title: Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression.
abstract: Glioblastoma (GBM) is the most common primary brain tumor and has a dismal prognosis. Amplification of chromosome 12q13-q15 (Cyclin-dependent kinase 4 (CDK4) amplicon) is frequently observed in numerous human cancers including GBM. Phosphoinositide 3-kinase enhancer (PIKE) is a group of GTP-binding proteins that belong to the subgroup of centaurin GTPase family, encoded by CENTG1 located in CDK4 amplicon. However, the pathological significance of CDK4 amplicon in GBM formation remains incompletely understood. In the current study, we show that co-expression of PIKE-A and CDK4 in TP53/PTEN double knockout GBM mouse model additively shortens the latency of glioma onset and survival compared to overexpression of these genes alone. Consequently, p-mTOR, p-Akt and p-ERK pathways are highly upregulated in the brain tumors, in alignment with their oncogenic activities by CDK4 and PIKE-A stably transfected in GBM cell lines. Hence, our findings support that PIKE amplification or overexpression coordinately acts with CDK4 to drive GBM tumorigenesis.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.|Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine; Atlanta, GA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.|Institute of Tumor Pharmacology, Jinan University College of Pharmacy, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine; Atlanta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pham
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine; Atlanta, GA, USA.|Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine; Atlanta, GA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.|Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China.
authors.forename: K
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005784:Gene Amplification; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins