Abstract
Mutations or loss of both alleles of the von Hippel-Lindau (VHL) tumor suppressor gene has been documented in sporadic renal cell carcinomas and neoplasms that arise in individuals having the VHL syndrome. The well-vascularized phenotype of tumors that form in VHL disease let us consider vascular endothelial growth factor (VEGF) as a mediator of tumor growth in VHL disease. Human renal carcinoma cells that either lacked endogenous wild-type VHL or were transfected with an inactive mutant VHL showed deregulated expression of VEGF on the mRNA and protein level that was reverted by introduction of wild-type VHL. Stimulation of proliferation of endothelial cells by conditioned medium of cells expressing mutant VHL was almost abolished by neutralizing the VEGF. In contrast, expression of basic fibroblast growth factor and of c-myc proto-oncogene was not affected by VHL. Our data suggest VEGF as the key tumor angiogenesis factor in VHL disease.
MeSH terms
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology*
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Endothelial Growth Factors / biosynthesis*
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / physiology
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Fibroblast Growth Factor 2 / biosynthesis
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Fibroblast Growth Factor 2 / genetics
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Gene Expression Regulation, Neoplastic / drug effects*
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Genes, Tumor Suppressor*
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Genes, myc
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Humans
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology*
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Ligases*
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Lymphokines / biosynthesis*
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Lymphokines / genetics
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Lymphokines / physiology
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Neovascularization, Pathologic / genetics
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Phenotype
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Protein Biosynthesis
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Proteins / genetics
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Proteins / physiology*
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Proto-Oncogene Mas
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Recombinant Fusion Proteins / metabolism
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
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Ubiquitin-Protein Ligases*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Von Hippel-Lindau Tumor Suppressor Protein
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von Hippel-Lindau Disease / genetics*
Substances
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Endothelial Growth Factors
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Lymphokines
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MAS1 protein, human
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Neoplasm Proteins
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Proteins
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Proto-Oncogene Mas
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Ligases
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VHL protein, human