Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is a dimeric protein which induces formation of new blood vessels (angiogenesis) through binding to VEGF-receptor-2 tyrosine kinase (VEGFR2 TK) or KDR (kinase insert domain-containing receptor) on the surface of endothelial cells. Angiogenesis has been shown to be essential for malignancy of tumors; therefore, VEGFR2 TK is a potential therapeutic target for the treatment of cancer. Sequence homology studies indicate that VEGFR2 TK contains three domains: extracellular (ligand-binding domain), transmembrane, and intracellular (catalytic domain). In this work, the catalytic domain of VEGFR2 TK was cloned and expressed in a soluble active form using a baculovirus expression system. In the absence of ligand, the enzyme is shown to catalyze its autophosphorylation in a time-dependent and enzyme-concentration-dependent manner, consistent with a trans mechanism for this reaction. Mass spectrometry analysis revealed incorporation of 5.5 +/- 0.5 mol of phosphate/mole of enzyme (monomer). In addition, the enzyme was shown to catalyze phosphorylation of a synthetic peptide, poly(E4Y). Using poly(E4Y) as substrate, the kinetic constants of both native and phosphorylated enzyme were determined. Enzyme phosphorylation increased catalytic efficiency of the enzyme by at least an order of magnitude. Furthermore, the enzyme was shown to catalyze the reverse reaction using phospho-poly(E4Y) as substrate. Cd2+ was found to be an inhibitor of the enzyme. Kinetic studies revealed that inhibition by Cd2+ was competitive with respect to Mg2+ and noncompetitive with respect to MgATP. These results indicate that Cd2+ competes for a second metal-binding site. Therefore, the reaction catalyzed by this enzyme was treated as a terreactant system. The kinetic mechanism of VEGFR2 TK was elucidated through the use of steady-state kinetic studies. According to these studies, the enzyme binds Mg2+ and MgATP in a random fashion followed by ordered addition of the peptide substrate. The release of product is also ordered, with MgADP being released last. The order of substrate binding was confirmed by using AMP-PCP, a dead-end inhibitor.
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PMID:Characterization and kinetic mechanism of catalytic domain of human vascular endothelial growth factor receptor-2 tyrosine kinase (VEGFR2 TK), a key enzyme in angiogenesis. 984 50

Vascular endothelial growth factor (VEGF), an endothelial cell mitogen, plays a role in angiogenesis and progression in malignant melanoma. VEGF expression was examined in 62 biopsy specimens of melanocytic proliferations, including 45 malignant melanomas, 3 cellular blue nevi, 12 atypical compound nevi, and 2 Spitz nevi. The cases of malignant melanoma included 11 in situ melanomas, 18 Clark Level II, 9 Clark Level III, and 7 Clark Level IV tissue samples. All of the specimens were fixed in formalin and embedded in paraffin. Cytoplasmic immunoreactivity for VEGF was demonstrated in 19 (42%) of 45 melanoma samples, but there was no immunoreactivity for VEGF exhibited by any of the atypical compound melanocytic nevi, cellular blue nevi, or Spitz nevi (P < .009). Immunoreactivity for VEGF was found to be related to tumor thickness (as evidenced by Clark level [P < .03]) and to absence of regression (P < .04). Although VEGF is not a useful prognostic indicator for malignant melanoma, it may be useful as a discriminating factor between malignant melanoma and benign melanocytic lesions, and it may offer some insight into tumor growth.
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PMID:Vascular endothelial growth factor expression in malignant melanoma: prognostic versus diagnostic usefulness. 1046 78

Vascular endothelial growth factor (VEGF) and C-KIT are involved in tumor progression in several human neoplasms. The aim of the present study has been to investigate their immunohistochemical expression in melanocytic lesions. We examined 11 compound nevi, 12 dysplastic nevi, and 18 melanomas. Immunostaining for VEGF was observed only in melanomas; c-kit expression was detected in melanomas (higher in radial than in vertical growth phase) and in nevi (predominantly in the junctional component). Our data indicate that assessment of VEGF expression might aid in the differential diagnosis between dysplastic nevi and melanomas. Moreover, VEGF might be a candidate for targeted therapy. The loss of c-kit expression might contribute to melanoma progression.
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PMID:Immunohistochemical expression of vascular endothelial growth factor (VEGF) and C-KIT in cutaneous melanocytic lesions. 1517 18

The blind subterranean mole rat superspecies Spalax ehrenbergi has evolved adaptations that allow it to survive and carry out intensive activities in its highly hypoxic underground sealed burrows. A key component of this adaptation is a higher capillary density in some Spalax tissues, primarily in muscles used in digging and in other energetic activities, resulting in a shorter diffusion distance for oxygen. Vascular endothelial growth factor (VEGF) is an angiogenic factor that is critical for angiogenesis during development and is found in response to tissue ischemia. We demonstrate here that due to physiological differences, the Spalax muscle regulatory mechanism for VEGF is different than in Rattus muscle. In vivo, the constitutive level of the VEGF mRNA and the mRNA levels of its transcriptional regulator HIF-1alpha and its mRNA stabilizer HuR are significantly higher in Spalax muscle than in Rattus muscle. Furthermore, as opposed to Rattus, the mRNA levels of HIF-1alpha, HuR, VEGF, as well as that of LDH-A, the enzyme that catalyzes the production of lactate, an accepted marker of anaerobic metabolism, are not increased in Spalax after hypoxia. However, ex vivo, when oxygenation by blood vessels is no longer relevant, the expression pattern of all these genes is similar in the two rodents under both normoxic and hypoxic conditions. Our studies provide evidence that the highly vascularized muscle in Spalax, the most energy consuming tissue during digging, is resistant to the effects of oxygen deprivation. The significance of these results with respect to ischemic vascular disease is abundantly clear.
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PMID:Increased blood vessel density provides the mole rat physiological tolerance to its hypoxic subterranean habitat. 1600 Mar 66

Vascular endothelial growth factor receptor (VEGF) plays a critical role in blood vessel formation and affects nerve growth and survival. VEGF receptor 2 (Flk1) functions as the major signal transducer of angiogenesis, mediating VEGF induction of endothelial tubulogenesis. We have cloned and analyzed expression of Flk1 in the blind subterranean mole rat Spalax ehrenbergi. Spalax experience abrupt and sharp changes in oxygen supply in their sealed underground niche and, hence, are genetically adapted to hypoxia and serve as a unique, natural mammalian model organism for hypoxia tolerance. Spalax Flk1 is relatively conserved at the nucleic acid and amino acid level compared to human, mouse, and rat orthologs. Reverse transcription-quantitative polymerase chain reaction was used to analyze Flk1 expression in muscle and brain of animals exposed to ambient or variant hypoxic oxygen levels at multiple stages of development. Transcript levels were compared with those obtained from Rattus, a primary model for human physiology. Our findings demonstrate that under normoxic conditions Flk1 patterns of expression correlate well with our previous investigations of VEGF expression. Exposure to hypoxic conditions resulted in divergent patterns of Flk1 expression between Spalax and Rattus and between muscle and brain. It appears that the regulatory mechanisms differentiating expression between the species and between tissues are most likely unique, suggesting that Flk1 expression may be regulated by multiple processes, including both angiogenesis and neurogenesis.
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PMID:Cloning and in vivo expression of vascular endothelial growth factor receptor 2 (Flk1) in the naturally hypoxia-tolerant subterranean mole rat. 1772 89

Vascular endothelial growth factors (VEGFs) have a leading role among variety of angiogenic factors. Together with their receptors, they play an important role in endothelial cell proliferation and/or elongation, migration and vascular morphogenesis. In order to determine their possible role in malignant melanoma progression, VEGF (representing VEGFA), VEGF-C and VEGFR-1, -2, -3 immunohistochemical expression on formalin-fixed, paraffin-embedded tissue sections were evaluated. A total of 196 tissue samples consisting of 130 malignant melanomas (MM) with various vertical depth of invasion, 15 metastatic melanomas, and 66 nevi including dysplastic nevi and melanocytic nevi were analysed. Production of both VEGFs were common in benign melanocytic tumors while MM exhibited significant upregulation of VEGF (p<0.0027) and VEGF-C (p<0.0001). The proteins were also detected within stromal cells surrounding tumors, particularly in fibrocytes/ fibroblasts, macrophages and endothelial cells. They also exhibited significant increase in malignant lesions (p<0.0001). VEGFRs were localized in tumor, as well in stromal cells. Although expression of VEGF receptors was significantly higher in MM versus nevi (p<0.002 for VEGFR-1, p<0.004 for VEGFR-2 and p<0.0001 for VEGFR-3), a considerable percentage of MM were negative. There were no correlations between sentinel node positivity and all investigated proteins. When clinical outcome was evaluated, progression of the disease positively correlated with VEGF (p<0,007) and VEGF-C (p<0,008) expression VEGF (p<0.001) and VEGF-C (p<0.0001) positively correlated with nestin expression in the capillary endothelium, which was used for angiogenesis detection. Our work demonstrated that upregulation of VEGFs is associated with progression of malignant melanomas. The protein expression in the tumor microenvironment highlights their importance in malignant stromal phenotype which may serve as a potential target for the anticancer therapy.
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PMID:The role of vascular endothelial growth factors and their receptors in malignant melanomas. 1850 36