title: Loss of PTEN facilitates HIF-1-mediated gene expression.
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.
authors.affiliation: Mayer Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University, Stanford, California 94305-5468 USA.
authors.forename: W
authors.initials: W
authors.lastname: Zundel
authors.forename: C
authors.initials: C
authors.lastname: Schindler
authors.forename: D
authors.initials: D
authors.lastname: Haas-Kogan
authors.forename: A
authors.initials: A
authors.lastname: Koong
authors.forename: F
authors.initials: F
authors.lastname: Kaper
authors.forename: E
authors.initials: E
authors.lastname: Chen
authors.forename: A R
authors.initials: AR
authors.lastname: Gottschalk
authors.forename: H E
authors.initials: HE
authors.lastname: Ryan
authors.forename: R S
authors.initials: RS
authors.lastname: Johnson
authors.forename: A B
authors.initials: AB
authors.lastname: Jefferson
authors.forename: D
authors.initials: D
authors.lastname: Stokoe
authors.forename: A J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D051545:Cyclooxygenase 1; D004268:DNA-Binding Proteins / Q000502:physiology*; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005816:Genetic Complementation Test; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D051059:PTEN Phosphohydrolase; D010732:Phosphofructokinase-1 / Q000096:biosynthesis / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D007334:Insulin-Like Growth Factor I; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017853:Phosphotransferases (Alcohol Group Acceptor); C046331:phosphoglucokinase; D010732:Phosphofructokinase-1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human