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

Increased expression of vascular endothelial growth factor (VEGF) contributes to the growth of many tumors by increasing angiogenesis. Although hypoxia is a potent inducer of VEGF, we previously showed that epidermal growth factor receptor amplification and loss of PTEN, both of which can increase phosphatidylinositol-3-kinase (PI3K) activity, increase VEGF expression. Using both adenoviral vectors and a cell line permanently expressing constitutively active myristoylated Akt (myrAkt), we show that activation of Akt, which is downstream of PI3K, increases VEGF expression in vitro and increases angiogenesis in a Matrigel plug assay. Transient transfection experiments using reporter constructs containing the VEGF promoter showed that up-regulation of VEGF by Akt is mediated through Sp1 binding sites located in the proximal promoter. Small interfering RNA directed against Sp1 prevented the induction of VEGF mRNA in response to myrAkt but not to hypoxia. Expression of myrAkt is associated with increased phosphorylation of Sp1 and its increased binding to a probe corresponding to the -88/-66 promoter region. In conclusion, our results indicate that Sp1 is required for transactivation of the VEGF by Akt. Others have proposed that the PI3K/Akt pathway can increase VEGF expression via the hypoxia-inducible factor 1 (HIF-1); however, our results suggest an alternative mechanism can also operate.
Mol Biol Cell 2004 Nov
PMID:Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. 1534 81

In this paper we present the expandability and flexibility features of the VEGA program (downloadable free of charge at http://www.ddl.unimi.it), for the development of custom applications, using it as a multipurpose graphical environment. VEGA can be customized using both plug-in architecture and script programming. The first is useful to add new features and functions, using homemade routines, written with the VEGA Plug-in Development Kit (SDK). With the second approach it is possible to design scripts in VEGA, using the REBOL language, in order to (1) add new functions or customize existing ones; (2) automate common procedures; and (3) allow network communications, by creating a bridge between VEGA and other applications (or other PCs) through the TCP/IP protocol.
J Comput Aided Mol Des 2004 Mar
PMID:VEGA--an open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming. 1536 17

Metastatic renal cell carcinomas (RCC) remain highly resistant to systemic therapy. RCCs are highly vascular tumors, which overproduce angiogenic peptides such as vascular endothelial growth factor (VEGF) even under normoxic conditions. A potential suggested role of antiangiogenic therapeutic strategies is the treatment of RCC by inhibiting VEGF production. The down-regulation of VEGF expression by glucocorticoids has recently been demonstrated in several cells. In this study, the direct effects of glucocorticoids on VEGF production by RCC cells were evaluated. Four RCC cell lines A498, RCC270, Caki1, and ACHN were treated with dexamethasone (DEX), hydrocortisone (HC), 5-alpha-dihydrotestosterone (DHT), or estradiol (E2). RU486 was used as a glucocorticoid receptor (GR) antagonist. Cell growth was studied with MTS assays. VEGF mRNA and protein were evaluated with quantitative real-time RT-PCR and ELISA, respectively, and GR expression was examined using RT-PCR and immunocytochemistry. All four RCC cell lines expressed GR. DEX at 100 nM down-regulated VEGF secretions by more than 50% in three lines (A498, RCC270, and Caki1) and had a weak inhibitory effect on ACHN cells. The effect of DEX on reducing VEGF mRNA levels in A498 cells was concentration-dependent and maximal at 100 nM (80% inhibition). HC had similar but weaker effects on VEGF production in the RCC cells, but E2 and DHT had no effect. RU486 reversed the effects of DEX. DEX at 1-1000 nM did not affect cell growth in any of the four RCC cell lines. This is the first study showing that glucocorticoids, at concentrations achievable in vivo by oral administration of low doses of DEX, have an inhibitory effect on VEGF mRNA expression and protein secretion of RCC cells possibly through the GR pathway. Furthermore, DEX might have a potential role in antiangiogenic therapeutic strategies by inhibiting VEGF production during metastatic RCC treatment.
Mol Cell Endocrinol 2004 Oct 29
PMID:Down-regulation of vascular endothelial growth factor in renal cell carcinoma cells by glucocorticoids. 1548

We evaluated the signaling pathways involved in regulating vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, in response to natural and synthetic progestins in breast cancer cells. Inhibition of the phosphoinositide-3'-kinase (PI3-kinase) signaling pathway or the specificity protein-1 (SP-1) transcription factor abolished both progesterone- and medroxyprogesterone acetate (MPA)-induced VEGF secretion from BT-474 and T47-DCO)cells. Inhibitors of the MAPK kinase 1/2/MAPK and N-terminal jun kinase/MAPK signaling pathways blocked both progesterone- and MPA-induced VEGF secretion in BT-474 cells. However, these inhibitors blocked only progesterone-, but not MPA-induced VEGF secretion in T47-DCO cells. Inhibitors of PI3-kinase or SP-1 blocked both progesterone- and MPA-induced increases in VEGF mRNA levels in T47-DCO cells. The proximal SP-1 sites within the VEGF promoter were critical for progestin-dependent induction of VEGF. In contrast, MAPK inhibitors did not block the progesterone- or MPA-induced increases in VEGF mRNA in T47-DCO cells, suggesting that MAPK inhibitors decreased progesterone-induced VEGF secretion in T47-DCO cells by blocking posttranscriptional mechanisms. The MAPK kinase/ERK/MAPK-independent induction of VEGF mediated by MPA was associated with the PRB [progesterone receptor (PR) B] isoform of the PR in T47-DCO cells. None of the inhibitors tested reduced basal PR levels or abrogated PR-dependent gene expression from a reporter plasmid, indicating that loss of PR function cannot explain any of the observed effects. Because the PI3-kinase signaling pathway and SP-1 transcription factor play critical roles in progestin-dependent VEGF induction, these may be useful targets for developing antiangiogenic therapies to prevent progression of progestin-dependent human breast cancers.
Mol Endocrinol 2005 Feb
PMID:Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced vascular endothelial growth factor levels in human breast cancer cells. 1552 72

The adult vasculature results from a network of vessels that is originally derived in the embryo by vasculogenesis, a process whereby vessels are formed de novo from endothelial cell (EC) precursors, known as angioblasts. During vasculogenesis, angioblasts proliferate and come together to form an initial network of vessels, also known as the primary capillary plexus. Sprouting and branching of new vessels from the preexisting vessels in the process of angiogenesis remodel the capillary plexus. Normal angiogenesis, a well-balanced process, is important in the embryo to promote primary vascular tree as well as an adequate vasculature from developing organs. On the other hand, pathological angiogenesis which frequently occurs in tumors, rheumatoid arthritis, diabetic retinopathy and other circumstances can induce their own blood supply from the preexisting vasculature in a route that is close to normal angiogenesis. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is perhaps the most important of pro-angiogenic cytokine because of its ability to regulate most of the steps in the angiogenic cascade. The main goal of this review article is to discuss the complex nature of the mode of action of VPF/VEGF on vascular endothelium. To this end, we conclude that more research needs to be done for completely understanding the VPF/VEGF biology with relation to angiogenesis.
Mol Cell Biochem 2004 Sep
PMID:Complexity in the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-receptors signaling. 1554 35

Nitric oxide (NO) and reactive oxygen species (ROS) are emerging as important regulators of angiogenesis. NO enhances VEGF synthesis in several cell types and is required for execution of VEGF angiogenic effect in endothelial cells. Similarly, hydrogen peroxide induces VEGF synthesis and recent studies indicate the involvement of ROS in signaling downstream of VEGF stimulation. VEGF synthesis can not only be enhanced by gene transfer of VEGF but also by overexpression of NO synthase genes. Here, we examined the possibility of augmentation of VEGF production by gene transfer of copper/zinc superoxide dismutase (CuZnSOD, SOD1). Overexpression of human SOD1 in mouse NIH 3T3 fibroblasts increased SOD activity, enhanced intracellular generation of H2O2 and significantly stimulated VEGF production as determined by increase in VEGF promoter activity, VEGF mRNA expression and VEGF protein synthesis. The stimulatory effect on VEGF synthesis induced by SOD1 gene transfer was reverted by overexpression of human catalase. The effect of H2O2 produced by engineered cells is mediated by activation of hypoxia-inducible factor response element (HRE) as well as Sp1 recognition site of VEGF promoter. This data suggest the feasibility of stimulation of angiogenesis by overexpression of SOD1.
Mol Cell Biochem 2004 Sep
PMID:Gene transfer of CuZn superoxide dismutase enhances the synthesis of vascular endothelial growth factor. 1554 46

Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, likely contributes to airway remodeling in asthma. We sought to examine the effects and mechanism of action of IL-6 family cytokines on VEGF release from human airway smooth muscle (HASM) cells. Oncostatin M (OSM), but not other IL-6 family cytokines, increased VEGF release, and IL-1beta enhanced OSM-induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1beta had no effect. IL-1beta did not augment the effects of OSM on VEGF promoter activity but did augment OSM-induced VEGF mRNA expression and mRNA stability. The STAT3 inhibitor piceatannol decreased both OSM-induced VEGF release and synergy between OSM and IL-1beta, without affecting responses to IL-1beta alone. Piceatannol also inhibited OSM-induced VEGF mRNA expression. In contrast, inhibitors of MAPK pathway had no effect on OSM or OSM plus IL-1beta-induced VEGF release. OSM increased type 1 IL-1 receptor (IL-1R1) mRNA expression, as measured by real-time PCR, and piceatannol attenuated this response. Consistent with the increase in IL-1R1 expression, OSM markedly augmented IL-1beta-induced VEGF, MCP-1, and IL-6 release. In summary, our data indicate OSM causes VEGF expression in HASM cells by a transcriptional mechanism involving STAT3. IL-1beta also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1beta on VEGF mRNA stability as well as effects of OSM on IL-1R1 expression. This is the first description of a role for OSM on IL-1R1 expression in any cell type. OSM may contribute to airway remodeling observed in chronic airway disease.
Am J Physiol Lung Cell Mol Physiol 2005 Jun
PMID:Oncostatin M causes VEGF release from human airway smooth muscle: synergy with IL-1beta. 1566 43

Hypoxia-inducible factor 1 (HIF-1) functions as a master regulator of oxygen homeostasis in metazoan species. HIF-1 mediates changes in gene transcription in response to changes in cellular oxygenation. The half-life of the HIF-1alpha subunit is determined by oxygen-dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation. Here, we demonstrate that OS-9, the protein product of a widely expressed gene, interacts with both HIF-1alpha and HIF-1alpha prolyl hydroxylases. OS-9 gain-of-function promotes HIF-1alpha hydroxylation, VHL binding, proteasomal degradation of HIF-1alpha, and inhibition of HIF-1-mediated transcription. OS-9 loss-of-function caused by RNA interference increases HIF-1alpha protein levels, HIF-1-mediated transcription, and VEGF mRNA expression under nonhypoxic conditions. These data indicate that OS-9 is an essential component of a multiprotein complex that regulates HIF-1alpha levels in an O2-dependent manner.
Mol Cell 2005 Feb 18
PMID:OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. 1572 Dec 54

Vascular endothelial growth factor (VEGF) plays a pivotal role in the regulation of microvascular permeability and angiogenesis, processes essential for normal endometrial growth and implantation. Estrogen [17beta-estradiol (E2)], via its receptor (ER alpha), rapidly stimulates VEGF expression in the uterus at the transcriptional level. The VEGF gene promoter, however, lacks a consensus estrogen response element (ERE), and attempts to identify the site through which E2 induces VEGF expression have yielded contradictory results. To address this question, we modified the chromatin immunoprecipitation method to identify transcription factors that interact with the VEGF promoter in the rat uterus in response to E2. Chromatin immunoprecipitation showed that both Sp1 and Sp3 were associated with a proximal, GC-rich region of the promoter before E2 treatment. E2 induced an increase in Sp1 binding and the recruitment of ER alpha, and the coactivator p300 to this region. The association of ER alpha persisted, however, after VEGF mRNA levels had declined again (at 4 h), indicating that other factors might be involved in that expression. Western analysis showed that both the alpha- and beta-subunits of the transcription factor hypoxia-inducible factor 1 (HIF-1), which regulates VEGF expression in response to hypoxia and several hormones and growth factors, were present in the uterus. Furthermore, E2 rapidly induced their recruitment to the -944 to -611 bp region of the VEGF promoter, which contains the hypoxia response element to which HIF-1 binds. This binding was transient, matching the pattern of E2-induced VEGF expression. These results indicate that HIF-1 is an important mediator of E2-induced VEGF expression in the uterus. In addition, E2 also induced a later increase in HIF-1alpha mRNA and protein expression in the uterus, suggesting that it may be required for longer term effects of E2 on the uterus as well. In contrast to the uterus, HEC1A cells cultured in 95% air-5% CO2 (and therefore 20% O2) contained no HIF-1alpha, consistent with the inability of E2 to stimulate the expression of VEGF by these and other cell types in vitro.
Mol Endocrinol 2005 Aug
PMID:Chromatin immunoprecipitation analysis of gene expression in the rat uterus in vivo: estrogen-induced recruitment of both estrogen receptor alpha and hypoxia-inducible factor 1 to the vascular endothelial growth factor promoter. 1577 98

Our previous studies have indicated that transforming growth factor (TGF)-beta1 and VEGF expression are increased in the smooth muscle cell (SMC) layer of the pulmonary vessels of lambs with pulmonary hypertension secondary to increased pulmonary blood flow. Furthermore, we found that TGF-beta1 expression increased before VEGF. Because of the increased blood flow in the shunt lambs, the SMC in the pulmonary vessels are exposed to increased levels of the mechanical force, cyclic stretch. Thus, in this study, using primary cultures of pulmonary arterial SMC isolated from pulmonary arteries of 4-wk-old lambs, we investigated the role of cyclic stretch in the apparent coordinated regulation of TGF-beta1 and VEGF. Our results demonstrated that cyclic stretch induced a significant increase in VEGF expression both at the mRNA and protein levels (P < 0.05). The increased VEGF mRNA was preceded by both an increased expression and secretion of TGF-beta1 and an increase in reactive oxygen species (ROS) generation. In addition, a neutralizing antibody against TGF-beta1 abolished the cyclic stretch-dependent increases in both superoxide generation and VEGF expression. Our data also demonstrated that cyclic stretch activated an NAD(P)H oxidase that was TGF-beta1 dependent and that NAD(P)H oxidase inhibitors abolished the cyclic stretch-dependent increase in VEGF expression. Therefore, our results indicate that cyclic stretch upregulates VEGF expression via the TGF-beta1-dependent activation of NAD(P)H oxidase and increased generation of ROS.
Am J Physiol Lung Cell Mol Physiol 2005 Aug
PMID:Cyclic stretch increases VEGF expression in pulmonary arterial smooth muscle cells via TGF-beta1 and reactive oxygen species: a requirement for NAD(P)H oxidase. 1582 Oct 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>