Access to the Nucleus and Functional Association with c-Myc Is Required for the Full Oncogenic Potential of Delta EGFR/EGFRvIII

作者：Gururaj Anupama E^*; Gibson Laura; Panchabhai Sonali; Bai MingHui; Manyam Ganiraju; Lu Yue; Latha Khatri; Rojas Marta L; Hwang Yeohyeon; Liang Shoudan; Bogler Oliver

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288(5): 3428-3438.

DOI：10.1074/jbc.M112.399352

Delta EGFR 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 Delta EGFR 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 Delta EGFR contribute strongly to its oncogenic function. Nuclear actions of Delta EGFR 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 Delta EGFR were corecruited to the promoters of and transcriptionally activated a subset of nuclear Delta EGFR chromatin targets. Knockdown of c-Myc decreased the expression of these targets and diminished Delta EGFR-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 Delta EGFR makes a unique contribution to its oncogenicity and propose that this venue provides new targets for therapeutic intervention.

• 出版日期2013-2-1