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)

Estrogens, which have been associated with several types of human and animal cancers, can induce tumor angiogenesis in the pituitary of Fischer 344 rats. The mechanistic details of tumor angiogenesis induction, during estrogen carcinogenesis, are still unknown. To elucidate the role of estrogen in the regulation of tumor angiogenesis in the pituitary of female rats, the density of blood vessels was analysed using factor VIII related antigen (FVIIIRAg) immunohistochemistry and the expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) was examined by Western blot and immunohistochemical analysis. The expression of VEGF receptor (VEGFR-2/Flk-1/KDR) was also examined by immunohistochemistry. The results demonstrated that 17beta-estradiol (E2) induces neovascularization, as well as the growth and enlargement of blood vessels after 7 days of exposure. The high tumor angiogenic potential was associated with an elevated VEGF/VPF protein expression in the E2 exposed pituitary of ovariectomized (OVEX) rats. VEGF/VPF and FVIIIRAg immunohistochemistry and endothelial specific lectin (UEA1) binding studies, indicate that the elevation of VEGF protein expression initially occurred in both blood vessels and non-endothelial cells. After 15 days of E2 exposure, VEGF/VPF protein expression, in the non-endothelial cell population, sharply declined and was restricted to the blood vessels. The function of non-endothelial-derived VEGF is not clear. Furthermore, immunohistochemical studies demonstrated that VEGFR-2 (flk-1/KDR), expression was elevated significantly in the endothelial cells of microblood vessels after 7 days of E2 exposure. These findings suggest that over expression of VEGF and its receptor (VEGFR-2) may play an important role in the initial step of the regulation of estrogen induced tumor angiogenesis in the rat pituitary.
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PMID:Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis. 921 97

Growth factors of the VEGF (vascular endothelial growth factor) family comprises 4 well characterized members that play a crucial role in the biology of blood vessels. They interact with 3 high affinity tyrosine kinase receptors (FLT1/VEGFR1, FLK1/KDR/VEGFR2, FLT4/VEGFR3). VEGF/VEGFR interactions have essential functions in blood vessel formation during development, specific phases of adult life, and in some pathological processes with neo-vascularization such as tumor growth.
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PMID:[Receptors for factors of the VEGF (Vascular Endothelial Growth Family)]. 923 64

FLT4 represents a recently cloned member of class III receptor tyrosine kinases which include receptors for the angiogenic growth factor VEGF, namely FLT1 and KDR. The ligand of FLT4 has been identified as VEGF-C which shares sequence homology with VEGF and P1GF. In the adult FLT4 shows a restricted expression pattern that is limited to lymphatic endothelia and endothelia of some high endothelial venules (HEV). FLT4 has also been detected in some tumor cell lines including the hematopoietic line HEL. We therefore investigated expression of FLT4 and its ligand VEGF-C in fresh samples from patients with AML. Using a sensitive PCR method we detected FLT4 m-RNA in 15 of 41 patients with de novo AML at diagnosis or relapse and in three of 12 patients with secondary AML. FLT4 expression was confirmed by immunocytochemistry in a subgroup of the studied patient population. FLT4 was also found in leukemic cell line U937, but not TF-1 and KG1a. VEGF-C expression was found in leukemic samples of four of seven FLT4-positive and four of six FLT4-negative patients. U937 cells also produced VEGF-C m-RNA. Interestingly, FLT4 expression was not detected in bone marrow samples of 15 normal volunteer donors or in CD34-positive cells from three additional donors. Possible autocrine and paracrine growth stimulation of leukemic blasts by VEGF-C is currently being investigated in our laboratory.
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PMID:Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia. 926 75

Vascular endothelial growth factor A (here referred to as VEGF) is an endothelium-specific growth factor that binds to two distinct receptor tyrosine kinases, designated Flt-1 and KDR/Flk-1. VEGF stimulates autophosphorylation of both receptors, but little is known about their signal transduction properties. In this study, we used porcine aortic endothelial (PAE) cells overexpressing KDR (PAE/KDR) to evaluate the interaction of KDR with intracellular proteins and compared them with Flt-1-expressing PAE cells (PAE/Flt-1). VEGF-induced stimulation of KDR results in the association and phosphorylation of the 46-, 52-, and 66-kDa isoforms of Shc and the induction of Shc-Grb2 complex formation. In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. Another strong candidate is mitogen-activated protein (MAP) kinase, which is strongly activated in response to VEGF stimulation as demonstrated by phosphorylation of the specific substrate myelin basic protein. Inhibition of MAP kinase activation by PD98059, a specific MAP kinase kinase inhibitor, results in inhibition of VEGF-induced proliferation of PAE/KDR cells. In contrast, VEGF-induced stimulation of Flt-1 does not activate MAP kinase in PAE/Flt-1 cells. In this study we provide the first two examples of molecules potentially capable of functionally counteracting the endothelial response to VEGF, namely SHP-1 and SHP-2. These two SH2 protein-tyrosine phosphatases physically associate with KDR secondary to VEGF stimulation, raising the interesting possibility that both molecules participate in the generation and/or modulation of VEGF-induced signals. Taken together, our results substantially broaden the spectrum of KDR-associating molecules, indicating that endothelial function and angiogenesis are regulated by a diverse network of signal transduction cascades.
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PMID:The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. 940 64

VEGF-C is a recently discovered secreted polypeptide related to the angiogenic mitogen VEGF. We have isolated the quail VEGF-C cDNA and shown that its protein product is secreted from transfected cells and interacts with the avian VEGFR3 and VEGFR2. In situ hybridization shows that quail VEGF-C mRNA is strongly expressed in regions destined to be rich in lymphatic vessels, particularly the mesenteries, mesocardium and myotome, in the region surrounding the jugular veins, and in the kidney. These expression sites are similar to those observed in the mouse embryo (E. Kukk, A. Lymboussaki, S. Taira, A. Kaipainen, M. Jeltsch, V. Joukov and K. Alitalo, 1996, Development 122, 3829-3837). We have observed VEGFR3-positive endothelial cells in proximity to most of the VEGF-C-expressing sites, suggesting functional relationships between this receptor-ligand couple. The comparison of the VEGF and VEGFR2 knockout phenotypes had suggested the existence of another ligand for VEGFR2. We therefore investigated the effect of VEGF-C on VEGFR2-positive cells isolated from the posterior mesoderm of gastrulating embryos. We have recently shown that VEGF binding triggers endothelial differentiation of these cells, whereas hemopoietic differentiation appears to be mediated by binding of a so far unidentified VEGFR2 ligand. We show here that VEGF-C also triggers endothelial differentiation of these cells, presumably via VEGFR2. These results indicate that VEGF and VEGF-C can act in a redundant manner via VEGFR2. In conclusion, VEGF-C appears to act during two different developmental phases, one early in posterior mesodermal VEGFR2-positive endothelial cell precursors which are negative for VEGFR3 and one later in regions rich in lymphatic vessels at a time when endothelial cells express both VEGFR2 and VEGFR3.
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PMID:Avian VEGF-C: cloning, embryonic expression pattern and stimulation of the differentiation of VEGFR2-expressing endothelial cell precursors. 943 94

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine and growth factor that has important roles in both pathological and physiological angiogenesis. VPF/VEGF induces vascular hyperpermeability, cell division, and other activities by interacting with two specific receptor tyrosine kinases, KDR/Flk-1 and Flt-1, that are selectively expressed on vascular endothelium. The signaling cascade that follows VPF/VEGF interaction with cultured endothelium is only partially understood but is known to result in increased intracellular calcium, activation of protein kinase C, and tyrosine phosphorylations of both receptors, phospholipase C-gamma (PLC-gamma) and phosphatidylinositol 3'-kinase. For many reasons, signaling events elicited in cultured endothelium may not mimic mediator effects on intact normal or tumor-induced microvessels in vivo. Therefore, we developed a system that would allow measurement of VPF/VEGF-induced signaling on intact microvessels. We used mouse mesentery, a tissue whose numerous microvessels are highly responsive to VPF/VEGF and that we found to express Flk-1 and Flt-1 selectively. At intervals after injecting VPF/VEGF i.p., mesenteries were harvested, extracted, and immunoprecipitated. Immunoblots confirmed that VPF/VEGF induced tyrosine phosphorylation of several proteins in mesenteric microvessels as in cultured endothelium: Flk-1; PLC-gamma; and mitogen-activated protein kinase. Similar phosphorylations were observed when mesentery was exposed to VPF/VEGF in vitro, or when mesenteries were harvested from mice bearing the mouse ovarian tumor ascites tumor, which itself secretes abundant VPF/VEGF. Other experiments further elucidated the VPF/VEGF signaling pathway, demonstrating phosphorylation of both PYK2 and focal adhesion kinase, activation of c-jun-NH2-kinase with phosphorylation of c-Jun, and an association between Flk-1 and PLC-gamma. In addition, we demonstrated translocation of mitogen-activated protein kinase to the cell nucleus in cultured endothelium. Taken together, these experiments describe a new model system with the potential for investigating signaling events in response to diverse mediators on intact microvessels in vivo and have further elucidated the VPF/VEGF signaling cascade.
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PMID:Vascular permeability factor/vascular endothelial growth factor-mediated signaling in mouse mesentery vascular endothelium. 951 16

Glioblastomas may develop rapidly without clinical and histopathological evidence of a less malignant precursor lesion (de novo or primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas typically show overexpression of EGFR, but rarely p53 mutations, while secondary glioblastomas frequently carry a p53 mutation, but usually lack overexpression of EGFR, suggesting that these glioblastoma subtypes develop through distinct genetic pathways. In the present study, we assessed the expression of Fas/APO-1 (CD95), an apoptosis-mediating cell membrane protein, and its relation to necrosis phenotype in primary and secondary glioblastomas. Large areas of ischemic necroses were observed in all 18 primary glioblastomas, but were significantly less frequent in secondary glioblastomas (10 of 19, 53%; p = 0.0004). Fas expression was predominantly observed in glioma cells surrounding large areas of necrosis and was thus significantly more frequent in primary glioblastomas (18 of 18, 100%) than in secondary glioblastomas (4 of 19, 21%; p < 0.0001), suggesting that these clinically and genetically defined subtypes of glioblastoma differ in the extent and mechanism of necrogenesis. Necrosis and microvascular proliferation are histologic hallmarks of the glioblastoma. Following incubation of glioblastoma cell lines under hypoxic/anoxic conditions for 24-48 hours, Fas mRNA levels remained unchanged, whereas VEGF expression was markedly upregulated. This suggests that in contrast to VEGF Fas expression is not induced by ischemia/hypoxia. Analysis of Fas mRNA levels in a glioblastoma cell line containing a p53 mutation and an inducible wild-type p53 gene showed little difference under induced and noninduced conditions, suggesting that in glioblastomas, Fas expression is not directly linked to the p53 status.
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PMID:Necrogenesis and Fas/APO-1 (CD95) expression in primary (de novo) and secondary glioblastomas. 960 Feb 16

Biological evidence suggests that interference with the function of the angiogenic growth factor receptor VEGFR2 (flk1/KDR) is a particularly promising strategy to inhibit tumor-induced angiogenesis. Proof of concept was established by developing a monoclonal rat anti-mouse VEGFR2 antibody (DC101) and showing that it potently blocked the binding of VEGF to its receptor, inhibited VEGF-induced signaling, and strongly blocked tumor growth in mice through an anti-angiogenic mechanism. Since DC101 does not cross-react with the human VEGFR2 KDR, anti-KDR monoclonal antibodies were generated by standard hybridoma technology and by using phage display library. High affinity antibodies (Kd = 4.9 x 10(-10)-1.1 x 10(-9) M) were found with both approaches. The anti-KDR antibodies compete on an equimolar basis with VEGF for binding to KDR and inhibit with similar potency the VEGF-induced signaling and mitogenesis in human endothelial cells. Although these antibodies cannot be tested for in vivo efficacy in standard murine tumor models because of lack of species cross-reactivity, the similarity of their in vitro properties with those of DC101 suggests that they may be effective in blocking KDR function in vivo.
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PMID:Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. 977 Jan 11

Vascular Endothelial Growth Factor-A (VEGF-A) is an endothelial-specific growth factor that induces angiogenesis, i.e., sprouting of capillaries from preexisting vessels in vivo. Endothelial nitric oxide synthase (eNOS) is an essential molecule in mediating VEGF-A-induced angiogenesis and endothelial function via production of nitric oxide (NO). Moreover, the protein level of eNOS is upregulated in response to VEGF-A. While VEGF-A-induced NO release in human trophoblast cells appears to be initiated via VEGF receptor-1, it is not clear which of the VEGF-receptors is mediating the signal for induction of eNOS protein expression. In addition, it is unclear whether other NOS isoforms are upregulated in response to VEGF-A stimulation. To address these questions, we stimulated human umbilical vein endothelial cells (HUVEC) with VEGF-A for 24 hours and evaluated expression of eNOS and iNOS protein. VEGF-A induces expression of both members of the NOS family. Using porcine aortic endothelial cells overexpressing either VEGF receptor-2 (PAE/KDR cells) or VEGF receptor-1 (PAE/Flt-1 cells), we have studied the regulation of iNOS and eNOS expression in response to VEGF-A stimulation. The activation of VEGF receptor-2 leads to an upregulation of both eNOS and iNOS protein, while stimulation of VEGF receptor-1 did not generate such a signal. Therefore, only VEGF receptor-2 mediates stimulation of eNOS and iNOS expression. We conclude that the two VEGF receptors have different and distinct functions regarding NO formation and NO release during VEGF-A-induced angiogenesis.
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PMID:VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). 983 77

Angiogenesis is regulated by various factors. In particular, VEGF and basic FGF are of much importance. We found that 8-(3-oxo-4,5,6-trihydroxy-3h-xanthen-9-yl)-1-naphthoic acid inhibited the binding of VEGF to KDR/Flk-1 (VEGF receptor-2) or Flt-1 (VEGF receptor-1) and that it inhibited the MAPK phosphorylation in HUVEC induced by VEGF or basic FGF but not by EGF. 8-(3-oxo-4,5,6-trihydroxy-3h-xanthen-9-yl)-1-naphthoic acid might be used as an inhibitor of VEGF and basic FGF signal transduction.
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PMID:8-(3-oxo-4,5,6-trihydroxy-3h-xanthen-9-yl)-1-naphthoic acid inhibits MAPK phosphorylation in endothelial cells induced by VEGF and bFGF. 985 90


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