Abstract
Angiogenesis, the formation of new blood vessels, is seen during embryonic development and tumor progression, but the mechanisms have remained unclear. Recent data indicate that developmental and tumor angiogenesis can be induced by cellular oncogenes, leading to the enhanced activity of molecules stimulating angiogenesis. However, activated oncogenes might also facilitate angiogenesis by down-regulating endogenous inhibitors of angiogenesis. We report here that enhanced expression of the N-myc oncogene in human neuroblastoma cells down-regulates an inhibitor of endothelial cell proliferation, identified by amino acid sequencing as being identical with activin A, a developmentally regulated protein. Down-regulation appears to involve interaction of the N-Myc protein with the activin A promoter. In addition, activin A inhibits both endothelial cell proliferation in vitro and angiogenesis in vivo, and it induces hemorrhage in vivo. We suggest that the N-myc-induced down-regulation of activin A could contribute to developmental and tumor angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activins
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Amino Acid Sequence
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Angiogenesis Inhibitors / genetics*
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Angiogenesis Inhibitors / isolation & purification
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Angiogenesis Inhibitors / pharmacology
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Animals
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Cattle
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Cell Division / drug effects
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Chick Embryo
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Down-Regulation / physiology
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / isolation & purification
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Endothelium, Vascular / chemistry
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Gene Expression Regulation, Neoplastic / physiology
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Genes, myc / genetics*
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Humans
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Inhibins / genetics*
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Inhibins / isolation & purification
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Inhibins / pharmacology
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Molecular Sequence Data
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Neovascularization, Pathologic / drug therapy*
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Neovascularization, Pathologic / genetics
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Neuroblastoma / blood supply
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Neuroblastoma / genetics*
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Neuroblastoma / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Sequence Homology, Amino Acid
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Transcription, Genetic / physiology
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Transfection
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Tumor Cells, Cultured
Substances
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Angiogenesis Inhibitors
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Endothelial Growth Factors
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Recombinant Proteins
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Activins
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Inhibins