The Vascular Endothelial Growth Factor Family: Identification of a Fourth Molecular Species and Characterization of Alternative Splicing of RNA

Houck, Keith A.; Ferrara, Napoleone; Winer, Jane; Cachianes, George; Li, Bing; Leung, David W. M.

doi:10.1210/mend-5-12-1806

Cited by 1,198 publications

(718 citation statements)

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“…Five different isoforms of VEGF transcripts encoding polypeptides of 206, 189, 165, 145 and 121 amino acids have been reported to be expressed in human cells (Houck et al, 1991;Tischer et al, 1991;Poltorak et al, 1997). Our results revealed that VEGF 121 and 165 were the predominant VEGF isoforms expressed by both benign and malignant human cell lines.…”

Section: Discussionsupporting

confidence: 53%

True

Chen¹,

Treweeke²,

Ke³

et al. 2000

Br J Cancer

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Vascular endothelial growth factor (VEGF) is one of the most potent factors for stimulating angiogenesis, an essential process required for expansion of primary tumour and dissemination of malignant cells. To investigate the possible role of VEGF in facilitating metastasis of prostate cancer via stimulating angiogenesis, we have used Northern and slot blotting, reverse transcription polymerase chain reaction, nucleotide sequence analysis and enzyme-linked immunosorbent assay to compare the VEGF expression in series of human and rat cell lines with either benign or malignant characteristics. We have also employed the chick chorioallantoic membrane (CAM) assay to measure the angiogenic activity of the VEGF derived from both benign and malignant cells. The level of VEGF mRNA expressed in the seven malignant human and rat cell lines is 3.5- to 10-fold higher than that expressed in the benign cell lines. The three metastatic variants, generated by transfection of a benign cell line with DNA extracted from prostate carcinoma cells, expressed 2.5 to 5 times more VEGF mRNA than their parental benign cells. While VEGF 121 and 165 were predominantly expressed by both the benign and malignant cells, the transcript representing VEGF 189 isoform was only detected in the malignant cells. At protein level, three human malignant cell lines produced more VEGF (2.7–7.9 ng ml −1 ) than the benign cell line (1.3 ng ml −1 ). CAM assay detected a VEGF-dependent angiogenic activity in the medium from malignant cells, but only a relatively weak VEGF-independent activity in the medium from benign cells. These results demonstrated that malignant cells did over-express VEGF and only the VEGF derived from malignant cells was angiogenically active. Thus, we suggest that the VEGF produced by malignant cells might play an important role in facilitating metastasis of prostatic cancer. © 2000 Cancer Research Campaign

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Section: Discussionsupporting

confidence: 53%

True

Chen¹,

Treweeke²,

Ke³

et al. 2000

Br J Cancer

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“…Differential splicing in exons 6 and 7 produces isoforms within each family with varying heparin binding activity (e.g. 189, 189b,165, 165b, etc) [14][15][16][17]. Since revascularisation and beta cell survival have been implicated in the short-and medium-term survival of islets, this study considers the role of the predominant pro-angiogenic, pro-epithelial survival isoform, VEGF 165 .…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

et al. 2007

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Aims/hypothesis Rapamycin, part of the immunosuppressive regimen of the Edmonton protocol, has been shown to inhibit vascular endothelial growth factor (VEGF) production and VEGF-mediated survival signalling in tumour cell lines. This study investigates the survival-promoting activities of VEGF in human islets and the effects of rapamycin on islet viability.Materials and methods Levels of VEGF and its receptors in isolated human islets and whole pancreas was determined by western blotting and immunostaining. Islet viability following VEGF or immunosuppressive drug treatment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Islet VEGF release was measured by ELISA. Mouse islets infected with an adenovirus expressing the gene for VEGF were transplanted syngeneically into streptozotocin-induced diabetic mice, with blood glucose levels measured three times per week. Results Isolated human islets produced multiple isoforms of VEGF and VEGF receptors 1, 2 and 3 and the coreceptor neuropilin 1. Exogenous VEGF (10 ng/ml) prevented human islet death induced by serum starvation, which suggests that VEGF can act as a survival factor for human islets. Transplantation of mouse islets infected with a VEGF-expressing adenovirus in a syngeneic model, improved glycaemic control at day 1 post-transplantation (p< 0.05). Rapamycin at 10 and 100 ng/ml significantly reduced islet VEGF release (by 37±4% and 43±6%, respectively; p<0.05) and at 100 ng/ml reduced islet viability (by 36±9%) and insulin release (by 47±7%, all vs vehicle-treated controls; p<0.05). Tacrolimus had no effect on islet VEGF release or viability. Conclusions/interpretation Our data suggest that rapamycin may have deleterious effects on islet survival posttransplantation, both through a direct effect on islet viability and indirectly through blockade of VEGF-mediated revascularisation.

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“…Alternative splicing of VEGF pre-mRNA leads to at least three peptides of 121, 165 and 189 amino acids. VEGF 206 is a rare form generated by an additional 17-amino acid insertion at position 116, only identi®ed in a human fetal liver cDNA library (Houck et al, 1991). Each VEGF isoform promotes the growth of endothelial cells, in vitro.…”

Section: Introductionmentioning

confidence: 99%