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)

A glomerulus is a functional unit of the kidney, and endothelial cells in the glomerulus are often exposed to more than 5 times higher pressure than peripheral capillaries. Glomerular development proceeds through angiogenesis and VEGF was shown to mediate the angiogenesis. VEGF is constitutively expressed in the glomerulus from the embryo to adults. When VEGF signal was blocked by the antibody, glomerular endothelial cells were swollen and capillary lumen was interrupted. Changes were more prominent in the juxta-medullary than in the cortical glomerulus. A major VEGF receptor, Flk-1/KDR, is specifically localized to the glomerular endothelial cell among tissues and more predominantly in the juxta-medullary than in the cortical glomerulus. As capillary pressure is higher in the juxta-medullary than in the cortical glomeruli, endothelial cells in the former are exposed to more tension than those in the latter. VEGF might be a protective molecule for endothelial cells against tension. The effect of VEGF on the repair of an impaired glomerulus was evaluated in the rat Thy-1 glomerulonephritis. VEGF inhibited early endothelial injury and accelerated consequent remodeling of the glomerulus. In the patient study, VEGF excretion in the urine was independent from its serum or plasma level, but increased as renal function decreased. VEGF signaling is essential in glomerular development, maintenance and repair. VEGF excreted in the urine might reflect its generation in the kidney and be a unique marker of renal function.
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PMID:[VEGF is an essential molecule for glomerular endothelial cells and its excretion in urine might be a unique marker of glomerular injury]. 1089 64

Promotion of tumour progression by thrombin is suggested by several clinical and laboratory observations. A plausible explanation for this effect of thrombin may be related to our previous findings that thrombin is a potent promoter of angiogenesis in the chick chorioallantoic membrane system (CAM) and in the Matrigel system in vivo. In this report we summarise the cellular and molecular actions of thrombin that could be contributing to the activation of angiogenic cascade. Treatment of endothelial cells with thrombin leads to activation of gelatinase A, which may allow for local dissolution of basement membrane, an essential first step of angiogenesis. Similarly thrombin-treated endothelial cells have diminished ability to adhere to collagen type IV and laminin. This new phenotype of endothelial cells can migrate and survive without attachment to extracellular matrix. Thrombin-treatment of endothelial cells increases the vectorial secretion of extracellular matrix proteins, a process essential at the final steps of angiogenesis. In addition, thrombin potentiates the VEGF-induced mitogenesis of endothelial cells. This can be explained by the upregulation of the VEGF receptors (KDR & flt-1) by thrombin treatment. All the aforementioned effects of thrombin are receptor mediated, dose-dependent and require only brief exposure of endothelial cells to thrombin for these actions of thrombin. The transduction mechanisms involved are via protein kinase C (PKC) and MAP-kinase pathways.
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PMID:On the mechanism(s) of thrombin induced angiogenesis. 1094 54

When quiescent endothelial cells (ECs) are exposed to angiogenic factor such as VEGF; ECs express proteases to degrade extracellular matrices, migrate, proliferate and form new vessels. However, the molecular mechanism of these events is not fully characterized yet. We are studying the signal transduction and transcriptional regulation of angiogenesis. We investigated the properties of two VEGF receptors, Flt-1 and KDR, by using two newly developed blocking monoclonal antibodies (mAbs), i.e., anti-human Flt-1 mAb and anti-human KDR mAb. VEGF elicited induction of transcription factor Ets-1 in human umbilical vein endothelial cells (HUVECs). This induction was mediated by the KDR/Flt-1 heterodimer and the KDR homodimer. The role of transcription factor Ets-1 in angiogenesis was further clarified. We established both high and low Ets-1 expressing EC lines, and compared angiogenic properties of these cell lines with a parental murine EC line, MSS31. The growth rate was almost identical among three cell lines. It appeared that gene expressions of matrix metalloproteinases (MMP-1, MMP-3, and MMP-9) as well as integrin beta 3 were correlated with the level of Ets-1 expression. As a result, the invasiveness was enhanced in high Ets-1 expressing cells and reduced in low Ets-1 expressing cells compared with parental cells, and high Ets-1 expressing cells made more tube-like structures in type 1 collagen gel. These results indicate that Ets-1 is a principle transcription factor converting ECs to the angiogeneic phenotype.
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PMID:Signal transduction and transcriptional regulation of angiogenesis. 1094 59

The signaling activity of Platelet-derived growth factors A and B (PDGF-A and PDGF-B) that is mediated through the two receptor kinases, PDGFR-alpha and PDGFR-beta has been shown to be critical for the development of the cardiovascular organs, the kidney, the lung and the central nervous system. During the cloning of genes for VEGF related proteins, we isolated a mouse cDNA that can encode for a protein of 345 amino acids. A comparison of the amino acid sequence reveals that this predicted gene product displays 95% identity to human PDGF-C. The mouse Pdgfc gene maps to a region of chromosome 17 that is syntenic to human chromosome 6p21.3 In E9. 5-E15.5 mouse embryo, Pdgfc is widely expressed in the surface ectoderm and later in the germinal layer of the skin, the olfactory and otic placode and their derivatives and the lining of the oral cavity. In the gut and visceral organs, such as the lung and the kidney, Pdgfc mRNA is first expressed in the endodermal epithelium and later in mesenchymal tissues associated with the endodermal structures. Similar to other PDGFs, Pdgfc is widely expressed in mesenchymal precursors and the myoblast of the smooth and skeletal muscles. Contrary to PDGF-A, Pdgfc is not expressed in the central nervous system, except in the cerebellum, and neurogenic derivatives of the neural crest cells. Pdgfc is also absent from the heart and the vascular endothelium
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PMID:The mouse Pdgfc gene: dynamic expression in embryonic tissues during organogenesis. 1096 Jul 85

Laboratory, histopathological, pharmacological and clinical evidence support the notion that a systemic activation of blood coagulation is often present in cancer patients. On the other hand, epidemiological studies provide evidence of an increased risk of cancer diagnosis following primary thromboembolism. Moreover, the metastatic ability of human breast cancer cells is correlated with the number of thrombin receptors of these cells, and thrombin treatment of B16 melanoma cells dramatically increases the number of lung metastases in rats. We have proposed that these tumour-promoting effects of thrombin can be explained by the ability of thrombin to activate angiogenesis, an essential requirement for tumour progression. Many of the cellular events involved in the angiogenic cascade can be activated by thrombin. At the molecular level, brief exposure of endothelial cells to thrombin causes an upregulation of the receptors (KDR and Flt-1) of VEGF, the key angiogenic mediator. This results in a synergistic effect of thrombin and VEGF in the activation of angiogenesis. In addition, thrombin activates cancer cells to secrete VEGF, thus causing a mutual stimulation between EC and CA cells. Cancer cells exposed to thrombin secrete metalloproteinase 92 KD and overexpress the integrin a(v)b(3), all of which are involved in tumour metastasis.
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PMID:Effects of thrombin/thrombosis in angiogenesis and tumour progression. 1096 95

Integrin-mediated cell attachment and growth factor stimulation often act synergistically on cell proliferation, differentiation, migration, and survival. Some of these synergistic effects depend on the physical interaction of integrins with growth factor receptors. Here we examine the nature of the physical interaction between the alpha(v)beta(3) integrin and two receptor tyrosine kinases (RTKs), the platelet-derived growth factor receptor beta (PDGF-Rbeta) and the vascular endothelial growth factor receptor 2 (VEGF-R2, also known as KDR and flk-1). Both of these RTKs associate with the alpha(v)beta(3) integrin but do not associate with beta(1) integrins. Furthermore, growth factor stimulation of these RTKs promotes increased cell proliferation and migration when cells are attached to the alpha(v)beta(3) ligand, vitronectin. We show that alpha(v)beta(3) in which the beta(3) cytoplasmic domain is deleted or replaced with the beta(1) cytoplasmic domain coimmunoprecipitates with PDGF-Rbeta and VEGF-R2. The beta(3) extracellular domain alone was sufficient for the PDGF-Rbeta association whereas the VEGF-R2 association required the presence of the alpha(v) subunit. Activation of the RTKs by their ligands was not required for them to associate with the integrin. Cell migration to PDGF was enhanced in the cells transfected with the chimeric subunit containing the beta(3) extracellular domain but not when that domain came from the beta(1) subunit. These results show that the interactions that lead to the association of the alpha(v)beta(3) integrin with PDGF-Rbeta and VEGF-R2 and enhancement of RTK activity take place outside the cell.
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PMID:Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. 1096 31

Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumor malignancy. In the present study, we investigated the mechanism underlying hypoxia-modulated apoptosis of serum-deprived HepG2 cells. Our results showed that hypoxia blocked the apoptosis, which was accompanied with decreased Bax/Bcl-2 ratio, inhibited cytochrome c release, and reduced caspase-3 activity. More importantly, increased expressions of VEGF and its receptor-2 (KDR) under hypoxic/serum-deprived condition suggest that VEGF may act as a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum deprivation-induced apoptosis, and anti-VEGF neutralizing antibody block anti-apoptotic activity of hypoxia. In addition, inhibitors of receptor tyrosine kinase blocked antiapoptosis of hypoxia. Our study further showed that rhVEGF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a specific inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic activity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 activity. Our data led us to conclude that induction of ERK phosphorylation and decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxia-induced VEGF prevents apoptosis of serum-deprived cells by activating the MAPK/ERK pathway. Taken together, we propose that hypoxia enhances survival of nutrient-depleted tumor cells by reducing susceptibility to apoptosis, which consequently leads to tumor malignancy.
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PMID:Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. 1103 Jan 51

Many similarities exist in the cellular responses elicited by VEGF and governed by integrins. Here, we identify a basis for these interrelationships: VEGF activates integrins. VEGF enhanced cell adhesion, migration, soluble ligand binding, and adenovirus gene transfer mediated by alphavbeta3 and also activated other integrins, alphavbeta5, alpha5beta1, and alpha2beta1, involved in angiogenesis. Certain tumor cells exhibited high spontaneous adhesion and migration, which were attributable to a VEGF-dependent autocrine/paracrine activation of integrins. This activation was mediated by the VEGFR2 receptor and regulated via phosphatidylinositol-3-kinase, Akt, and the PTEN signaling axis. Thus, integrin activation provides a mechanism for VEGF to induce a broad spectrum of cellular responses.
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PMID:A mechanism for modulation of cellular responses to VEGF: activation of the integrins. 1109 Jun 23

SU5416 [3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1, 3-dihydro-indol-2-one], an inhibitor of VEGF (vascular endothelial growth factor) receptor tyrosine kinase, Flk-1/KDR (fetal liver kinase 1/kinase insert domain-containing receptor), also known as VEGF receptor 2 (VEGFR2) is in advanced clinical trials for treatment of AIDS-related Kaposi's sarcoma and colorectal and nonsmall cell lung cancers. Since this chemical class has not been studied previously with therapeutic intent, the present study was designed to investigate the in vitro metabolism of SU5416 by mouse, rat, dog, monkey, and human liver microsomes and to identify the major metabolites of SU5416. An HPLC procedure was developed and validated to resolve and quantify SU5416 and its metabolites. To evaluate the in vitro metabolism of SU5416, pooled liver microsomes from mice, rats, dogs, monkeys, and humans were incubated with SU5416 (25 microM) in the presence of an NADPH-generating system. In the presence of NADPH, mouse, rat, dog, monkey, and human liver microsomes converted SU5416 to at least 12, 9, 9, 7, and 6 polar metabolites, respectively. Microsomal metabolism of SU5416 showed marked species differences in the levels of different metabolites formed. The overall rate of SU5416 metabolism by liver microsomes from the species examined followed the rank order: monkey > or = mouse approximately rat > dog > human. Two major metabolites of SU5416 were identified, a hydroxymethyl derivative of SU5416 (M12) and a carboxylic acid derivative of SU5416 (M6), by spectroscopic methods and comparison with authentic compounds. Both of these oxidative metabolites were further metabolized in vivo through glucuronidation. The metabolic fate of SU5416 in microsomes from various species as well as data from in vivo biotransformation in the rat are discussed.
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PMID:Biotransformation of the anti-angiogenic compound SU5416. 1109 90

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000
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PMID:Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. 1112 Nov 33


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