Abstract
In glioblastoma-derived cell lines, PTEN does not significantly alter apoptotic sensitivity or cause complete inhibition of DNA synthesis. However, in these cell lines PTEN regulates hypoxia- and IGF-1-induced angiogenic gene expression by regulating Akt activation of HIF-1 activity. Restoration of wild-type PTEN to glioblastoma cell lines lacking functional PTEN ablates hypoxia and IGF-1 induction of HIF-1-regulated genes. In addition, Akt activation leads to HIF-1alpha stabilization, whereas PTEN attenuates hypoxia-mediated HIF-1alpha stabilization. We propose that loss of PTEN during malignant progression contributes to tumor expansion through the deregulation of Akt activity and HIF-1-regulated gene expression.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis
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Brain Neoplasms / genetics*
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Brain Neoplasms / pathology
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Cell Hypoxia / genetics
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Culture Media, Serum-Free / pharmacology
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Cyclooxygenase 1
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DNA-Binding Proteins / physiology*
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Disease Progression
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics
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Gene Deletion
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Gene Expression Regulation, Neoplastic / genetics*
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Genetic Complementation Test
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Glioblastoma / genetics*
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Glioblastoma / pathology
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Insulin-Like Growth Factor I / pharmacology*
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Isoenzymes / biosynthesis
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Isoenzymes / genetics
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Lymphokines / biosynthesis
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Lymphokines / genetics
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Membrane Proteins
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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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Nuclear Proteins / physiology*
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PTEN Phosphohydrolase
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Phosphofructokinase-1 / biosynthesis
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Phosphofructokinase-1 / genetics
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Phosphoric Monoester Hydrolases / deficiency*
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology
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Phosphotransferases (Alcohol Group Acceptor) / biosynthesis
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Prostaglandin-Endoperoxide Synthases / biosynthesis
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Prostaglandin-Endoperoxide Synthases / genetics
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Recombinant Fusion Proteins / physiology
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Transcription Factors*
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Culture Media, Serum-Free
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DNA-Binding Proteins
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Endothelial Growth Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Isoenzymes
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Lymphokines
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Membrane Proteins
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Neoplasm Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Transcription Factors
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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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Insulin-Like Growth Factor I
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Cyclooxygenase 1
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PTGS1 protein, human
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Prostaglandin-Endoperoxide Synthases
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Phosphotransferases (Alcohol Group Acceptor)
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phosphoglucokinase
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Phosphofructokinase-1
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human