Abstract
Malignant gliomas are the most common and the most lethal primary brain tumors in adults. Among malignant gliomas, 60%-80% show loss of P14ARF tumor suppressor activity due to somatic alterations of the INK4A/ARF genetic locus. The tumor suppressor activity of P14ARF is in part a result of its ability to prevent the degradation of P53 by binding to and sequestering HDM2. However, the subsequent finding of P14ARF loss in conjunction with TP53 gene loss in some tumors suggests the protein may have other P53-independent tumor suppressor functions. Here, we report what we believe to be a novel tumor suppressor function for P14ARF as an inhibitor of tumor-induced angiogenesis. We found that P14ARF mediates antiangiogenic effects by upregulating expression of tissue inhibitor of metalloproteinase-3 (TIMP3) in a P53-independent fashion. Mechanistically, this regulation occurred at the gene transcription level and was controlled by HDM2-SP1 interplay, where P14ARF relieved a dominant negative interaction of HDM2 with SP1. P14ARF-induced expression of TIMP3 inhibited endothelial cell migration and vessel formation in response to angiogenic stimuli produced by cancer cells. The discovery of this angiogenesis regulatory pathway may provide new insights into P53-independent P14ARF tumor-suppressive mechanisms that have implications for the development of novel therapies directed at tumors and other diseases characterized by vascular pathology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain Neoplasms / blood supply*
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Brain Neoplasms / metabolism
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Cell Line, Transformed
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Chemotaxis / drug effects
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Corneal Neovascularization / physiopathology
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Culture Media, Conditioned / pharmacology
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Endothelial Cells / pathology
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Fibroblasts / drug effects
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Gene Expression Regulation, Neoplastic*
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Genes, p53
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Glioblastoma / blood supply*
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Glioblastoma / metabolism
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Humans
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Mice
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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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Neovascularization, Pathologic / physiopathology*
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Proto-Oncogene Proteins c-mdm2 / physiology
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RNA Interference
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / physiology
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Sp1 Transcription Factor / physiology
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Tissue Inhibitor of Metalloproteinase-3 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-3 / biosynthesis*
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Tissue Inhibitor of Metalloproteinase-3 / genetics
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Tissue Inhibitor of Metalloproteinase-3 / physiology
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Transcription, Genetic
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Tumor Cells, Cultured / metabolism
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Tumor Suppressor Protein p14ARF / physiology*
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Up-Regulation
Substances
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Culture Media, Conditioned
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Neoplasm Proteins
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Sp1 Transcription Factor
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TIMP3 protein, human
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Tissue Inhibitor of Metalloproteinase-3
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Tumor Suppressor Protein p14ARF
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2