Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid to prostaglandins (PGs) and other eicosanoids. Nitric oxide synthase (NOS) is the enzyme that catalyzes the formation of nitric oxide (NO), a regulator of vascular permeability, from the guanidino nitrogen atom of L-arginine. Two isoforms of both enzymes occur: a constitutive one, Cox-1 and the inducible counterpart Cox-2; also NOS has a constitutive counterparts (cNOS) and an inducible form, called iNOS. The inducible isoforms of both enzymes are of maximum interest. It has been recently shown that cyclooxygenase-2 (Cox-2) is inducible by a variety of stimuli and that eicosanoids, mainly of the PGE2 species, are inducers of basic regulator of angiogenesis, including VEGF/VPF, bFGF, TGF-beta, PDGF, and endothelin-1. In addition, iNOS is inducible by Cox-2. p53 down-regulates the angiogenic process at various levels: it induces thrombospondin-1, a powerful antiangiogenic factor, down-regulates VEGF and NOS and, in addition, down-regulates hypoxia-induced angiogenesis, either inducing apoptosis or enhancing antiangiogenetic factors. It is noteworthy how important the p53 oncosuppressor is in the angiogenesis of solid tumor growth. Cox-2, iNOS and p53 are thus fundamental play-makers of the angiogenic process: they are discussed in detail and a tentative hierarchical cascade is proposed.
Int J Mol Med 1998 Dec
PMID:Cox-2, iNOS and p53 as play-makers of tumor angiogenesis (review). 985 Jul 41

We investigated whether blood angiogenic factor (vascular endothelial growth factor, VEGF; angiogenin; basic fibroblast growth factor, bFGF; platelet-derived growth factor-AB, PDGF-AB) levels change during menstrual cycle of healthy premenopausal females or after menopause. We also measured the serum angiogenic factor levels in 34 operable breast cancer patients and compared them to those of healthy volunteer controls. No differences in the four angiogenic factor levels were found between the follicular and luteal phases of normal menstruation. However, angiogenin and bFGF levels were higher in pre-menopausal females than post-menopausal female and young male healthy volunteers. In cancer patients, the sero-positivity rate of the bFGF was 8.8% with menstrual-state-unmatched cut-off points, which increased to 36.4% with menstrual-state-matched cut-off points. This discrepancy was especially high in post-menopausal cancer patients. In conclusion, physiological elevation of the bFGF during normal menstruation can influence the precise interpretation of the pathological elevation of the bFGF in pre-menopausal breast cancer patients.
Int J Mol Med 1998 Oct
PMID:Menstrual state should be considered in determining sero-positivity of soluble angiogenic factors in breast cancer. 985 36

Mutation of the von Hippel-Lindau tumor suppressor gene (vhl) causes the von Hippel-Lindau cancer syndrome as well as sporadic renal clear cell carcinoma. To pursue our study of the intracellular localization of VHL protein in relation to its function, we fused VHL to the green fluorescent protein (GFP) to produce the VHL-GFP fusion protein. Like VHL, VHL-GFP binds to elongins B and C and Cullin-2 and regulates target gene product levels, including levels of vascular endothelial growth factor and glucose transporter 1. VHL-GFP localizes predominantly to the cytoplasm, with some detectable nuclear signal. Inhibition of transcription by actinomycin D or 5,6-dichlorobenzimidazole riboside (DRB) causes VHL to be redistributed to the nucleus. A cellular fusion assay was used to demonstrate that inhibition of transcription induces a decrease in the nuclear export rate of VHL. The dependence of transcription for trafficking is lost with a deletion of exon 2, a region with a mutation causing a splice defect in the VHL gene in sporadic renal clear cell carcinoma. Addition of a strong nuclear export signal (NES) derived from the Rev protein results in complete nuclear exclusion and abrogates the redistribution of VHL-GFP-NES into the nucleus upon inhibition of transcription. Leptomycin B, which inhibits NES-mediated nuclear export, reverts the distribution of VHL-GFP-NES to that of VHL-GFP and restores sensitivity to actinomycin D and DRB. Uncoupling of VHL-GFP trafficking to transcription either by an exon 2 deletion or fusion to NES abolishes VHL function. We suggest that VHL function requires not only nuclear or cytoplasmic localization, but also exon 2-mediated transcription-dependent trafficking between these two cellular compartments.
Mol Cell Biol 1999 Feb
PMID:Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein. 989 Oct 82

Angiogenesis is essential for normal mammalian development and is controlled by the local balance of pro- and antiangiogenic factors. Here we describe a novel mouse cDNA sequence encoding sFLT-1 that is a potent antagonist to vascular endothelial growth factor (VEGF) and show for the first time its in vivo production. In situ hybridization and Northern blot analysis with probes specific for sFLT-1 or FLT-1 showed that the relative abundance of their mRNAs changed markedly in spongiotrophoblast cells in the placenta as gestation progressed. On day 11 of pregnancy, sFLT-1 mRNA was undetectable but FLT-1 readily apparent, and by day 17 sFLT-1 mRNA was abundant but FLT-1 barely detectable. sFLT-1 was identified in conditioned medium of cultured placenta from day 17 pregnant mice and likely to be present in the circulation, as there is a substantial increase of VEGF-binding activity in the serum from day 13 of pregnancy, which coincides with the abundant sFLT-1 expression in placenta. Expression of sFLT-1 was also observed in adult lung, kidney, liver, and uterus. These data suggest a novel mechanism of regulation of angiogenesis by alternative splicing of FLT-1 pre-mRNA. Treatment of pregnant mice with exogenous VEGF from day 9 to 17 of pregnancy, which alters the ratio of VEGF to sFLT-1, resulted in an increase in the number of resorption sites and fibrin deposition in the placenta of ongoing pregnancies. These findings have important implications for understanding placental function and may be relevant in a range of disease states.
Mol Endocrinol 1999 Apr
PMID:Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity. 1019 60

Five antibodies against vascular endothelial growth factor 165 (VEGF165) were obtained. These antibodies, Ab-2, Ab-20, Ab-153, Ab-309, Ab-342, were able to recognize not only native VEGF165, but also reducing VEGF165. Three of the antibodies, Ab-153, Ab-309, Ab-342, were identified as VEGF165 neutralizing antibody on the basis of its ability to inhibit the proliferation of human umbilical vein endothelial cells (HUVEC) induced by VEGF165 and the binding of [125I]-VEGF165 to receptors on HUVEC. The fragments of E1 (VEGF120-135) and E2 (VEGF46-60) recognized by neutralizing antibodies may be related the receptor binding domain of VEGF.
Biochem Mol Biol Int 1999 Feb
PMID:Monoclonal antibodies against vascular endothelial growth factor 165 (VEGF165): neutralization of biological activity and recognition of the epitope. 1020 60

Signaling pathways mediating the antiangiogenic action of 16K human (h)PRL include inhibition of vascular endothelial growth factor (VEGF)-induced activation of the mitogen-activated protein kinases (MAPK). To determine at which step 16K hPRL acts to inhibit VEGF-induced MAPK activation, we assessed more proximal events in the signaling cascade. 16K hPRL treatment blocked VEGF-induced Raf-1 activation as well as its translocation to the plasma membrane. 16K hPRL indirectly increased cAMP levels; however, the blockade of Raf-1 activation was not dependent on the stimulation of cAMP-dependent protein kinase (PKA), but rather on the inhibition of the GTP-bound Ras. The VEGF-induced tyrosine phosphorylation of the VEGF receptor, Flk-1, and its association with the Shc/Grb2/Ras-GAP (guanosine triphosphatase-activating protein) complex were unaffected by 16K hPRL treatment. In contrast, 16K hPRL prevented the VEGF-induced phosphorylation and dissociation of Sos from Grb2 at 5 min, consistent with inhibition by 16K hPRL of the MEK/MAPK feedback on Sos. The inhibition of Ras activation was paralleled by the increased phosphorylation of 120 kDa proteins comigrating with Ras-GAP. Taken together, these findings show that 16K hPRL inhibits the VEGF-induced Ras activation; this antagonism represents a novel and potentially important mechanism for the control of angiogenesis.
Mol Endocrinol 1999 May
PMID:16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells. 1031 20

The expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), VEGFR-1/Flt-1 and VEGFR-2/Flk-1, was investigated by immunohistochemical and northern blot analysis during lung carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine (BHP) in male Wistar rats. After BHP was given in the drinking water for 12 wk, the rats were maintained without further treatment until they were killed at 20-28 wk. Immunohistochemical studies revealed VEGF expression in almost all malignancies, the reaction being strongly positive in most adenocarcinomas (15 of 18; 83.3%) and squamous cell carcinomas (four of five; 80.0%), but less so in a total of 120 adenomas and 136 alveolar hyperplasias. In addition, VEGF mRNA and VEGFR mRNAs were found to be overexpressed in most adenocarcinomas and squamous cell carcinomas as well as in one to three of the five adenomas tested. The results indicated that VEGF and VEGFRs play important roles in the acquisition of malignant potential by preneoplastic lung lesions induced by BHP in rats. Moreover, overexpression of VEGF was related to upregulation of VEGFR-1/Flt-1 and VEGFR-2/Flk-1 expression in malignant and premalignant lung lesions.
Mol Carcinog 1999 Apr
PMID:Expression of vascular endothelial growth factor and its receptors during lung carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine in rats. 1032 65

The aim of this study was to quantify and localize the mRNA expression of the vascular endothelial growth factor (VEGF) receptors Flt1, KDR and sflt, in human endometrium throughout the menstrual cycle. Since neoangiogenesis is crucial during embryonic implantation, we postulate that endometrial receptivity to VEGF may be altered during the luteal phase in order to support implantation. Human endometrium was collected and specified as early proliferative (n = 3), mid-proliferative (n = 4), late proliferative (n = 3), early secretory (n = 2), mid-secretory (n = 4), and late secretory (n = 4). Competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate the mRNA values throughout the menstrual cycle. Additionally, four samples were separated into epithelial and stromal-enriched cell fractions and competitive RT-PCR was carried out to specify the distribution of the mRNA expression. While mRNA for the transmembraneous receptors Flt1 and KDR was shown to be present at almost constant values throughout the menstrual cycle, the soluble receptor, sflt, had a three-fold higher level of transcription during mid-proliferative and late proliferative when compared with early proliferative and the entire secretory phase. The expression of Flt1, KDR and sflt mRNA was detected in both isolated endometrial epithelial and stromal cell fractions. In conclusion, the down-regulation of sflt, which functions as a soluble antagonist, during the luteal phase may act to sensitize the maternal endothelial receptors to angiogenetic stimuli secreted by the implanting embryo.
Mol Hum Reprod 1999 May
PMID:Expression of mRNA for vascular endothelial growth factor transmembraneous receptors Flt1 and KDR, and the soluble receptor sflt in cycling human endometrium. 1033 68

Receptor tyrosine kinases (RTKs) are single-pass transmembrane receptors that possess intrinsic cytoplasmic enzymatic activity, catalyzing the transfer of the gamma-phosphate of ATP to tyrosine residues in protein substrates. RTKs are essential components of signal transduction pathways that affect cell proliferation, differentiation, migration and metabolism. Included in this large protein family are the insulin receptor and the receptors for growth factors such as epidermal growth factor, fibroblast growth factor and vascular endothelial growth factor. Receptor activation occurs through ligand binding, which facilitates receptor dimerization and autophosphorylation of specific tyrosine residues in the cytoplasmic portion. The phosphotyrosine residues either enhance receptor catalytic activity or provide docking sites for downstream signaling proteins. Over the past several years, structural studies employing X-ray crystallography have advanced our understanding of the molecular mechanisms by which RTKs recognize their ligands and are activated by dimerization and tyrosine autophosphorylation. This review will highlight the key results that have emerged from these structural studies.
Prog Biophys Mol Biol 1999
PMID:Structural analysis of receptor tyrosine kinases. 1035 3

Endothelial cells are known to be involved in different growth promoting processes like angioneogenesis, atherosclerosis or haematopoiesis. A great number of polypeptide growth factors crucial in this context have been isolated and they may be expressed in endothelial cells in either a constitutional or an inducible manner. The aim of the study was to examine the cytokine-inducibility of growth factor gene expression in endothelial cells. As uniform stimulators interleukin 1-alpha (IL-1alpha) and tumour necrosis factor (TNF)-alpha were chosen. Human umbilical arterial endothelial cells (HUAEC) were treated with either IL-1alpha or TNF-alpha and the gene expression of various growth factors was detected by reverse transcription-polymerase chain reaction (RT-PCR). We could demonstrate in HUAEC that stimulation with IL-1alpha- and TNF-alpha led to the mRNA expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) which are crucial in the process of angioneogenesis and atherosclerosis as well as of the granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) and stem cell factor (SCF) which are main growth factors in haematopoiesis. The demonstration of the inducibility of a wide range of various growth factor genes in endothelial cells is of major interest regarding the growth regulatory role of the endothelium.
Mol Cell Probes 1999 Jun
PMID:Cytokine-inducible growth factor gene expression in human umbilical endothelial cells. 1036 46


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