title: Access to the nucleus and functional association with c-Myc is required for the full oncogenic potential of ΔEGFR/EGFRvIII.
abstract: ΔEGFR is a potent glioblastoma oncogene which has been studied primarily as a plasma membrane kinase. Using intracranial xenograft studies in mice, we show that blocking ΔEGFR access to the nucleus attenuates its tumorigenicity and, conversely, that promoting nuclear accumulation enhances this, providing the first in vivo evidence that the nuclear actions of ΔEGFR contribute strongly to its oncogenic function. Nuclear actions of ΔEGFR include regulation of gene expression by participation in chromatin-bound complexes, and genome-wide mapping of these sequences by chromatin immunoprecipitation and massively parallel sequencing identified 2294 peaks. Bioinformatic analysis showed enrichment of the E-box motif in the dataset, and c-Myc and ΔEGFR were corecruited to the promoters of and transcriptionally activated a subset of nuclear ΔEGFR chromatin targets. Knockdown of c-Myc decreased the expression of these targets and diminished ΔEGFR-stimulated anchorage-independent colony formation. We conclude that transcriptional regulation of target genes by association with gene regulatory chromatin in cooperation with c-Myc by nuclear ΔEGFR makes a unique contribution to its oncogenicity and propose that this venue provides new targets for therapeutic intervention.
authors.affiliation: Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. aegururaj@mdanderson.org
authors.forename: Anupama E
authors.initials: AE
authors.lastname: Gururaj
authors.forename: Laura
authors.initials: L
authors.lastname: Gibson
authors.forename: Sonali
authors.initials: S
authors.lastname: Panchabhai
authors.forename: MingHui
authors.initials: M
authors.lastname: Bai
authors.forename: Ganiraju
authors.initials: G
authors.lastname: Manyam
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.forename: Khatri
authors.initials: K
authors.lastname: Latha
authors.forename: Marta L
authors.initials: ML
authors.lastname: Rojas
authors.forename: Yeohyeon
authors.initials: Y
authors.lastname: Hwang
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.forename: Oliver
authors.initials: O
authors.lastname: Bogler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D024721:E-Box Elements / Q000235:genetics; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D015894:Genome, Human / Q000235:genetics; D005910:Glioma / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors