Both v-Ha-Ras and v-Raf Stimulate Expression of the Vascular Endothelial Growth Factor in NIH 3T3 Cells

Grugel, S.; Finkenzeller, Günter; Weindel, Karin; Barleon, Bernhard; Marmé, Dieter

doi:10.1074/jbc.270.43.25915

Cited by 303 publications

(150 citation statements)

References 45 publications

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“…Activated ras induces a similar jump in VEGF mRNA in NIH3T3 ®broblasts (Grugel et al, 1995) and in human epithelial cells of colonic origin (Rak et al, 1995). It has been suggested that ras stimulates VEGF transcription via AP-1 sites in its promoter (Grugel et Saez et al, 1995).…”

Section: Discussionmentioning

confidence: 98%

“…Some, like sis, encode inducers of angiogenesis, others increase the secretion of pro-angiogenic proteases or stimulate cells to elaborate angiogenic molecules. For example, production of the potent inducer VEGF (vascular endothelial growth factor) is stimulated by ras in NIH3T3 ®broblasts (Grugel et al, 1995) and in intestinal cell lines (Rak et al, 1995) where its continued secretion at high levels depends on the continued presence of the activated oncogene. Depending on the cell type, oncogenes occasionally contribute to the angiogenic phenotype by downregulating inhibitors of angiogenesis, as activated ras decreases levels of inhibitory thrombospondin in bronchial epithelial cells (Zabrenetsky et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity

1997

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity

1997

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“…Astrocytomas secrete high levels of the potent and endothelial speci®c angiogenic factor VEGF (Plate et al, 1992), whose expression through increased transcription or enhanced mRNA stability is highly regulated by hypoxia Goldberg and Schneider, 1994;Levy et al, 1996). Ras appears to play a pivotal role in regulating the secretion of VEGF, as expression of oncogenic Ras induces VEGF expression in NIH3T3 (Grugel et al, 1995) and non-tumorigenic intestinal epithelial cells (Rak et al, 1995). We therefore investigated whether FTIs have an additional antiangiogenic role through inhibition of VEGF secretion, under either normoxic or hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

1999

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While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras.GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their e ect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its e ect. L-744,832 demonstrates both cytostatic and cytotoxic e ects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in highgrade astrocytomas (EGFRvIII/p140 EGF-R ) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchoragedependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G 1 /M and G 2 /S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21 WAF1/CIP1 , but this induction is not necessary for the cell cycle inhibitory e ects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic e ects.

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“…Enhanced VEGF expression has been reported upon activation of protein kinase C by tumor promoters, and in cells harbouring activated oncogenes, such as ras, raf, and src (Grugel et al, 1995;Rak et al, 1995;Mukhopadhyay et al, 1995). In addition, hypoxia, as well as inactivation of p53 and of von Hippel-Lindau tumor suppressor genes, respectively, result in elevated VEGF mRNA levels (Schweiki et al, 1992;Finkenzeller et al, 1995;Kieser et al, 1994;Siemeister et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression

Finkenzeller

Sparacio

Technau³

et al. 1997

Oncogene

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182

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Stimulation of NIH3T3 cells with platelet-derived growth factor (PDGF)-BB enhances expression of vascular endothelial growth factor (VEGF), an endothelial cell-speci®c mitogen and a key mediator of tumor angiogenesis. Here, we identi®ed cis-acting VEGF promoter elements and trans-acting factors which are involved in PDGF-stimulated VEGF expression. By 5'-deletion and transient transfection analysis, a G+C-rich region at 785 to 750 of the human VEGF promoter was shown to be necessary and su cient for both PDGF inducible and basal expression. The region contains three potential recognition sites for Sp1 transcription factors, which overlap with two Egr-1 sites. Mutations that abolish the ability of Sp1 to interact with the VEGF promoter element also abrogate expression induced by PDGF. Mutations of the potential Egr-1 binding sites did not a ect PDGF responsiveness. Gel shift and antibody supershift analyses showed that Sp1 and Sp3 interact constitutively with the VEGF promoter element. Our data strongly suggest that enhanced VEGF gene expression in PDGF-induced NIH3T3 cells is mediated by Sp1 and/or Sp3 transcription factors bound to the 785 to 750 promoter region of the VEGF gene.

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Both v-Ha-Ras and v-Raf Stimulate Expression of the Vascular Endothelial Growth Factor in NIH 3T3 Cells

Cited by 303 publications

References 45 publications

Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity

Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression

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