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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Targeting retroviral vectors to tumor vasculature is an important goal of cancer gene therapy. In this study, we report a novel targeting approach wherein IgG-binding peptides were inserted into the Moloney murine leukemia virus (MuLV) envelope (env) protein. The modifications on the viral env included replacement of the entire receptor binding region of the viral env with protein A (or ZZ) domains. The truncated env incorporating IgG-binding motifs (known as proteins) provided the targeting function, while the co-expressed wild-type (WT) env protein enabled viral fusion and cell entry. An anti-human VEGF receptor (Flk-1/KDR) antibody served as a molecular bridge, directing the retroviral vector to the endothelial cell. Hence, the IgG-targeted vectors bound to the Flk-1/KDR antibody which in turn bound to VEGF receptors on Kaposi sarcoma, KSY1, endothelial cells. The net effect was increased viral fusion and infectivity of IgG-bound retroviral vectors when compared to non-targeted vectors bearing WT env alone. These data provide the proof of concept that IgG-binding vector/VEGF receptor antibody complexes may be used to enhance retroviral gene delivery to activated endothelial cells.
Int J Mol Med 2001 Oct
PMID:Retroviral vectors bearing IgG-binding motifs for antibody-mediated targeting of vascular endothelial growth factor receptors. 1156 69

Endothelial cell proliferation and migration is initiated by growth factors including FGF and VEGF that bind to specific transmembrane receptor tyrosine kinases. Mechanisms that regulate in vivo expression of fibroblast growth factor receptors (FGFR) and vascular endothelial growth factor receptors (VEGFR) are not well understood. Since it is well known that different matrices influence the proliferation and migration of endothelial cells in culture, we hypothesized that changes in the extracellular matrix environment can regulate growth factor receptors on endothelial cells. We cultured human microvascular endothelial cells on different matrices (vitronectin, laminin, fibronectin, fibrin, and collagen IV) and examined for the presence of growth factor receptors (FGFR-1, FGFR-2, VEGFR-1, and VEGFR-2). We show that vitronectin increased the presence of all four growth factor receptors and most notably, VEGFR-1. In contrast, fibrin decreased all four receptors, especially FGFR-1 and FGFR-2. Inhibiting phosphotyrosine signaling abolished immunostaining for all four receptors, regardless of the matrix, but was not dependent on activating the Fyn-Shc pathway. Cells plated on vitronectin in the presence of blocking antibodies to integrins alphavbeta3 and alphavbeta5 similarly decreased presence of these growth factor receptors. Our data suggests a possible mechanism of how matrix-integrin interactions regulate endothelial cell responsiveness to growth factors and anchorage-dependent cell growth.
Mol Cell Biochem 2001 Aug
PMID:Integrin activation is required for VEGF and FGF receptor protein presence on human microvascular endothelial cells. 1169 2

Under low-oxygen conditions, cells develop an adaptive program that leads to the induction of several genes, which are transcriptionally regulated by hypoxia-inducible factor 1 (HIF-1). On the other hand, there are other factors which modulate the HIF-1-mediated induction of some genes by binding to cis-acting motifs present in their promoters. Here, we show that c-Jun functionally cooperates with HIF-1 transcriptional activity in different cell types. Interestingly, a dominant-negative mutant of c-Jun which lacks its transactivation domain partially inhibits HIF-1-mediated transcription. This cooperative effect is not due to an increase in the nuclear amount of the HIF-1alpha subunit, nor does it require direct binding of c-Jun to DNA. c-Jun and HIF-1alpha are able to associate in vivo but not in vitro, suggesting that this interaction involves the participation of additional proteins and/or a posttranslational modification of these factors. In this context, hypoxia induces phosphorylation of c-Jun at Ser(63) in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser(63) and Ser(73) impair its functional cooperation with HIF-1. The functional interplay between c-Jun and HIF-1 provides a novel insight into the regulation of some genes, such as the one for VEGF, which is a key regulator of tumor angiogenesis.
Mol Cell Biol 2002 Jan
PMID:c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. 1173 18

A complete VEGF system consisting of the ligand and two of its receptors has been detected for the first time in the bovine cumulus-oocyte-complex (COC). In the course of a 24 hr in vitro maturation procedure (IVM), expression of the smaller VEGF transcripts and their specific receptors flt and flk changed remarkably in a time-dependent manner as observed by RT-PCR. The transcript concentrations of VEGF declined within 24 hr of culture, whereas both receptor mRNAs were found enriched between 6 and 12 hr of IVM. In the follicular fluid of growing ovarian follicles, immunoreactive VEGF, measured by RIA, increased significantly, reaching highest concentrations immediately before ovulation of the oocyte. The immunohistochemical localization of VEGF in bovine COCs revealed strong signals within the cumulus cell complex clearly extending beyond the oocyte cytoplasm at the beginning of in vitro maturation. After 24 hr, IVM immunoreactive VEGF disappeared remarkably from cumulus cells and the oocyte cytoplasm. An exogenous application of VEGF at the beginning of a 24 hr IVM significantly improved cleavage rates of zygotes and their development into bovine embryos showing obvious synergistic effects in combination with FSH, when compared with untreated control embryos. In addition, the number of blastomeres in deriving blastocysts increased after VEGF supplementation. These results indicate a functional VEGF system controlling important events beside the known angiogenetic effect during in vivo and in vitro maturation of the bovine COC, possibly affecting the early embryonic viability.
Mol Reprod Dev 2002 May
PMID:Expression of the vascular endothelial growth factor and its receptors and effects of VEGF during in vitro maturation of bovine cumulus-oocyte complexes (COC). 1193 58

In this article we consider the factors responsible for the unique nature of the pericellular matrix of solid tumors and we discuss the role of alterations of tumor blood vessel structure. We examine the role of VEGF (vascular endothelial growth factor), a factor controlling permeability of capillaries, plasma protein extravasation, and the formation of a fibrin barrier. We discuss how this barrier could be destroyed by metalloproteinases bound on the surface of endothelial cells migrating through the matrix and how these enzymes are responsible for the activation of gelatinases that destroy basement membranes. The process called tubulogenesis, which gives rise to hyperpermeable tumor capillaries, will also be described. Alterations of the blood vessel structure leading to hypoxia of the matrix, and accumulation of plasma proteins and of blood cells will be treated. Finally, we review some of the strategies that might exploit this knowledge about the nature of the tumoral matrix for designing novel anticancer treatments.
Mol Biotechnol 2002 May
PMID:Angiogenesis and the unique nature of tumor matrix. 1198 61

This review is intended to discuss the newly discovered role of preconditioning which should make it an attractive therapeutic stimulus for repairing the injured myocardium. We recently found that apart from rendering the myocardium tolerant to ischemic reperfusion injury, preconditioning also potentiates angiogenesis. Our study demonstrated for the first time that both ischemic and hypoxic preconditioning triggered myocardial angiogenesis at the capillary and arteriolar levels which nicely corroborated with the improved myocardial contractile function. Hypoxic preconditioning resulted in the stimulation of VEGF, the most potent angiogenic factor known to date. In concert, endothelial cell specific tyrosine kinase receptors, Tie 1, Tie 2 and Flt-1 and Flk-1 were also significantly enhanced in the preconditioned myocardium. The redox-regulated transcription factor NF kappa B was found to play an essential role in the preconditioning regulation of angiogenesis.
J Cell Mol Med
PMID:Potentiation of angiogenic response by ischemic and hypoxic preconditioning of the heart. 1200 66

The effects of angiogenic growth factors on the growth, vascular architecture and the downstream cytokine signaling of sarcomas are unknown. These are of potential great importance since sarcoma, like endothelium, is of mesodermal origin and therefore could grow in response to these factors. Three human sarcomas (leiomyosarcoma SK-LMS-1, liposarcoma SW872 and fibrosarcoma SW684) and one murine fibrosarcoma (KHT) were grown in nude and C3H/He mice, respectively. Tumor structural vessels, perfused vessels and hypoxia were quantified immunohistochemically. Fast-growing murine KHT tumors had a markedly higher number of structural vessels compared with the human sarcomas. In both murine and human sarcomas, approximately half of the total structural vessels were perfused, and the numbers of perfused vessels decreased with increasing tumor volume. In vitro, basal mRNA expression of several angiogenic growth factors and their receptors differed between two of the human sarcoma cell lines, SK-LMS-1 and SW872. Compared with SK-LMS-1, untreated SW872 cells had higher levels of mRNA expression for FGF11, FGF14, angiopoietin, CD105 and VEGFR1. Two sarcoma cell lines were also treated with 10 ng/ml of six angiogenic growth factors (FGF1, FGF2, FGF7, FGF10, VEGF and SCF) for 24 h, and mRNA expression of endogenous FGF family members (FGF1, FGF2, FGF10, FGF11, FGF13 and FGF14) were quantitatively measured using RNase protection at various times following treatments. Again, SW872 cells were more responsive to exogenous growth factor treatment compared with SK-LMS-1 cells in terms of the elevation of endogenous FGF mRNA expression. In the SW872 cells, all of the exogenous angiogenic growth factor treatments, except for VEGF, upregulated endogenous FGF1, FGF2 and FGF14 mRNA expression. The SK-LMS-1 cells, in contrast, only responded to exogenous FGF1, FGF7 and FGF10, but did not respond to VEGF.
Comp Biochem Physiol A Mol Integr Physiol 2002 May
PMID:Comparison and modulation of angiogenic responses by FGFs, VEGF and SCF in murine and human fibrosarcomas. 1206 86

Hybridization with cDNA arrays was used to obtain expression profiles of 214 protein-tyrosine kinase, protein-tyrosine phosphatase, dual-specific phosphatase, and other genes for kidney carcinomas (KC) and normal kidney tissues of 34 patients and for seven carcinoma cell lines. Computer analysis revealed three clusters of genes coexpressed in KC. A proliferating-cell gene cluster included MET, VIM, MYC, TOP2A, PCNA, etc. A neoangiogenesis and blood-cell gene cluster included LCK, HCK, FGR, MMP9, CSFR1, VEGF, FLT1, and KDR. A cluster corresponding to normal, differentiated kidney cells included ERBB2 (HER2) for receptor protein-tyrosine kinase, several phosphatase genes (PTPRE, PTPRB, DUSP9), and EGF. The results suggested that MET, DUSP9, PCNA, TOP2A, and VIM may serve as diagnostic and prognostic markers in KC. Tubulin and topoisomerase II were assumed to be promising targets for cell proliferation inhibitors in KC.
Mol Biol (Mosk)
PMID:[Molecular portrait of human kidney carcinomas: the gene expression profiling of protein-tyrosine kinases and tyrosine phosphatases which controlled regulatory signals in the cells]. 1206 34

Brn-3a, a member of the POU gene family (so-called because of the similarity with the group of transcription factors Pit, Oct, and Unc), was found in neuronal cells engaged in the transcription activity of the p1 and p2 promoters of the most powerful antiapoptotic gene, namely, Bcl-2. The alternative splicing of Brn-3a mRNA produces two molecular forms: a longer, Bcl-2 transactivating form, and a shorter inactive form, lacking 84 AA in the aminoterminus. In neuronal cells, following Brn-3a gene transfection and superexpression, an increase of 30 fold of the Bcl-2 protein occurs, leading to apoptosis protection. However, recent works demonstrate that Brn-3a expression is not restricted to neuronal cells, as its activity was detected also in cancer cells of non-neuronal nature. Looking for mechanisms linking Brn-3a to carcinogenesis, we discuss the role of this transcription factor in influencing Bcl-2/p53 antagonism and Bcl-2/VEGF induction of tumor angiogenesis, concluding this review with a proposal for the oncogenic nature of Brn-3a.
Mol Biotechnol 2002 Oct
PMID:Brn-3a, a neuronal transcription factor of the POU gene family: indications for its involvement in cancer and angiogenesis. 1240 60

This study was designed to test the hypothesis that transcutaneous ultrasound (US) exposure may augment the transfection efficiency and biological outcome associated with nonviral DNA gene transfer. Hindlimb muscles of New Zealand White rabbits were transfected with the reporter plasmid pCMV-beta, with or without US exposure. Optimization studies employed US exposure at various frequencies, mechanical indices, duty cycles, durations of exposure, and exposure time points. Based on these results, we explored the effect of US exposure on nonviral gene transfer of vascular endothelial growth factor (VEGF, phVEGF165) to promote neovascularization of ischemic hindlimbs. Ultrasound at 1 MHz, 100 W/cm(2), 6% duty cycle, and 5 minutes exposure time, applied immediately following DNA injection, was found to be the most effective among the settings tested, increasing beta-galactosidase expression approximately 20 fold. Compared with US exposure alone, or phVEGF165 only, phVEGF165 + US exposure yielded a statistically significant improvement in revascularization, as determined by calf blood pressure ratio, angiographic score, intravascular Doppler blood flow, and capillary/myocyte ratio. These data demonstrate that ultrasound, when applied directly after intramuscular gene transfer, significantly increases transfection efficiency in vivo. The biological significance of this finding was confirmed by augmented limb perfusion in response to US exposure and naked VEGF DNA.
Mol Ther 2002 Nov
PMID:Transcutaneous ultrasound augments naked DNA transfection of skeletal muscle. 1240 55


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