title: Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis.
abstract: Inactivation of the tumor suppressor gene PTEN and overexpression of VEGF are two of the most common events observed in high-grade malignant gliomas. The purpose of this study was to determine whether PTEN controls VEGF expression in gliomas under normoxic conditions. Transfer of PTEN to human glioma cells resulted in the transduction of a functional PTEN protein as evidenced by the upregulation of p27 and modification of the phosphorylation status of Akt. Under normoxic conditions, enzyme-linked immunosorbent assay and Northern blot analyses showed downregulation of VEGF in PTEN-treated cells. Moreover, conditioned media from PTEN-treated glioma cells significantly diminished the ability of endothelial cells to grow and migrate. Western blot assays demonstrated that, in a normoxic environment, PTEN downregulates HIF-1 alpha. Finally, promoter activity assays showed that the VEGF promoter region containing the HIF-1alpha binding site is necessary and sufficient for PTEN-mediated downregulation of VEGF. Experiments with PI3-K inhibitors and kinase assays suggested that PI3-K is mediating the effect of PTEN on VEGF, and not the p42/p48 or p38 MAP kinases. These results indicate that restoration of PTEN function in gliomas may induce therapeutic effect by downregulating VEGF. Furthermore, this close functional relationship between PTEN and VEGF suggests that a better understanding of the transduction signal regulated by PTEN might enhance the knowledge of the cause and physiology of vascular and inflammatory diseases.
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: Candelaria
authors.initials: C
authors.lastname: Gomez-Manzano
authors.forename: Juan
authors.initials: J
authors.lastname: Fueyo
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Tricia L
authors.initials: TL
authors.lastname: Glass
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Juinn-Lin
authors.initials: JL
authors.lastname: Liu
authors.forename: Sushma L
authors.initials: SL
authors.lastname: Jasti
authors.forename: Ta-Jen
authors.initials: TJ
authors.lastname: Liu
authors.forename: Charles A
authors.initials: CA
authors.lastname: Conrad
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
mesh_terms: D002455:Cell Division; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010100:Oxygen / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; C497442:HIF1A protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human