change in KDR affinity (Kd = 260 +/- 51 pM, normoxia-CM versus Kd = 281 +/- 94 pM, hypoxia-CM) and no change in EC number (35.6 +/- 5.9 x 10(3) ECs/cm2, normoxia-CM versus 33.5 +/- 5.5 x 10(3) ECs/cm2, hypoxia-CM). Similar results were obtained using CM from hypoxic smooth muscle cells. KDR upregulation was not prevented by addition to the hypoxia-CM of neutralizing antibodies against VEGF, tumor necrosis factor-alpha, transforming growth factor beta 1 or basic fibroblast growth factor. Similarly, addition of VEGF or lactic acid to the normoxia-CM had no effect on VEGF binding. We conclude that mechanism(s) initiated by hypoxia can induce KDR receptor upregulation in ECs. Hypoxic cells, normal or neoplastic, not only can produce VEGF/VPF, but can also modulate its effects via paracrine induction of VEGF/VPF receptors in ECs.
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PMID:Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. 856 69

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), plays an important role in the angiogenesis associated with the growth of many human and animal tumors. VPF/VEGF stimulates endothelial cell growth and increases microvascular permeability by interacting with two endothelial cell tyrosine kinase receptors, KDR and flt-1. We studied 16 cases of AIDS-associated Kaposi's sarcoma (KS), 2 cases of cutaneous angiosarcoma, and 6 cases of capillary hemangioma by in situ hybridization for expression of VPF/VEGF, KDR, and flt-1 mRNAs. We also performed immunohistochemical staining for VPF/VEGF protein in 15 cases. Tumor cells in KS and angiosarcoma strongly expressed KDR but not flt-1 mRNA. Endothelial cells in small stromal vessels in and around these tumors strongly expressed both KDR and flt-1 mRNAs. Tumor cells expressed VPF/VEGF mRNA strongly in only one case of KS, adjacent to an area of necrosis. This was also the only case in which the tumor cells stained substantially for VPF/VEGF protein. VPF/VEGF mRNA and protein were, however, strongly expressed by squamous epithelium in areas of hyperplasia and near areas of ulceration overlying tumors. VPF/VEGF mRNA was also expressed focally at lower levels by infiltrating inflammatory cells, probably macrophages. The strong expression of both KDR and flt-1 in small stromal vessels in and around tumors suggests that VPF/VEGF may be an important regulator of the edema and angiogenesis seen in these tumors. The strong expression of KDR by tumor cells in KS and angiosarcoma implies that VPF/VEGF may also have a direct effect on tumor cells. Tumor cells in four of six capillary hemangiomas strongly expressed both KDR and flt-1 mRNAs in contrast to the high level expression of only KDR observed in the malignant vascular tumors studied. Neither VPF/VEGF mRNA or protein were strongly expressed in capillary hemangiomas. VPF/VEGF and its receptors may play an important but as yet incompletely understood role in the pathogenesis of both benign and malignant vascular tumors.
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PMID:Strong expression of kinase insert domain-containing receptor, a vascular permeability factor/vascular endothelial growth factor receptor in AIDS-associated Kaposi's sarcoma and cutaneous angiosarcoma. 864 48

Angiogenesis is a critical factor in the growth, progression, and metastatic spread of solid tumors. Furthermore, angiogenesis has been correlated with prognosis in patients with ovarian cancer. The pathogenesis of the angiogenic events in ovarian cancer, however, are not well defined. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine that has been shown to be an important regulator of tumor angiogenesis. The purpose of the present study was to define the expression of VPF/VEGF and its receptors flt-1 and KDR in ovarian tumors. Four specimens of normal ovarian cortex and 41 specimens of benign (4), borderline (8), and malignant (29) ovarian tumors were studied by in situ hybridization, and in some cases by immunohistochemical analysis. VPF/VEGF protein was also determined by an immunofluorometric assay in cyst fluids obtained from 11 patients, including 7 benign, 2 borderline, and 2 malignant tumors. VPF/VEGF mRNA and protein were expressed by the neoplastic cells in all of the malignant tumors evaluated, with the majority of tumors (28 of 29) showing strong expression of mRNA. Serous borderline tumors had variable VPF/VEGF mRNA expression, with two of six cases showing focal strong expression and four showing low-level expression. No definite expression of VPF/VEGF was seen in two cases of mucinous borderline tumors. No strong expression of VPF/VEGF mRNA was observed in normal ovarian cortex, including surface epithelium, or benign tumors. Substantially higher VPF protein concentrations were detected in cyst fluids of the two malignant (60, 440 pM) and two borderline tumors (210, 590 pM) than in the seven benign serous cysts (mean, 10 +/- 3 pM). In addition, microvascular endothelial cells strongly expressed mRNA of the VPF/VEGF receptors flt-1 and KDR and immunostained for VPF/VEGF protein in the majority of malignant and borderline tumors examined. These findings suggest that VPF/VEGF plays an important role in the angiogenesis associated with ovarian neoplasms.
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PMID:Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. 866 14


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