title: Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity.
abstract: Hypoxia and necrosis are fundamental features of glioblastoma (GBM) and their emergence is critical for the rapid biological progression of this fatal tumor; yet, underlying mechanisms are poorly understood. We have suggested that vaso-occlusion following intravascular thrombosis could initiate or propagate hypoxia and necrosis in GBM. Tissue factor (TF), the main cellular initiator of coagulation, is overexpressed in GBMs and likely favors a thrombotic microenvironment. Epidermal growth factor receptor (EGFR) amplification and PTEN loss are two common genetic alterations seen in GBM but not in lower-grade astrocytomas that could be responsible for TF up-regulation. The most frequent EGFR mutation in GBM involves deletion of exons 2 to 7, resulting in the expression of a constitutively active receptor, EGFRvIII. Here, we show that overexpression of EGFR or EGFRvIII in human glioma cells causes increased basal TF expression and that stimulation of EGFR by its ligand, EGF, leads to a marked dose-dependent up-regulation of TF. In all cases, increased TF expression led to accelerated plasma coagulation in vitro. EGFR-mediated TF expression depended most strongly on activator protein-1 (AP-1) transcriptional activity and was associated with c-Jun NH(2)-terminal kinase (JNK) and JunD activation. Restoration of PTEN expression in PTEN-deficient GBM cells diminished EGFR-induced TF expression by inhibiting JunD/AP-1 transcriptional activity. PTEN mediated this effect by antagonizing phosphatidylinositol 3-kinase activity, which in turn attenuated both Akt and JNK activities. These mechanisms are likely at work in vivo, as EGFR expression was highly correlated with TF expression in human high-grade astrocytoma specimens.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Rong
authors.forename: Vladimir E
authors.initials: VE
authors.lastname: Belozerov
authors.forename: Carol
authors.initials: C
authors.lastname: Tucker-Burden
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D013925:Thromboplastin; D018808:Transcription Factor AP-1; C410723:epidermal growth factor receptor VIII; C494929:PTEN protein, human